Embryology - User contributions [en-gb]

User:Z3330539

2012-10-16T23:03:43Z

Z3330539: /* Lab Attendance */

== Lab Attendance ==

Lab 1--[[User:Z3330539|Z3330539]] 11:49, 25 July 2012 (EST)

Lab 2 [[User:Z3330539|Z3330539]] 10:52, 1 August 2012 (EST)

Lab 3 --[[User:Z3330539|Z3330539]] 10:04, 8 August 2012 (EST)--

Lab 4 --[[User:Z3330539|Z3330539]] 09:59, 15 August 2012 (EST)--

Lab 5 --[[User:Z3330539|Z3330539]] 10:10, 22 August 2012 (EST)--

Lab 6 --[[User:Z3330539|Z3330539]] 10:08, 29 August 2012 (EST)--

Lab 7 --[[User:Z3330539|Z3330539]] 10:14, 12 September 2012 (EST)--

Lab 8 --[[User:Z3330539|Z3330539]] 10:03, 19 September 2012 (EST)--

Lab 9 --[[User:Z3330539|Z3330539]] 10:08, 26 September 2012 (EST)--

Lab 10 --[[User:Z3330539|Z3330539]] 10:07, 3 October 2012 (EST)--

Lab 11 --[[User:Z3330539|Z3330539]] 10:10, 10 October 2012 (EST)--

Lab 12 --[[User:Z3330539|Z3330539]] 10:03, 17 October 2012 (EST)--

==Lab 1 Assessment==
--[[User:Z8600021|Mark Hill]] 18:04, 10 September 2012 (EST) Please do not include spaces before your sub-headings as this will affect formatting. I have corrected Lab 1, please correct other subheadings yourself before final assessment.

===Task 1===

Identify the origin of In Vitro Fertilization and the 2010 Nobel Prize winner associated with this technique and add a correctly formatted link to the Nobel page.

-In Vitro Fertilization (IVF) technology is the combining/fusion of the males sperm and females egg/s outside the body, then later implanting this fertilized oocyte into the female uterus. This technique involves the regulation of the female cycle and monitoring of ovulation. This in vitro technique/concept has been present and studied for many years, with earliest recordings of such scientific research/findings; such test tube babies; occurring as early as 1950’s. The scientist who won the Nobel Prize in 2010, for his efforts and involvement in the discovery implementation of IVF techniques was the physiologist Robert Edwards. This was an honor given in the current medicine. Edwards with a fellow associate were the first recorded successful pregnancy and birth of the first and second IVF babies to be delivered in the late 1970’s and the 1980’s. Following this successful implantation, development and implantation other countries including Australia began to use this technique, for situations and individuals with fertility problems. Recent developments in this field of medicine and physiology have been on hormones involved in oocyte maturation, ovarian cycles such as follicle stimulating hormone, as well as the way in which sperm is administered in order for fertilization to occur.

Links: [1] [2]

===Task 2===

Identify and add a PubMed reference link to a recent paper on fertilization and describe its key findings (1-2 paragraphs).

- “Molecular Origin of Female Meiotic Aneuploidies”

This article addresses the molecular and physiological mechanisms underlying the abnormalities in pregnancy which occur as a result of aneuploidy. It discusses the disruption of the cohesion and separation of the homologues at the centromeres and the polar ends of the spindle, which can result in miscarriage and loss of pregnancy. Lack of separation of these homologues prevents the production of two separate daughter chromatids. These errors can occur either toward the end of meiosis one and also in meiosis two, and in some instances meiosis two errors can arise as a result of meiosis one errors that were not resolved. In this article, there is particular emphasis placed upon the process of female meiosis, as the major causes of errors that can lead to aneuploidy. Major errors which occur are reduced cohesion prior to separation in meiosis two, errors in trisomies, as well as premature segregation, resulting in errors of chromatid pairing and oocyte development in fertilization. Studies are being performed to examine the role, or lack of role which certain proteins play at these stages of female fertilization in order to reduce these abnormalities in conventional and IVF development, in particular in females who fall pregnant at later maternal ages. Examining the molecular mechanisms that occur when there is loss of expression of key proteins such as SMC1 alpha and beta, Scc1 and ReC8, which leads to decrease in cohesin and reduce achiasmate, ultimately leading to lack of separation of the homologues.

[3]

NB: Originally uploaded this into the discussion/my talk page, the night before, prior to moving it into my Page (z3330539).

--[[User:Z8600021|Mark Hill]] 18:04, 10 September 2012 (EST) Answers to the 2 questions are correct. I am concerned that the text in answer to question 1 appears to be from a source that has not been cited, could you please clarify this for me (for an extra mark). You have failed to transfer the citation links correctly from your discussion page to here, and the citation links located there are not correctly formatted. You have used UNSW Library links rather than the PubMed citation number or reference format as shown in the class (and below). '''7/10'''

As a reference number link - PMID 22841925

As a formatted reference - <pubmed>22841925</pubmed>

==Lab 2 Assessment==

====Task 1====
[[File:Immunofluorescent_FN1_and_integrin_on_blastocytes.gif]]

====Task2====

A protein which is involved in the implantation process is Rac1, which is the RAS pathway related C3 botulinum toxin substrate 1. This protein expression allows for embryonic trophoblasts to invade the stromal cell layer and when activated also allows for migration and motility of the cells of the stromal layer. All of these factors lead to the promotion of implantation.

[http://www.ncbi.nlm.nih.gov/pubmed/18838676]

--[[User:Z8600021|Mark Hill]] 18:22, 10 September 2012 (EST) Question 1 is not correctly linked to the appropriate reference, a serious error. Therefore you have not completed the assessment correctly, I will need to delete the image if you cannot fix the referencing and alter your mark accordingly. Image is also too small to be useful and in GIF format. Question 2 is fine, please see my previous assessment comment on referencing. '''6/10'''

As a reference number link - PMID 18838676

As a formatted reference - <pubmed>18838676</pubmed>

==Lab 3 Assessment==

====Task 1====

Gestational age refers to the period of time, generally 14 days before the last day of the females menstrual cycle. Where as post fertilization age is the period from the point of conception/ fertilization of egg by the sperm; this mainly occurs in the middle of the menstrual cycle duration.

Gestational age is used as a clinical method of human development due to the fact that time/point of fertilization can be unknown or variable, women may have sporadic menses and ovulation, females may not be able to recall the last day of their menstrual cycle. The use of gestational age may be an approximation/generalization, however, it is more useful in reducing the variables that can occur, which are mentioned above, as last day of menstrual cycle is predominately able to be recalled by the female, and 14 days are added in order to establish room for possible variations.

References:

1. [http://emedicine.medscape.com/article/259269-overview]

====Task 2====

Somites, which are present in pairs, are derived from the paraxial mesoderm and are involved in week 4 of embryonic development. Somites progressively differentiate into sclerotome, dermatome and myotome.

Sclerotome are the central cells of the somites are are located ventromedially in relation to orientation of the notochord. Sclerotome form vertebral and bone and connective of the vertebral column and are have chondrocytes present.

Dermatome are located dorsolaterally to the notochord and involved in the differentiation into dermis and epidermis.

Finally myotome are located more dorsomedially and are involved in differentiation to skeletal muscle. This involves myoblast cells. Depending on the type, these can either lie dorsomedially and then migrate to form epaxial or hypaxial muscle groups in development.

References:

1. [http://www.embryology.ch/anglais/mmuskel/skelett02.html]
2. [http://www.ncbi.nlm.nih.gov/books/NBK10085/]

--[[User:Z8600021|Mark Hill]] 18:30, 10 September 2012 (EST) Question 1 answer is correct, but your text is confusing in relation to LMP. Question 2 describes the correct somite components, and bone, CT and skeletal muscle. But you have incorrectly identified epidermis as mesoderm in origin, this is ectodermal and not from the somite. '''9/10'''

==Lab 4 Assessment==
====Task 1====

The placenta within the developing fetus performs many functions, via maternal-embryonic nutrient transfer and later embryo-fetal nutrient transfer. Early in development diagnostic tests are able to be performed in order to examine if there are any abnormalities, either genetic or hematological, for example, within the growing embryo. These test and consecutive results are able to be obtained through the placenta. Some techniques are non-invasive, while others can be invasive for the mother. Two test which are performed through placenta diagnostics are a chorion biopsy (chorion villus sampling) and umbilical cord blood sampling. These two prenatal tests are both invasive and involve extraction of tissue and blood samples via injection of a thin needle into either the maternal cervix or abdominal wall in order to reach the uterus and retrieve samples from the placenta or the umbilical cord (the end which lies close to the placenta or the umbilical vein). Once samples are collected they are them examined within laboratories and analyzed for developmental abnormalities.

Though there is partial risk of miscarriage, these tests have been found to be successful in diagnosis of abnormalities such as down syndrome and pathological blood disorders such as Rh disease. The defects in early cell division in the embryo, with specific reference to down syndrome (trisomy 21) can be detected, as well as the compatibility between maternal and embryonic blood in relation to Rh disease. This gives the ability to detect whether there will be a maternal immune response, as a result of lack of blood compatibility (i.e. maternal immune response triggered post birth of first delivered child).

References:

1. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166195/pdf/mxr008.pd]
2. [http://www.embryology.ch/anglais/jfetalperiod/diagno04.html]
3. [http://www.centrahealth.com/health-library]

====Task 2====

An article which discusses the possibilities for cord stems cells to be used in therapeutically is '''Human umbilical cord mesenchymal stem cells and the treatment of spinal cord injury'''.
This review article discusses the potential for umbilical cord stems cells to be used in the therapeutic treatment of spinal chord injury or disease.

Through analysis of resent findings, researchers have discovered the similar characteristic within cord stem cells that are found in bone marrow. Cord stem cells have been found to be an alternative source for mesenchymal stems cells, and therefore are seen as a promising alternative for transplantation procedures, as they are able to differentiate into numerous cells and tissues such as bone and cartilage; as well as self renewal and growth properties.
Furthermore, this area of research is being considered due to the fact that there are limitations surrounding transplantation of bone marrow mesenchymal cells, such as viral contraction and cellular amount.

The spinal cord consists of a complex molecular and cellular framework, such as astrocytes, microglia cells and myelin proteins. As a result of these many constituent, when the spine is injured or diseased, treatment is difficult due to the degenerative nature/course which these problems can occur. However, through the isolation of these cord stem cells from embryonic umbilical cord, treatment may be something that soon can be highly successful with further research and clinical development. Furthermore, isolation of these umbilcal cord stems cells are more ethically supported than isolation of bone marrow mensenchymal cells.

Further research and studies are required, however, due to the fact that some attempts, methods and techniques of recent isolations have failed. Furthermore, future areas of developmental research may include longitudinal and clinical research that can further increase awareness of umbilical cord mesenchymal cell transplantation as an alternative for complex injuries, such as those to the spinal cord.

References:
1. [http://www.ncbi.nlm.nih.gov/pubmed/19187651]
2. [http://www.cmj.org/Periodical/PDF/200911959717530.pdf]

--[[User:Z8600021|Mark Hill]] 16:27, 11 September 2012 (EST) Both these answers are excellent. '''10/10'''

===Lab 7 Assessment===

====Task 1====

a) Satellite cells are mononuclear progenitor cells that are involved in postnatal development and regeneration of skeletal muscle fibres.

b) Satellite cells can remain quiescent until they are activated by extracellular stimuli. The first example where satellite cells become activated is when there is local damage or injury to the muscles. The second example of where satellite cells can be activated is when muscles undergo hypertrophy. Although satellite cells do not have to be activated in order for muscle hypertrophy, studies have shown that they can become activated. In these cases satellite cells re-enter into the cell cycle, and myoblasts/myofibers proliferate in order to repair and/or replace cells during muscle loading or when cell injury occurs. <ref><pubmed>17213900</pubmed></ref>

====Task 2====

When motor neurons sustain a long-term injury to spinal chord studies have shown that muscle fibres undergo muscular atrophy; muscles fibres cells decrease. This muscle wasting is potentially the result of inactivation of muscles due to lack of synaptic signalling from main central conducting systems, such as the motor neurons of the spinal chord. <ref><pubmed>8265728</pubmed></ref>
Furthermore, post spinal chord injury results in a transformation of muscle fibres. Predominately these fibres consist of both type 1 (slow) and type 2 (fast) fibre patterning, however, slow twitch fibres; specifically Type IIB, become principal after motor neuron damage. This can result in lead to reduction in the amount of fat mass, therefore contribute to wasting and weight loss. <ref><pubmed>9044514</pubmed></ref>

'Reference List'

1. <pubmed>17213900</pubmed>

2. <pubmed>8265728</pubmed>

3. <pubmed>9044514</pubmed>

[http://athletics.wikia.com/wiki/Type_II_Muscle_Fiber]
[http://www.skeletalmusclejournal.com/content/1/1/7]

==Lab 8 Assessment: Peer/Group Evaluations==

===Vision===

There is a good balance of images and text throughout the page. Prior to final assessment the page outline and formatting of image and text positioning is required. The first image at the top the page, requires correct referencing and acknowledgement that it has been uploaded as part of a student assignment. This is also required for the image titled “Eyediagramcolour1”.

Since the previous lab, held in week 9, it is positive to see that the group has altered some of the uploaded image information, with particular reference to the self-drawn/uploaded images.

The area of the page which shows that there is a “useful links” heading and an external link within the current research section, should be placed or moved into the external links section at the bottom of the page with the appropriate information that Dr. Hill has required for placing external links on a page. Also, the references within the ‘current research’ section may also be required to be apart of the reference list.

I found this page visually appealing and I liked that this group have included an image gallery section. The use of the external links were appropriate to the topic and that the extent of the glossary for now is good, however, by the final evaluation would potentially need to be larger. Finally found that the headings for each segment of the broader topic were well positioned and relevant.

===Taste===

The page that you have created is very extensive and was well formatted in relation to the ratio of images to text on the page.
Found that the colours and use of table for the breakdown of information in relation to ‘Timeline of developmental process’ and ‘history of discoveries’ condensed the material and made it easily understandable. This made me want to keep reading.

With majority of the images that are uploaded onto the page there needs to be the correct information and referencing provided for the summary box. From where the image was sourced (ideally of reliable and scientific literature in origin), identifying that it has been uploaded for a student assignment and copyright information-permission to use uploaded image and any other information that is pertaining to the topic and why the image was used/relevant.
Further, those of you within your group that have drawn an uploaded image, have to ensure that you have stated in the summary box that it was student drawn prior to final assessment/evaluation.

The glossary is able to be expanded upon and potentially ensuring that the words that are being explained/elaborated are bolded. As a reader, I would find it easier to read and distinguish if they were bolded.
The reference list that has been developed appears to demonstrate that as a group you have are well read and researched, however, the citation errors will have to be addressed and resolved prior to final marking of the project. I really appreciated the layout (headings, summary and images) of the page.

===Olfaction===

For me this is one of the best projects of the 6 groups. It is extremely well researched, as seen through the extensive reference list. It is evident that the group has gone above and beyond, researching even more than required for the topic, or standards set by other groups, such as clinical approaches, and much information on current research.

I found that the formatting in the upper part of the page, specifically the section under the title ‘normal function’ was a bit awkward in relation to text and image positioning. It felt that it was not consistent with the flow of the rest of the page.
Also the first table may require an in-filled colour or even lines (can be a light or pale colour), just so each column and the single uploaded image is more defined and linked to the correct year/individual.

The ‘Choanal Atresia’ tomography image requires acknowledgement that the image was uploaded as part of a university assessment. However, really appreciated the breakdown of where the arrows were pointing and the relevance in relation to your specific topic.
Images for the tables need to be finalized and uploaded; ensuring that there is appropriate referencing, whether they are student drawn, or sourced from the literature.
Found that the student drawn diagrams were really detailed and easy to understand and appreciate. Each was also relevant to the topics, which they were linked/associated to.

===Abnormal Vision===

It was very good to see that this interesting topic has been well researched and that there are a number of references appropriately cited in the page.

Currently, there is a lot of text that, I as a reader, felt overwhelmed when assessing. More/larger images may need to be uploaded, or the correct formatting/resizing of existing images in order to potential rectify these concerns. It is noteworthy, however, that the ratio between text and imaging improves toward the bottom end of the page.
It was good to see that there was all relevant summary, referencing and uploading information for the images that were present. Keep in mind that there is an option, and we have been encouraged to upload images that have been student drawn.

The over all formatting of the page, besides being packed with written information, had a couple of spacing issues, from extreme spaces between the bullet point genes and consequent descriptions, in the ‘abnormal lens development section’, to virtually no singular spacing between the research timeline. in the ‘Genes’ section.

A way to aid to the above so that the page potentially is more visually appealing, is to place the genes and subsequent function into tables, or even placing the timeline information in a table form, or adding originality by actually placing this information on a timeline generated by one of the group members.
Overall though, I found that it was a very engaging topic and page presented.

===Hearing===

This is a well-formatted project page. There is a great balance and positioning of image and text information throughout. The way that the information, headings and subheadings are positioned made the contents flow and engaging. I especially found the image of the dog with the big ears, and the opening line of the introduction “Can you hear me!” drew me in as a reader. Just be sure in editing prior to the final assessment date that there are no grammatical errors, such as missing question marks (?).

Some of the uploaded images, such as the ‘normal cochlear’ image in the inner ear sub-heading of the development section, require, that information is attached stating the image was uploaded as part of a university assessment. The drawn or student edited drawings were well used and uploaded, having the appropriate summary and uploading information required.

The tables were very effective in presenting the information in a concise way, and I found that the summary box for the inner ear was well put together in highlighting the key points. Images still need to be uploaded prior to the final assessment date in the tables as indicated.

Finally, external links that are in the environment section and in some of the tables rows will need to be transferred to the external links section and appropriately numbered and formatted once in this sections.
The reference list is very well established, however, ensure that the template citation of reference 56 is correctly formatted before final project date.

==Lab 9 Assessment==

===Task 1===

A recent research review article, which was found in relation to development of the thyroid- endocrine organ, was The thyroid hormone responsive protein (THRP) has a critical role in the embryogenesis of Xenopus laevis. Though this article pertains to embryology of the frog, it highlights the significance THRP has in endocrine, and entire embryology through this animal model.

This article demonstrates the link between the endocrine system and neuronal embryogenesis and the effects that can occur if there are mutations or over expression of protein levels produced/controlled by the thyroid.
THRP normally is controlled and responsive via the thyroid gland. It is also a reading frame for expression of proteins and genes that are involved in c-Abl signaling (such as Abi-2), which contribute significantly to neuronal development. In this article, in vivo tests were performed, whereby THRP was expressed in vectors, during development, in order to establish the effect this neurotoxin protein had upon the neuronal development in Xenopus laevis (frogs). In places where there was over expression of THRP, tadpoles demonstrated severe malformations, which correlated to similar findings in previous mouse model studies mouse models, resulting in spinal chord deformation.

This demonstrates that the thyroid plays a significant role as a control and regulating centre for the expression and release of proteins such as THRP. Without its normal development and function, embryonic, neuronal development can be negatively effected, leading to postnatal deformities of the central nervous system (CNS).

====Reference====
<pubmed> 2109522</pubmed>

===Task 2===

Teeth develop embryonically through a balance between epithelial and ecto-mesenchyme (ectoderm) of the oropharyngeal cavity. Development also involves the neural crest and the first f the pharyngeal arches. Teeth begin development at week 6 (stage 16-17) and postnatal alterations and maturations occur.

Other tissues that are involved in teeth development are odontoblasts, which originate from the neural crest. Which are involved in bud formation of the tooth in initial week 6 developments. Odontoblasts secrete predentin, which when calcified becomes a potein called dentin, which work in conjunction with enamel (secreted by specific cells called ameloblasts), to strengthen and develop teeth.

When teeth form, they progress from an initial lamina layer, then progression to placode (dental) formations, and progress morphologically through bud formation, to cap and then finally to a bell shape; developing into the gum space beneath teeth. At the sites of dental placode formation, there is growth of epithelial cells, which will secrete elements such as enamel teeth strengthening.

Finally, many odontogenic genes are present in these stages, which allow for signaling and transcription factor activation and encoding of genes related to teeth development.

====Reference====
<pubmed>19266065</pubmed>

==Lab 11 Assessment==

The recent understanding and development of Induced pluripotent stem cells (iPSC) in medical, scientific and biotechnological fields has opened up many areas of research. Scientists are now formatting their research around transcription factors, such as Sox2 and Oct4, which were initially and currently, used to formulate induced stem cells.
This area of research has expanded capabilities of producing models of human disease, understanding of human physiology and potential treatments.

A current research article that has applied methods of iPSC in order to understand a pathological process is Induced Pluripotent Stem Cell Models of Progranulin-Deficient Frontotemporal Dementia Uncover Specific Reversible Neuronal Defects. Frontal and temporal dementia (frontotemporal-FTD) is unfortunately not fully understood in relation to underlying mechanisms of disease and has no current treatment. However, through observing clinical manifestations and neuronal tests, researchers have found a link between pathology of FTD and mutations occurring of the genes that affect patients neurologically.

In particular the heterozygous mutation of progranulin (PGRN S116X), has been found to be present in case of FTD. Patients with FTD demonstrated depletion in the amount of protein product produced (haploinsufficiency). In this article, patient iPSC lineages were produced in order to establish a molecular understanding of the PGRN S116X mutations and develop a model of PGRN haploinsufficency.

From this, researchers were able to recognize the various signaling pathways involved, such as MEK and PI3K. As a result defects that occurred along the pathways where also observed in cases where there was deficiency in PGRN and therefore mutation. This finding has lead to questions surrounding particular treatment options and further iPSC lineage generation for other proteins that may be affected genetically through signaling pathways and mutations.

<pubmed>23063362</pubmed>

User:Z3330539

2012-10-16T21:37:20Z

Z3330539: /* Lab 11 Assessment */

== Lab Attendance ==

Lab 1--[[User:Z3330539|Z3330539]] 11:49, 25 July 2012 (EST)

Lab 2 [[User:Z3330539|Z3330539]] 10:52, 1 August 2012 (EST)

Lab 3 --[[User:Z3330539|Z3330539]] 10:04, 8 August 2012 (EST)--

Lab 4 --[[User:Z3330539|Z3330539]] 09:59, 15 August 2012 (EST)--

Lab 5 --[[User:Z3330539|Z3330539]] 10:10, 22 August 2012 (EST)--

Lab 6 --[[User:Z3330539|Z3330539]] 10:08, 29 August 2012 (EST)--

Lab 7 --[[User:Z3330539|Z3330539]] 10:14, 12 September 2012 (EST)--

Lab 8 --[[User:Z3330539|Z3330539]] 10:03, 19 September 2012 (EST)--

Lab 9 --[[User:Z3330539|Z3330539]] 10:08, 26 September 2012 (EST)--

Lab 10 --[[User:Z3330539|Z3330539]] 10:07, 3 October 2012 (EST)--

Lab 11 --[[User:Z3330539|Z3330539]] 10:10, 10 October 2012 (EST)--

==Lab 1 Assessment==
--[[User:Z8600021|Mark Hill]] 18:04, 10 September 2012 (EST) Please do not include spaces before your sub-headings as this will affect formatting. I have corrected Lab 1, please correct other subheadings yourself before final assessment.

===Task 1===

Identify the origin of In Vitro Fertilization and the 2010 Nobel Prize winner associated with this technique and add a correctly formatted link to the Nobel page.

-In Vitro Fertilization (IVF) technology is the combining/fusion of the males sperm and females egg/s outside the body, then later implanting this fertilized oocyte into the female uterus. This technique involves the regulation of the female cycle and monitoring of ovulation. This in vitro technique/concept has been present and studied for many years, with earliest recordings of such scientific research/findings; such test tube babies; occurring as early as 1950’s. The scientist who won the Nobel Prize in 2010, for his efforts and involvement in the discovery implementation of IVF techniques was the physiologist Robert Edwards. This was an honor given in the current medicine. Edwards with a fellow associate were the first recorded successful pregnancy and birth of the first and second IVF babies to be delivered in the late 1970’s and the 1980’s. Following this successful implantation, development and implantation other countries including Australia began to use this technique, for situations and individuals with fertility problems. Recent developments in this field of medicine and physiology have been on hormones involved in oocyte maturation, ovarian cycles such as follicle stimulating hormone, as well as the way in which sperm is administered in order for fertilization to occur.

Links: [1] [2]

===Task 2===

Identify and add a PubMed reference link to a recent paper on fertilization and describe its key findings (1-2 paragraphs).

- “Molecular Origin of Female Meiotic Aneuploidies”

This article addresses the molecular and physiological mechanisms underlying the abnormalities in pregnancy which occur as a result of aneuploidy. It discusses the disruption of the cohesion and separation of the homologues at the centromeres and the polar ends of the spindle, which can result in miscarriage and loss of pregnancy. Lack of separation of these homologues prevents the production of two separate daughter chromatids. These errors can occur either toward the end of meiosis one and also in meiosis two, and in some instances meiosis two errors can arise as a result of meiosis one errors that were not resolved. In this article, there is particular emphasis placed upon the process of female meiosis, as the major causes of errors that can lead to aneuploidy. Major errors which occur are reduced cohesion prior to separation in meiosis two, errors in trisomies, as well as premature segregation, resulting in errors of chromatid pairing and oocyte development in fertilization. Studies are being performed to examine the role, or lack of role which certain proteins play at these stages of female fertilization in order to reduce these abnormalities in conventional and IVF development, in particular in females who fall pregnant at later maternal ages. Examining the molecular mechanisms that occur when there is loss of expression of key proteins such as SMC1 alpha and beta, Scc1 and ReC8, which leads to decrease in cohesin and reduce achiasmate, ultimately leading to lack of separation of the homologues.

[3]

NB: Originally uploaded this into the discussion/my talk page, the night before, prior to moving it into my Page (z3330539).

--[[User:Z8600021|Mark Hill]] 18:04, 10 September 2012 (EST) Answers to the 2 questions are correct. I am concerned that the text in answer to question 1 appears to be from a source that has not been cited, could you please clarify this for me (for an extra mark). You have failed to transfer the citation links correctly from your discussion page to here, and the citation links located there are not correctly formatted. You have used UNSW Library links rather than the PubMed citation number or reference format as shown in the class (and below). '''7/10'''

As a reference number link - PMID 22841925

As a formatted reference - <pubmed>22841925</pubmed>

==Lab 2 Assessment==

====Task 1====
[[File:Immunofluorescent_FN1_and_integrin_on_blastocytes.gif]]

====Task2====

A protein which is involved in the implantation process is Rac1, which is the RAS pathway related C3 botulinum toxin substrate 1. This protein expression allows for embryonic trophoblasts to invade the stromal cell layer and when activated also allows for migration and motility of the cells of the stromal layer. All of these factors lead to the promotion of implantation.

[http://www.ncbi.nlm.nih.gov/pubmed/18838676]

--[[User:Z8600021|Mark Hill]] 18:22, 10 September 2012 (EST) Question 1 is not correctly linked to the appropriate reference, a serious error. Therefore you have not completed the assessment correctly, I will need to delete the image if you cannot fix the referencing and alter your mark accordingly. Image is also too small to be useful and in GIF format. Question 2 is fine, please see my previous assessment comment on referencing. '''6/10'''

As a reference number link - PMID 18838676

As a formatted reference - <pubmed>18838676</pubmed>

==Lab 3 Assessment==

====Task 1====

Gestational age refers to the period of time, generally 14 days before the last day of the females menstrual cycle. Where as post fertilization age is the period from the point of conception/ fertilization of egg by the sperm; this mainly occurs in the middle of the menstrual cycle duration.

Gestational age is used as a clinical method of human development due to the fact that time/point of fertilization can be unknown or variable, women may have sporadic menses and ovulation, females may not be able to recall the last day of their menstrual cycle. The use of gestational age may be an approximation/generalization, however, it is more useful in reducing the variables that can occur, which are mentioned above, as last day of menstrual cycle is predominately able to be recalled by the female, and 14 days are added in order to establish room for possible variations.

References:

1. [http://emedicine.medscape.com/article/259269-overview]

====Task 2====

Somites, which are present in pairs, are derived from the paraxial mesoderm and are involved in week 4 of embryonic development. Somites progressively differentiate into sclerotome, dermatome and myotome.

Sclerotome are the central cells of the somites are are located ventromedially in relation to orientation of the notochord. Sclerotome form vertebral and bone and connective of the vertebral column and are have chondrocytes present.

Dermatome are located dorsolaterally to the notochord and involved in the differentiation into dermis and epidermis.

Finally myotome are located more dorsomedially and are involved in differentiation to skeletal muscle. This involves myoblast cells. Depending on the type, these can either lie dorsomedially and then migrate to form epaxial or hypaxial muscle groups in development.

References:

1. [http://www.embryology.ch/anglais/mmuskel/skelett02.html]
2. [http://www.ncbi.nlm.nih.gov/books/NBK10085/]

--[[User:Z8600021|Mark Hill]] 18:30, 10 September 2012 (EST) Question 1 answer is correct, but your text is confusing in relation to LMP. Question 2 describes the correct somite components, and bone, CT and skeletal muscle. But you have incorrectly identified epidermis as mesoderm in origin, this is ectodermal and not from the somite. '''9/10'''

==Lab 4 Assessment==
====Task 1====

The placenta within the developing fetus performs many functions, via maternal-embryonic nutrient transfer and later embryo-fetal nutrient transfer. Early in development diagnostic tests are able to be performed in order to examine if there are any abnormalities, either genetic or hematological, for example, within the growing embryo. These test and consecutive results are able to be obtained through the placenta. Some techniques are non-invasive, while others can be invasive for the mother. Two test which are performed through placenta diagnostics are a chorion biopsy (chorion villus sampling) and umbilical cord blood sampling. These two prenatal tests are both invasive and involve extraction of tissue and blood samples via injection of a thin needle into either the maternal cervix or abdominal wall in order to reach the uterus and retrieve samples from the placenta or the umbilical cord (the end which lies close to the placenta or the umbilical vein). Once samples are collected they are them examined within laboratories and analyzed for developmental abnormalities.

Though there is partial risk of miscarriage, these tests have been found to be successful in diagnosis of abnormalities such as down syndrome and pathological blood disorders such as Rh disease. The defects in early cell division in the embryo, with specific reference to down syndrome (trisomy 21) can be detected, as well as the compatibility between maternal and embryonic blood in relation to Rh disease. This gives the ability to detect whether there will be a maternal immune response, as a result of lack of blood compatibility (i.e. maternal immune response triggered post birth of first delivered child).

References:

1. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166195/pdf/mxr008.pd]
2. [http://www.embryology.ch/anglais/jfetalperiod/diagno04.html]
3. [http://www.centrahealth.com/health-library]

====Task 2====

An article which discusses the possibilities for cord stems cells to be used in therapeutically is '''Human umbilical cord mesenchymal stem cells and the treatment of spinal cord injury'''.
This review article discusses the potential for umbilical cord stems cells to be used in the therapeutic treatment of spinal chord injury or disease.

Through analysis of resent findings, researchers have discovered the similar characteristic within cord stem cells that are found in bone marrow. Cord stem cells have been found to be an alternative source for mesenchymal stems cells, and therefore are seen as a promising alternative for transplantation procedures, as they are able to differentiate into numerous cells and tissues such as bone and cartilage; as well as self renewal and growth properties.
Furthermore, this area of research is being considered due to the fact that there are limitations surrounding transplantation of bone marrow mesenchymal cells, such as viral contraction and cellular amount.

The spinal cord consists of a complex molecular and cellular framework, such as astrocytes, microglia cells and myelin proteins. As a result of these many constituent, when the spine is injured or diseased, treatment is difficult due to the degenerative nature/course which these problems can occur. However, through the isolation of these cord stem cells from embryonic umbilical cord, treatment may be something that soon can be highly successful with further research and clinical development. Furthermore, isolation of these umbilcal cord stems cells are more ethically supported than isolation of bone marrow mensenchymal cells.

Further research and studies are required, however, due to the fact that some attempts, methods and techniques of recent isolations have failed. Furthermore, future areas of developmental research may include longitudinal and clinical research that can further increase awareness of umbilical cord mesenchymal cell transplantation as an alternative for complex injuries, such as those to the spinal cord.

References:
1. [http://www.ncbi.nlm.nih.gov/pubmed/19187651]
2. [http://www.cmj.org/Periodical/PDF/200911959717530.pdf]

--[[User:Z8600021|Mark Hill]] 16:27, 11 September 2012 (EST) Both these answers are excellent. '''10/10'''

===Lab 7 Assessment===

====Task 1====

a) Satellite cells are mononuclear progenitor cells that are involved in postnatal development and regeneration of skeletal muscle fibres.

b) Satellite cells can remain quiescent until they are activated by extracellular stimuli. The first example where satellite cells become activated is when there is local damage or injury to the muscles. The second example of where satellite cells can be activated is when muscles undergo hypertrophy. Although satellite cells do not have to be activated in order for muscle hypertrophy, studies have shown that they can become activated. In these cases satellite cells re-enter into the cell cycle, and myoblasts/myofibers proliferate in order to repair and/or replace cells during muscle loading or when cell injury occurs. <ref><pubmed>17213900</pubmed></ref>

====Task 2====

When motor neurons sustain a long-term injury to spinal chord studies have shown that muscle fibres undergo muscular atrophy; muscles fibres cells decrease. This muscle wasting is potentially the result of inactivation of muscles due to lack of synaptic signalling from main central conducting systems, such as the motor neurons of the spinal chord. <ref><pubmed>8265728</pubmed></ref>
Furthermore, post spinal chord injury results in a transformation of muscle fibres. Predominately these fibres consist of both type 1 (slow) and type 2 (fast) fibre patterning, however, slow twitch fibres; specifically Type IIB, become principal after motor neuron damage. This can result in lead to reduction in the amount of fat mass, therefore contribute to wasting and weight loss. <ref><pubmed>9044514</pubmed></ref>

'Reference List'

1. <pubmed>17213900</pubmed>

2. <pubmed>8265728</pubmed>

3. <pubmed>9044514</pubmed>

[http://athletics.wikia.com/wiki/Type_II_Muscle_Fiber]
[http://www.skeletalmusclejournal.com/content/1/1/7]

==Lab 8 Assessment: Peer/Group Evaluations==

===Vision===

There is a good balance of images and text throughout the page. Prior to final assessment the page outline and formatting of image and text positioning is required. The first image at the top the page, requires correct referencing and acknowledgement that it has been uploaded as part of a student assignment. This is also required for the image titled “Eyediagramcolour1”.

Since the previous lab, held in week 9, it is positive to see that the group has altered some of the uploaded image information, with particular reference to the self-drawn/uploaded images.

The area of the page which shows that there is a “useful links” heading and an external link within the current research section, should be placed or moved into the external links section at the bottom of the page with the appropriate information that Dr. Hill has required for placing external links on a page. Also, the references within the ‘current research’ section may also be required to be apart of the reference list.

I found this page visually appealing and I liked that this group have included an image gallery section. The use of the external links were appropriate to the topic and that the extent of the glossary for now is good, however, by the final evaluation would potentially need to be larger. Finally found that the headings for each segment of the broader topic were well positioned and relevant.

===Taste===

The page that you have created is very extensive and was well formatted in relation to the ratio of images to text on the page.
Found that the colours and use of table for the breakdown of information in relation to ‘Timeline of developmental process’ and ‘history of discoveries’ condensed the material and made it easily understandable. This made me want to keep reading.

With majority of the images that are uploaded onto the page there needs to be the correct information and referencing provided for the summary box. From where the image was sourced (ideally of reliable and scientific literature in origin), identifying that it has been uploaded for a student assignment and copyright information-permission to use uploaded image and any other information that is pertaining to the topic and why the image was used/relevant.
Further, those of you within your group that have drawn an uploaded image, have to ensure that you have stated in the summary box that it was student drawn prior to final assessment/evaluation.

The glossary is able to be expanded upon and potentially ensuring that the words that are being explained/elaborated are bolded. As a reader, I would find it easier to read and distinguish if they were bolded.
The reference list that has been developed appears to demonstrate that as a group you have are well read and researched, however, the citation errors will have to be addressed and resolved prior to final marking of the project. I really appreciated the layout (headings, summary and images) of the page.

===Olfaction===

For me this is one of the best projects of the 6 groups. It is extremely well researched, as seen through the extensive reference list. It is evident that the group has gone above and beyond, researching even more than required for the topic, or standards set by other groups, such as clinical approaches, and much information on current research.

I found that the formatting in the upper part of the page, specifically the section under the title ‘normal function’ was a bit awkward in relation to text and image positioning. It felt that it was not consistent with the flow of the rest of the page.
Also the first table may require an in-filled colour or even lines (can be a light or pale colour), just so each column and the single uploaded image is more defined and linked to the correct year/individual.

The ‘Choanal Atresia’ tomography image requires acknowledgement that the image was uploaded as part of a university assessment. However, really appreciated the breakdown of where the arrows were pointing and the relevance in relation to your specific topic.
Images for the tables need to be finalized and uploaded; ensuring that there is appropriate referencing, whether they are student drawn, or sourced from the literature.
Found that the student drawn diagrams were really detailed and easy to understand and appreciate. Each was also relevant to the topics, which they were linked/associated to.

===Abnormal Vision===

It was very good to see that this interesting topic has been well researched and that there are a number of references appropriately cited in the page.

Currently, there is a lot of text that, I as a reader, felt overwhelmed when assessing. More/larger images may need to be uploaded, or the correct formatting/resizing of existing images in order to potential rectify these concerns. It is noteworthy, however, that the ratio between text and imaging improves toward the bottom end of the page.
It was good to see that there was all relevant summary, referencing and uploading information for the images that were present. Keep in mind that there is an option, and we have been encouraged to upload images that have been student drawn.

The over all formatting of the page, besides being packed with written information, had a couple of spacing issues, from extreme spaces between the bullet point genes and consequent descriptions, in the ‘abnormal lens development section’, to virtually no singular spacing between the research timeline. in the ‘Genes’ section.

A way to aid to the above so that the page potentially is more visually appealing, is to place the genes and subsequent function into tables, or even placing the timeline information in a table form, or adding originality by actually placing this information on a timeline generated by one of the group members.
Overall though, I found that it was a very engaging topic and page presented.

===Hearing===

This is a well-formatted project page. There is a great balance and positioning of image and text information throughout. The way that the information, headings and subheadings are positioned made the contents flow and engaging. I especially found the image of the dog with the big ears, and the opening line of the introduction “Can you hear me!” drew me in as a reader. Just be sure in editing prior to the final assessment date that there are no grammatical errors, such as missing question marks (?).

Some of the uploaded images, such as the ‘normal cochlear’ image in the inner ear sub-heading of the development section, require, that information is attached stating the image was uploaded as part of a university assessment. The drawn or student edited drawings were well used and uploaded, having the appropriate summary and uploading information required.

The tables were very effective in presenting the information in a concise way, and I found that the summary box for the inner ear was well put together in highlighting the key points. Images still need to be uploaded prior to the final assessment date in the tables as indicated.

Finally, external links that are in the environment section and in some of the tables rows will need to be transferred to the external links section and appropriately numbered and formatted once in this sections.
The reference list is very well established, however, ensure that the template citation of reference 56 is correctly formatted before final project date.

==Lab 9 Assessment==

===Task 1===

A recent research review article, which was found in relation to development of the thyroid- endocrine organ, was The thyroid hormone responsive protein (THRP) has a critical role in the embryogenesis of Xenopus laevis. Though this article pertains to embryology of the frog, it highlights the significance THRP has in endocrine, and entire embryology through this animal model.

This article demonstrates the link between the endocrine system and neuronal embryogenesis and the effects that can occur if there are mutations or over expression of protein levels produced/controlled by the thyroid.
THRP normally is controlled and responsive via the thyroid gland. It is also a reading frame for expression of proteins and genes that are involved in c-Abl signaling (such as Abi-2), which contribute significantly to neuronal development. In this article, in vivo tests were performed, whereby THRP was expressed in vectors, during development, in order to establish the effect this neurotoxin protein had upon the neuronal development in Xenopus laevis (frogs). In places where there was over expression of THRP, tadpoles demonstrated severe malformations, which correlated to similar findings in previous mouse model studies mouse models, resulting in spinal chord deformation.

This demonstrates that the thyroid plays a significant role as a control and regulating centre for the expression and release of proteins such as THRP. Without its normal development and function, embryonic, neuronal development can be negatively effected, leading to postnatal deformities of the central nervous system (CNS).

====Reference====
<pubmed> 2109522</pubmed>

===Task 2===

Teeth develop embryonically through a balance between epithelial and ecto-mesenchyme (ectoderm) of the oropharyngeal cavity. Development also involves the neural crest and the first f the pharyngeal arches. Teeth begin development at week 6 (stage 16-17) and postnatal alterations and maturations occur.

Other tissues that are involved in teeth development are odontoblasts, which originate from the neural crest. Which are involved in bud formation of the tooth in initial week 6 developments. Odontoblasts secrete predentin, which when calcified becomes a potein called dentin, which work in conjunction with enamel (secreted by specific cells called ameloblasts), to strengthen and develop teeth.

When teeth form, they progress from an initial lamina layer, then progression to placode (dental) formations, and progress morphologically through bud formation, to cap and then finally to a bell shape; developing into the gum space beneath teeth. At the sites of dental placode formation, there is growth of epithelial cells, which will secrete elements such as enamel teeth strengthening.

Finally, many odontogenic genes are present in these stages, which allow for signaling and transcription factor activation and encoding of genes related to teeth development.

====Reference====
<pubmed>19266065</pubmed>

==Lab 11 Assessment==

The recent understanding and development of Induced pluripotent stem cells (iPSC) in medical, scientific and biotechnological fields has opened up many areas of research. Scientists are now formatting their research around transcription factors, such as Sox2 and Oct4, which were initially and currently, used to formulate induced stem cells.
This area of research has expanded capabilities of producing models of human disease, understanding of human physiology and potential treatments.

A current research article that has applied methods of iPSC in order to understand a pathological process is Induced Pluripotent Stem Cell Models of Progranulin-Deficient Frontotemporal Dementia Uncover Specific Reversible Neuronal Defects. Frontal and temporal dementia (frontotemporal-FTD) is unfortunately not fully understood in relation to underlying mechanisms of disease and has no current treatment. However, through observing clinical manifestations and neuronal tests, researchers have found a link between pathology of FTD and mutations occurring of the genes that affect patients neurologically.

In particular the heterozygous mutation of progranulin (PGRN S116X), has been found to be present in case of FTD. Patients with FTD demonstrated depletion in the amount of protein product produced (haploinsufficiency). In this article, patient iPSC lineages were produced in order to establish a molecular understanding of the PGRN S116X mutations and develop a model of PGRN haploinsufficency.

From this, researchers were able to recognize the various signaling pathways involved, such as MEK and PI3K. As a result defects that occurred along the pathways where also observed in cases where there was deficiency in PGRN and therefore mutation. This finding has lead to questions surrounding particular treatment options and further iPSC lineage generation for other proteins that may be affected genetically through signaling pathways and mutations.

<pubmed>23063362</pubmed>

User:Z3330539

2012-10-16T20:53:53Z

Z3330539: /* Reference */

== Lab Attendance ==

Lab 1--[[User:Z3330539|Z3330539]] 11:49, 25 July 2012 (EST)

Lab 2 [[User:Z3330539|Z3330539]] 10:52, 1 August 2012 (EST)

Lab 3 --[[User:Z3330539|Z3330539]] 10:04, 8 August 2012 (EST)--

Lab 4 --[[User:Z3330539|Z3330539]] 09:59, 15 August 2012 (EST)--

Lab 5 --[[User:Z3330539|Z3330539]] 10:10, 22 August 2012 (EST)--

Lab 6 --[[User:Z3330539|Z3330539]] 10:08, 29 August 2012 (EST)--

Lab 7 --[[User:Z3330539|Z3330539]] 10:14, 12 September 2012 (EST)--

Lab 8 --[[User:Z3330539|Z3330539]] 10:03, 19 September 2012 (EST)--

Lab 9 --[[User:Z3330539|Z3330539]] 10:08, 26 September 2012 (EST)--

Lab 10 --[[User:Z3330539|Z3330539]] 10:07, 3 October 2012 (EST)--

Lab 11 --[[User:Z3330539|Z3330539]] 10:10, 10 October 2012 (EST)--

==Lab 1 Assessment==
--[[User:Z8600021|Mark Hill]] 18:04, 10 September 2012 (EST) Please do not include spaces before your sub-headings as this will affect formatting. I have corrected Lab 1, please correct other subheadings yourself before final assessment.

===Task 1===

Identify the origin of In Vitro Fertilization and the 2010 Nobel Prize winner associated with this technique and add a correctly formatted link to the Nobel page.

-In Vitro Fertilization (IVF) technology is the combining/fusion of the males sperm and females egg/s outside the body, then later implanting this fertilized oocyte into the female uterus. This technique involves the regulation of the female cycle and monitoring of ovulation. This in vitro technique/concept has been present and studied for many years, with earliest recordings of such scientific research/findings; such test tube babies; occurring as early as 1950’s. The scientist who won the Nobel Prize in 2010, for his efforts and involvement in the discovery implementation of IVF techniques was the physiologist Robert Edwards. This was an honor given in the current medicine. Edwards with a fellow associate were the first recorded successful pregnancy and birth of the first and second IVF babies to be delivered in the late 1970’s and the 1980’s. Following this successful implantation, development and implantation other countries including Australia began to use this technique, for situations and individuals with fertility problems. Recent developments in this field of medicine and physiology have been on hormones involved in oocyte maturation, ovarian cycles such as follicle stimulating hormone, as well as the way in which sperm is administered in order for fertilization to occur.

Links: [1] [2]

===Task 2===

Identify and add a PubMed reference link to a recent paper on fertilization and describe its key findings (1-2 paragraphs).

- “Molecular Origin of Female Meiotic Aneuploidies”

This article addresses the molecular and physiological mechanisms underlying the abnormalities in pregnancy which occur as a result of aneuploidy. It discusses the disruption of the cohesion and separation of the homologues at the centromeres and the polar ends of the spindle, which can result in miscarriage and loss of pregnancy. Lack of separation of these homologues prevents the production of two separate daughter chromatids. These errors can occur either toward the end of meiosis one and also in meiosis two, and in some instances meiosis two errors can arise as a result of meiosis one errors that were not resolved. In this article, there is particular emphasis placed upon the process of female meiosis, as the major causes of errors that can lead to aneuploidy. Major errors which occur are reduced cohesion prior to separation in meiosis two, errors in trisomies, as well as premature segregation, resulting in errors of chromatid pairing and oocyte development in fertilization. Studies are being performed to examine the role, or lack of role which certain proteins play at these stages of female fertilization in order to reduce these abnormalities in conventional and IVF development, in particular in females who fall pregnant at later maternal ages. Examining the molecular mechanisms that occur when there is loss of expression of key proteins such as SMC1 alpha and beta, Scc1 and ReC8, which leads to decrease in cohesin and reduce achiasmate, ultimately leading to lack of separation of the homologues.

[3]

NB: Originally uploaded this into the discussion/my talk page, the night before, prior to moving it into my Page (z3330539).

--[[User:Z8600021|Mark Hill]] 18:04, 10 September 2012 (EST) Answers to the 2 questions are correct. I am concerned that the text in answer to question 1 appears to be from a source that has not been cited, could you please clarify this for me (for an extra mark). You have failed to transfer the citation links correctly from your discussion page to here, and the citation links located there are not correctly formatted. You have used UNSW Library links rather than the PubMed citation number or reference format as shown in the class (and below). '''7/10'''

As a reference number link - PMID 22841925

As a formatted reference - <pubmed>22841925</pubmed>

==Lab 2 Assessment==

====Task 1====
[[File:Immunofluorescent_FN1_and_integrin_on_blastocytes.gif]]

====Task2====

A protein which is involved in the implantation process is Rac1, which is the RAS pathway related C3 botulinum toxin substrate 1. This protein expression allows for embryonic trophoblasts to invade the stromal cell layer and when activated also allows for migration and motility of the cells of the stromal layer. All of these factors lead to the promotion of implantation.

[http://www.ncbi.nlm.nih.gov/pubmed/18838676]

--[[User:Z8600021|Mark Hill]] 18:22, 10 September 2012 (EST) Question 1 is not correctly linked to the appropriate reference, a serious error. Therefore you have not completed the assessment correctly, I will need to delete the image if you cannot fix the referencing and alter your mark accordingly. Image is also too small to be useful and in GIF format. Question 2 is fine, please see my previous assessment comment on referencing. '''6/10'''

As a reference number link - PMID 18838676

As a formatted reference - <pubmed>18838676</pubmed>

==Lab 3 Assessment==

====Task 1====

Gestational age refers to the period of time, generally 14 days before the last day of the females menstrual cycle. Where as post fertilization age is the period from the point of conception/ fertilization of egg by the sperm; this mainly occurs in the middle of the menstrual cycle duration.

Gestational age is used as a clinical method of human development due to the fact that time/point of fertilization can be unknown or variable, women may have sporadic menses and ovulation, females may not be able to recall the last day of their menstrual cycle. The use of gestational age may be an approximation/generalization, however, it is more useful in reducing the variables that can occur, which are mentioned above, as last day of menstrual cycle is predominately able to be recalled by the female, and 14 days are added in order to establish room for possible variations.

References:

1. [http://emedicine.medscape.com/article/259269-overview]

====Task 2====

Somites, which are present in pairs, are derived from the paraxial mesoderm and are involved in week 4 of embryonic development. Somites progressively differentiate into sclerotome, dermatome and myotome.

Sclerotome are the central cells of the somites are are located ventromedially in relation to orientation of the notochord. Sclerotome form vertebral and bone and connective of the vertebral column and are have chondrocytes present.

Dermatome are located dorsolaterally to the notochord and involved in the differentiation into dermis and epidermis.

Finally myotome are located more dorsomedially and are involved in differentiation to skeletal muscle. This involves myoblast cells. Depending on the type, these can either lie dorsomedially and then migrate to form epaxial or hypaxial muscle groups in development.

References:

1. [http://www.embryology.ch/anglais/mmuskel/skelett02.html]
2. [http://www.ncbi.nlm.nih.gov/books/NBK10085/]

--[[User:Z8600021|Mark Hill]] 18:30, 10 September 2012 (EST) Question 1 answer is correct, but your text is confusing in relation to LMP. Question 2 describes the correct somite components, and bone, CT and skeletal muscle. But you have incorrectly identified epidermis as mesoderm in origin, this is ectodermal and not from the somite. '''9/10'''

==Lab 4 Assessment==
====Task 1====

The placenta within the developing fetus performs many functions, via maternal-embryonic nutrient transfer and later embryo-fetal nutrient transfer. Early in development diagnostic tests are able to be performed in order to examine if there are any abnormalities, either genetic or hematological, for example, within the growing embryo. These test and consecutive results are able to be obtained through the placenta. Some techniques are non-invasive, while others can be invasive for the mother. Two test which are performed through placenta diagnostics are a chorion biopsy (chorion villus sampling) and umbilical cord blood sampling. These two prenatal tests are both invasive and involve extraction of tissue and blood samples via injection of a thin needle into either the maternal cervix or abdominal wall in order to reach the uterus and retrieve samples from the placenta or the umbilical cord (the end which lies close to the placenta or the umbilical vein). Once samples are collected they are them examined within laboratories and analyzed for developmental abnormalities.

Though there is partial risk of miscarriage, these tests have been found to be successful in diagnosis of abnormalities such as down syndrome and pathological blood disorders such as Rh disease. The defects in early cell division in the embryo, with specific reference to down syndrome (trisomy 21) can be detected, as well as the compatibility between maternal and embryonic blood in relation to Rh disease. This gives the ability to detect whether there will be a maternal immune response, as a result of lack of blood compatibility (i.e. maternal immune response triggered post birth of first delivered child).

References:

1. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166195/pdf/mxr008.pd]
2. [http://www.embryology.ch/anglais/jfetalperiod/diagno04.html]
3. [http://www.centrahealth.com/health-library]

====Task 2====

An article which discusses the possibilities for cord stems cells to be used in therapeutically is '''Human umbilical cord mesenchymal stem cells and the treatment of spinal cord injury'''.
This review article discusses the potential for umbilical cord stems cells to be used in the therapeutic treatment of spinal chord injury or disease.

Through analysis of resent findings, researchers have discovered the similar characteristic within cord stem cells that are found in bone marrow. Cord stem cells have been found to be an alternative source for mesenchymal stems cells, and therefore are seen as a promising alternative for transplantation procedures, as they are able to differentiate into numerous cells and tissues such as bone and cartilage; as well as self renewal and growth properties.
Furthermore, this area of research is being considered due to the fact that there are limitations surrounding transplantation of bone marrow mesenchymal cells, such as viral contraction and cellular amount.

The spinal cord consists of a complex molecular and cellular framework, such as astrocytes, microglia cells and myelin proteins. As a result of these many constituent, when the spine is injured or diseased, treatment is difficult due to the degenerative nature/course which these problems can occur. However, through the isolation of these cord stem cells from embryonic umbilical cord, treatment may be something that soon can be highly successful with further research and clinical development. Furthermore, isolation of these umbilcal cord stems cells are more ethically supported than isolation of bone marrow mensenchymal cells.

Further research and studies are required, however, due to the fact that some attempts, methods and techniques of recent isolations have failed. Furthermore, future areas of developmental research may include longitudinal and clinical research that can further increase awareness of umbilical cord mesenchymal cell transplantation as an alternative for complex injuries, such as those to the spinal cord.

References:
1. [http://www.ncbi.nlm.nih.gov/pubmed/19187651]
2. [http://www.cmj.org/Periodical/PDF/200911959717530.pdf]

--[[User:Z8600021|Mark Hill]] 16:27, 11 September 2012 (EST) Both these answers are excellent. '''10/10'''

===Lab 7 Assessment===

====Task 1====

a) Satellite cells are mononuclear progenitor cells that are involved in postnatal development and regeneration of skeletal muscle fibres.

b) Satellite cells can remain quiescent until they are activated by extracellular stimuli. The first example where satellite cells become activated is when there is local damage or injury to the muscles. The second example of where satellite cells can be activated is when muscles undergo hypertrophy. Although satellite cells do not have to be activated in order for muscle hypertrophy, studies have shown that they can become activated. In these cases satellite cells re-enter into the cell cycle, and myoblasts/myofibers proliferate in order to repair and/or replace cells during muscle loading or when cell injury occurs. <ref><pubmed>17213900</pubmed></ref>

====Task 2====

When motor neurons sustain a long-term injury to spinal chord studies have shown that muscle fibres undergo muscular atrophy; muscles fibres cells decrease. This muscle wasting is potentially the result of inactivation of muscles due to lack of synaptic signalling from main central conducting systems, such as the motor neurons of the spinal chord. <ref><pubmed>8265728</pubmed></ref>
Furthermore, post spinal chord injury results in a transformation of muscle fibres. Predominately these fibres consist of both type 1 (slow) and type 2 (fast) fibre patterning, however, slow twitch fibres; specifically Type IIB, become principal after motor neuron damage. This can result in lead to reduction in the amount of fat mass, therefore contribute to wasting and weight loss. <ref><pubmed>9044514</pubmed></ref>

'Reference List'

1. <pubmed>17213900</pubmed>

2. <pubmed>8265728</pubmed>

3. <pubmed>9044514</pubmed>

[http://athletics.wikia.com/wiki/Type_II_Muscle_Fiber]
[http://www.skeletalmusclejournal.com/content/1/1/7]

==Lab 8 Assessment: Peer/Group Evaluations==

===Vision===

There is a good balance of images and text throughout the page. Prior to final assessment the page outline and formatting of image and text positioning is required. The first image at the top the page, requires correct referencing and acknowledgement that it has been uploaded as part of a student assignment. This is also required for the image titled “Eyediagramcolour1”.

Since the previous lab, held in week 9, it is positive to see that the group has altered some of the uploaded image information, with particular reference to the self-drawn/uploaded images.

The area of the page which shows that there is a “useful links” heading and an external link within the current research section, should be placed or moved into the external links section at the bottom of the page with the appropriate information that Dr. Hill has required for placing external links on a page. Also, the references within the ‘current research’ section may also be required to be apart of the reference list.

I found this page visually appealing and I liked that this group have included an image gallery section. The use of the external links were appropriate to the topic and that the extent of the glossary for now is good, however, by the final evaluation would potentially need to be larger. Finally found that the headings for each segment of the broader topic were well positioned and relevant.

===Taste===

The page that you have created is very extensive and was well formatted in relation to the ratio of images to text on the page.
Found that the colours and use of table for the breakdown of information in relation to ‘Timeline of developmental process’ and ‘history of discoveries’ condensed the material and made it easily understandable. This made me want to keep reading.

With majority of the images that are uploaded onto the page there needs to be the correct information and referencing provided for the summary box. From where the image was sourced (ideally of reliable and scientific literature in origin), identifying that it has been uploaded for a student assignment and copyright information-permission to use uploaded image and any other information that is pertaining to the topic and why the image was used/relevant.
Further, those of you within your group that have drawn an uploaded image, have to ensure that you have stated in the summary box that it was student drawn prior to final assessment/evaluation.

The glossary is able to be expanded upon and potentially ensuring that the words that are being explained/elaborated are bolded. As a reader, I would find it easier to read and distinguish if they were bolded.
The reference list that has been developed appears to demonstrate that as a group you have are well read and researched, however, the citation errors will have to be addressed and resolved prior to final marking of the project. I really appreciated the layout (headings, summary and images) of the page.

===Olfaction===

For me this is one of the best projects of the 6 groups. It is extremely well researched, as seen through the extensive reference list. It is evident that the group has gone above and beyond, researching even more than required for the topic, or standards set by other groups, such as clinical approaches, and much information on current research.

I found that the formatting in the upper part of the page, specifically the section under the title ‘normal function’ was a bit awkward in relation to text and image positioning. It felt that it was not consistent with the flow of the rest of the page.
Also the first table may require an in-filled colour or even lines (can be a light or pale colour), just so each column and the single uploaded image is more defined and linked to the correct year/individual.

The ‘Choanal Atresia’ tomography image requires acknowledgement that the image was uploaded as part of a university assessment. However, really appreciated the breakdown of where the arrows were pointing and the relevance in relation to your specific topic.
Images for the tables need to be finalized and uploaded; ensuring that there is appropriate referencing, whether they are student drawn, or sourced from the literature.
Found that the student drawn diagrams were really detailed and easy to understand and appreciate. Each was also relevant to the topics, which they were linked/associated to.

===Abnormal Vision===

It was very good to see that this interesting topic has been well researched and that there are a number of references appropriately cited in the page.

Currently, there is a lot of text that, I as a reader, felt overwhelmed when assessing. More/larger images may need to be uploaded, or the correct formatting/resizing of existing images in order to potential rectify these concerns. It is noteworthy, however, that the ratio between text and imaging improves toward the bottom end of the page.
It was good to see that there was all relevant summary, referencing and uploading information for the images that were present. Keep in mind that there is an option, and we have been encouraged to upload images that have been student drawn.

The over all formatting of the page, besides being packed with written information, had a couple of spacing issues, from extreme spaces between the bullet point genes and consequent descriptions, in the ‘abnormal lens development section’, to virtually no singular spacing between the research timeline. in the ‘Genes’ section.

A way to aid to the above so that the page potentially is more visually appealing, is to place the genes and subsequent function into tables, or even placing the timeline information in a table form, or adding originality by actually placing this information on a timeline generated by one of the group members.
Overall though, I found that it was a very engaging topic and page presented.

===Hearing===

This is a well-formatted project page. There is a great balance and positioning of image and text information throughout. The way that the information, headings and subheadings are positioned made the contents flow and engaging. I especially found the image of the dog with the big ears, and the opening line of the introduction “Can you hear me!” drew me in as a reader. Just be sure in editing prior to the final assessment date that there are no grammatical errors, such as missing question marks (?).

Some of the uploaded images, such as the ‘normal cochlear’ image in the inner ear sub-heading of the development section, require, that information is attached stating the image was uploaded as part of a university assessment. The drawn or student edited drawings were well used and uploaded, having the appropriate summary and uploading information required.

The tables were very effective in presenting the information in a concise way, and I found that the summary box for the inner ear was well put together in highlighting the key points. Images still need to be uploaded prior to the final assessment date in the tables as indicated.

Finally, external links that are in the environment section and in some of the tables rows will need to be transferred to the external links section and appropriately numbered and formatted once in this sections.
The reference list is very well established, however, ensure that the template citation of reference 56 is correctly formatted before final project date.

==Lab 9 Assessment==

===Task 1===

A recent research review article, which was found in relation to development of the thyroid- endocrine organ, was The thyroid hormone responsive protein (THRP) has a critical role in the embryogenesis of Xenopus laevis. Though this article pertains to embryology of the frog, it highlights the significance THRP has in endocrine, and entire embryology through this animal model.

This article demonstrates the link between the endocrine system and neuronal embryogenesis and the effects that can occur if there are mutations or over expression of protein levels produced/controlled by the thyroid.
THRP normally is controlled and responsive via the thyroid gland. It is also a reading frame for expression of proteins and genes that are involved in c-Abl signaling (such as Abi-2), which contribute significantly to neuronal development. In this article, in vivo tests were performed, whereby THRP was expressed in vectors, during development, in order to establish the effect this neurotoxin protein had upon the neuronal development in Xenopus laevis (frogs). In places where there was over expression of THRP, tadpoles demonstrated severe malformations, which correlated to similar findings in previous mouse model studies mouse models, resulting in spinal chord deformation.

This demonstrates that the thyroid plays a significant role as a control and regulating centre for the expression and release of proteins such as THRP. Without its normal development and function, embryonic, neuronal development can be negatively effected, leading to postnatal deformities of the central nervous system (CNS).

====Reference====
<pubmed> 2109522</pubmed>

===Task 2===

Teeth develop embryonically through a balance between epithelial and ecto-mesenchyme (ectoderm) of the oropharyngeal cavity. Development also involves the neural crest and the first f the pharyngeal arches. Teeth begin development at week 6 (stage 16-17) and postnatal alterations and maturations occur.

Other tissues that are involved in teeth development are odontoblasts, which originate from the neural crest. Which are involved in bud formation of the tooth in initial week 6 developments. Odontoblasts secrete predentin, which when calcified becomes a potein called dentin, which work in conjunction with enamel (secreted by specific cells called ameloblasts), to strengthen and develop teeth.

When teeth form, they progress from an initial lamina layer, then progression to placode (dental) formations, and progress morphologically through bud formation, to cap and then finally to a bell shape; developing into the gum space beneath teeth. At the sites of dental placode formation, there is growth of epithelial cells, which will secrete elements such as enamel teeth strengthening.

Finally, many odontogenic genes are present in these stages, which allow for signaling and transcription factor activation and encoding of genes related to teeth development.

====Reference====
<pubmed>19266065</pubmed>

==Lab 11 Assessment==

User:Z3330539

2012-10-09T23:11:01Z

Z3330539: /* Lab Attendance */

== Lab Attendance ==

Lab 1--[[User:Z3330539|Z3330539]] 11:49, 25 July 2012 (EST)

Lab 2 [[User:Z3330539|Z3330539]] 10:52, 1 August 2012 (EST)

Lab 3 --[[User:Z3330539|Z3330539]] 10:04, 8 August 2012 (EST)--

Lab 4 --[[User:Z3330539|Z3330539]] 09:59, 15 August 2012 (EST)--

Lab 5 --[[User:Z3330539|Z3330539]] 10:10, 22 August 2012 (EST)--

Lab 6 --[[User:Z3330539|Z3330539]] 10:08, 29 August 2012 (EST)--

Lab 7 --[[User:Z3330539|Z3330539]] 10:14, 12 September 2012 (EST)--

Lab 8 --[[User:Z3330539|Z3330539]] 10:03, 19 September 2012 (EST)--

Lab 9 --[[User:Z3330539|Z3330539]] 10:08, 26 September 2012 (EST)--

Lab 10 --[[User:Z3330539|Z3330539]] 10:07, 3 October 2012 (EST)--

Lab 11 --[[User:Z3330539|Z3330539]] 10:10, 10 October 2012 (EST)--

==Lab 1 Assessment==
--[[User:Z8600021|Mark Hill]] 18:04, 10 September 2012 (EST) Please do not include spaces before your sub-headings as this will affect formatting. I have corrected Lab 1, please correct other subheadings yourself before final assessment.

===Task 1===

Identify the origin of In Vitro Fertilization and the 2010 Nobel Prize winner associated with this technique and add a correctly formatted link to the Nobel page.

-In Vitro Fertilization (IVF) technology is the combining/fusion of the males sperm and females egg/s outside the body, then later implanting this fertilized oocyte into the female uterus. This technique involves the regulation of the female cycle and monitoring of ovulation. This in vitro technique/concept has been present and studied for many years, with earliest recordings of such scientific research/findings; such test tube babies; occurring as early as 1950’s. The scientist who won the Nobel Prize in 2010, for his efforts and involvement in the discovery implementation of IVF techniques was the physiologist Robert Edwards. This was an honor given in the current medicine. Edwards with a fellow associate were the first recorded successful pregnancy and birth of the first and second IVF babies to be delivered in the late 1970’s and the 1980’s. Following this successful implantation, development and implantation other countries including Australia began to use this technique, for situations and individuals with fertility problems. Recent developments in this field of medicine and physiology have been on hormones involved in oocyte maturation, ovarian cycles such as follicle stimulating hormone, as well as the way in which sperm is administered in order for fertilization to occur.

Links: [1] [2]

===Task 2===

Identify and add a PubMed reference link to a recent paper on fertilization and describe its key findings (1-2 paragraphs).

- “Molecular Origin of Female Meiotic Aneuploidies”

This article addresses the molecular and physiological mechanisms underlying the abnormalities in pregnancy which occur as a result of aneuploidy. It discusses the disruption of the cohesion and separation of the homologues at the centromeres and the polar ends of the spindle, which can result in miscarriage and loss of pregnancy. Lack of separation of these homologues prevents the production of two separate daughter chromatids. These errors can occur either toward the end of meiosis one and also in meiosis two, and in some instances meiosis two errors can arise as a result of meiosis one errors that were not resolved. In this article, there is particular emphasis placed upon the process of female meiosis, as the major causes of errors that can lead to aneuploidy. Major errors which occur are reduced cohesion prior to separation in meiosis two, errors in trisomies, as well as premature segregation, resulting in errors of chromatid pairing and oocyte development in fertilization. Studies are being performed to examine the role, or lack of role which certain proteins play at these stages of female fertilization in order to reduce these abnormalities in conventional and IVF development, in particular in females who fall pregnant at later maternal ages. Examining the molecular mechanisms that occur when there is loss of expression of key proteins such as SMC1 alpha and beta, Scc1 and ReC8, which leads to decrease in cohesin and reduce achiasmate, ultimately leading to lack of separation of the homologues.

[3]

NB: Originally uploaded this into the discussion/my talk page, the night before, prior to moving it into my Page (z3330539).

--[[User:Z8600021|Mark Hill]] 18:04, 10 September 2012 (EST) Answers to the 2 questions are correct. I am concerned that the text in answer to question 1 appears to be from a source that has not been cited, could you please clarify this for me (for an extra mark). You have failed to transfer the citation links correctly from your discussion page to here, and the citation links located there are not correctly formatted. You have used UNSW Library links rather than the PubMed citation number or reference format as shown in the class (and below). '''7/10'''

As a reference number link - PMID 22841925

As a formatted reference - <pubmed>22841925</pubmed>

==Lab 2 Assessment==

====Task 1====
[[File:Immunofluorescent_FN1_and_integrin_on_blastocytes.gif]]

====Task2====

A protein which is involved in the implantation process is Rac1, which is the RAS pathway related C3 botulinum toxin substrate 1. This protein expression allows for embryonic trophoblasts to invade the stromal cell layer and when activated also allows for migration and motility of the cells of the stromal layer. All of these factors lead to the promotion of implantation.

[http://www.ncbi.nlm.nih.gov/pubmed/18838676]

--[[User:Z8600021|Mark Hill]] 18:22, 10 September 2012 (EST) Question 1 is not correctly linked to the appropriate reference, a serious error. Therefore you have not completed the assessment correctly, I will need to delete the image if you cannot fix the referencing and alter your mark accordingly. Image is also too small to be useful and in GIF format. Question 2 is fine, please see my previous assessment comment on referencing. '''6/10'''

As a reference number link - PMID 18838676

As a formatted reference - <pubmed>18838676</pubmed>

==Lab 3 Assessment==

====Task 1====

Gestational age refers to the period of time, generally 14 days before the last day of the females menstrual cycle. Where as post fertilization age is the period from the point of conception/ fertilization of egg by the sperm; this mainly occurs in the middle of the menstrual cycle duration.

Gestational age is used as a clinical method of human development due to the fact that time/point of fertilization can be unknown or variable, women may have sporadic menses and ovulation, females may not be able to recall the last day of their menstrual cycle. The use of gestational age may be an approximation/generalization, however, it is more useful in reducing the variables that can occur, which are mentioned above, as last day of menstrual cycle is predominately able to be recalled by the female, and 14 days are added in order to establish room for possible variations.

References:

1. [http://emedicine.medscape.com/article/259269-overview]

====Task 2====

Somites, which are present in pairs, are derived from the paraxial mesoderm and are involved in week 4 of embryonic development. Somites progressively differentiate into sclerotome, dermatome and myotome.

Sclerotome are the central cells of the somites are are located ventromedially in relation to orientation of the notochord. Sclerotome form vertebral and bone and connective of the vertebral column and are have chondrocytes present.

Dermatome are located dorsolaterally to the notochord and involved in the differentiation into dermis and epidermis.

Finally myotome are located more dorsomedially and are involved in differentiation to skeletal muscle. This involves myoblast cells. Depending on the type, these can either lie dorsomedially and then migrate to form epaxial or hypaxial muscle groups in development.

References:

1. [http://www.embryology.ch/anglais/mmuskel/skelett02.html]
2. [http://www.ncbi.nlm.nih.gov/books/NBK10085/]

--[[User:Z8600021|Mark Hill]] 18:30, 10 September 2012 (EST) Question 1 answer is correct, but your text is confusing in relation to LMP. Question 2 describes the correct somite components, and bone, CT and skeletal muscle. But you have incorrectly identified epidermis as mesoderm in origin, this is ectodermal and not from the somite. '''9/10'''

==Lab 4 Assessment==
====Task 1====

The placenta within the developing fetus performs many functions, via maternal-embryonic nutrient transfer and later embryo-fetal nutrient transfer. Early in development diagnostic tests are able to be performed in order to examine if there are any abnormalities, either genetic or hematological, for example, within the growing embryo. These test and consecutive results are able to be obtained through the placenta. Some techniques are non-invasive, while others can be invasive for the mother. Two test which are performed through placenta diagnostics are a chorion biopsy (chorion villus sampling) and umbilical cord blood sampling. These two prenatal tests are both invasive and involve extraction of tissue and blood samples via injection of a thin needle into either the maternal cervix or abdominal wall in order to reach the uterus and retrieve samples from the placenta or the umbilical cord (the end which lies close to the placenta or the umbilical vein). Once samples are collected they are them examined within laboratories and analyzed for developmental abnormalities.

Though there is partial risk of miscarriage, these tests have been found to be successful in diagnosis of abnormalities such as down syndrome and pathological blood disorders such as Rh disease. The defects in early cell division in the embryo, with specific reference to down syndrome (trisomy 21) can be detected, as well as the compatibility between maternal and embryonic blood in relation to Rh disease. This gives the ability to detect whether there will be a maternal immune response, as a result of lack of blood compatibility (i.e. maternal immune response triggered post birth of first delivered child).

References:

1. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166195/pdf/mxr008.pd]
2. [http://www.embryology.ch/anglais/jfetalperiod/diagno04.html]
3. [http://www.centrahealth.com/health-library]

====Task 2====

An article which discusses the possibilities for cord stems cells to be used in therapeutically is '''Human umbilical cord mesenchymal stem cells and the treatment of spinal cord injury'''.
This review article discusses the potential for umbilical cord stems cells to be used in the therapeutic treatment of spinal chord injury or disease.

Through analysis of resent findings, researchers have discovered the similar characteristic within cord stem cells that are found in bone marrow. Cord stem cells have been found to be an alternative source for mesenchymal stems cells, and therefore are seen as a promising alternative for transplantation procedures, as they are able to differentiate into numerous cells and tissues such as bone and cartilage; as well as self renewal and growth properties.
Furthermore, this area of research is being considered due to the fact that there are limitations surrounding transplantation of bone marrow mesenchymal cells, such as viral contraction and cellular amount.

The spinal cord consists of a complex molecular and cellular framework, such as astrocytes, microglia cells and myelin proteins. As a result of these many constituent, when the spine is injured or diseased, treatment is difficult due to the degenerative nature/course which these problems can occur. However, through the isolation of these cord stem cells from embryonic umbilical cord, treatment may be something that soon can be highly successful with further research and clinical development. Furthermore, isolation of these umbilcal cord stems cells are more ethically supported than isolation of bone marrow mensenchymal cells.

Further research and studies are required, however, due to the fact that some attempts, methods and techniques of recent isolations have failed. Furthermore, future areas of developmental research may include longitudinal and clinical research that can further increase awareness of umbilical cord mesenchymal cell transplantation as an alternative for complex injuries, such as those to the spinal cord.

References:
1. [http://www.ncbi.nlm.nih.gov/pubmed/19187651]
2. [http://www.cmj.org/Periodical/PDF/200911959717530.pdf]

--[[User:Z8600021|Mark Hill]] 16:27, 11 September 2012 (EST) Both these answers are excellent. '''10/10'''

===Lab 7 Assessment===

====Task 1====

a) Satellite cells are mononuclear progenitor cells that are involved in postnatal development and regeneration of skeletal muscle fibres.

b) Satellite cells can remain quiescent until they are activated by extracellular stimuli. The first example where satellite cells become activated is when there is local damage or injury to the muscles. The second example of where satellite cells can be activated is when muscles undergo hypertrophy. Although satellite cells do not have to be activated in order for muscle hypertrophy, studies have shown that they can become activated. In these cases satellite cells re-enter into the cell cycle, and myoblasts/myofibers proliferate in order to repair and/or replace cells during muscle loading or when cell injury occurs. <ref><pubmed>17213900</pubmed></ref>

====Task 2====

When motor neurons sustain a long-term injury to spinal chord studies have shown that muscle fibres undergo muscular atrophy; muscles fibres cells decrease. This muscle wasting is potentially the result of inactivation of muscles due to lack of synaptic signalling from main central conducting systems, such as the motor neurons of the spinal chord. <ref><pubmed>8265728</pubmed></ref>
Furthermore, post spinal chord injury results in a transformation of muscle fibres. Predominately these fibres consist of both type 1 (slow) and type 2 (fast) fibre patterning, however, slow twitch fibres; specifically Type IIB, become principal after motor neuron damage. This can result in lead to reduction in the amount of fat mass, therefore contribute to wasting and weight loss. <ref><pubmed>9044514</pubmed></ref>

'Reference List'

1. <pubmed>17213900</pubmed>

2. <pubmed>8265728</pubmed>

3. <pubmed>9044514</pubmed>

[http://athletics.wikia.com/wiki/Type_II_Muscle_Fiber]
[http://www.skeletalmusclejournal.com/content/1/1/7]

==Lab 8 Assessment: Peer/Group Evaluations==

===Vision===

There is a good balance of images and text throughout the page. Prior to final assessment the page outline and formatting of image and text positioning is required. The first image at the top the page, requires correct referencing and acknowledgement that it has been uploaded as part of a student assignment. This is also required for the image titled “Eyediagramcolour1”.

Since the previous lab, held in week 9, it is positive to see that the group has altered some of the uploaded image information, with particular reference to the self-drawn/uploaded images.

The area of the page which shows that there is a “useful links” heading and an external link within the current research section, should be placed or moved into the external links section at the bottom of the page with the appropriate information that Dr. Hill has required for placing external links on a page. Also, the references within the ‘current research’ section may also be required to be apart of the reference list.

I found this page visually appealing and I liked that this group have included an image gallery section. The use of the external links were appropriate to the topic and that the extent of the glossary for now is good, however, by the final evaluation would potentially need to be larger. Finally found that the headings for each segment of the broader topic were well positioned and relevant.

===Taste===

The page that you have created is very extensive and was well formatted in relation to the ratio of images to text on the page.
Found that the colours and use of table for the breakdown of information in relation to ‘Timeline of developmental process’ and ‘history of discoveries’ condensed the material and made it easily understandable. This made me want to keep reading.

With majority of the images that are uploaded onto the page there needs to be the correct information and referencing provided for the summary box. From where the image was sourced (ideally of reliable and scientific literature in origin), identifying that it has been uploaded for a student assignment and copyright information-permission to use uploaded image and any other information that is pertaining to the topic and why the image was used/relevant.
Further, those of you within your group that have drawn an uploaded image, have to ensure that you have stated in the summary box that it was student drawn prior to final assessment/evaluation.

The glossary is able to be expanded upon and potentially ensuring that the words that are being explained/elaborated are bolded. As a reader, I would find it easier to read and distinguish if they were bolded.
The reference list that has been developed appears to demonstrate that as a group you have are well read and researched, however, the citation errors will have to be addressed and resolved prior to final marking of the project. I really appreciated the layout (headings, summary and images) of the page.

===Olfaction===

For me this is one of the best projects of the 6 groups. It is extremely well researched, as seen through the extensive reference list. It is evident that the group has gone above and beyond, researching even more than required for the topic, or standards set by other groups, such as clinical approaches, and much information on current research.

I found that the formatting in the upper part of the page, specifically the section under the title ‘normal function’ was a bit awkward in relation to text and image positioning. It felt that it was not consistent with the flow of the rest of the page.
Also the first table may require an in-filled colour or even lines (can be a light or pale colour), just so each column and the single uploaded image is more defined and linked to the correct year/individual.

The ‘Choanal Atresia’ tomography image requires acknowledgement that the image was uploaded as part of a university assessment. However, really appreciated the breakdown of where the arrows were pointing and the relevance in relation to your specific topic.
Images for the tables need to be finalized and uploaded; ensuring that there is appropriate referencing, whether they are student drawn, or sourced from the literature.
Found that the student drawn diagrams were really detailed and easy to understand and appreciate. Each was also relevant to the topics, which they were linked/associated to.

===Abnormal Vision===

It was very good to see that this interesting topic has been well researched and that there are a number of references appropriately cited in the page.

Currently, there is a lot of text that, I as a reader, felt overwhelmed when assessing. More/larger images may need to be uploaded, or the correct formatting/resizing of existing images in order to potential rectify these concerns. It is noteworthy, however, that the ratio between text and imaging improves toward the bottom end of the page.
It was good to see that there was all relevant summary, referencing and uploading information for the images that were present. Keep in mind that there is an option, and we have been encouraged to upload images that have been student drawn.

The over all formatting of the page, besides being packed with written information, had a couple of spacing issues, from extreme spaces between the bullet point genes and consequent descriptions, in the ‘abnormal lens development section’, to virtually no singular spacing between the research timeline. in the ‘Genes’ section.

A way to aid to the above so that the page potentially is more visually appealing, is to place the genes and subsequent function into tables, or even placing the timeline information in a table form, or adding originality by actually placing this information on a timeline generated by one of the group members.
Overall though, I found that it was a very engaging topic and page presented.

===Hearing===

This is a well-formatted project page. There is a great balance and positioning of image and text information throughout. The way that the information, headings and subheadings are positioned made the contents flow and engaging. I especially found the image of the dog with the big ears, and the opening line of the introduction “Can you hear me!” drew me in as a reader. Just be sure in editing prior to the final assessment date that there are no grammatical errors, such as missing question marks (?).

Some of the uploaded images, such as the ‘normal cochlear’ image in the inner ear sub-heading of the development section, require, that information is attached stating the image was uploaded as part of a university assessment. The drawn or student edited drawings were well used and uploaded, having the appropriate summary and uploading information required.

The tables were very effective in presenting the information in a concise way, and I found that the summary box for the inner ear was well put together in highlighting the key points. Images still need to be uploaded prior to the final assessment date in the tables as indicated.

Finally, external links that are in the environment section and in some of the tables rows will need to be transferred to the external links section and appropriately numbered and formatted once in this sections.
The reference list is very well established, however, ensure that the template citation of reference 56 is correctly formatted before final project date.

==Lab 9 Assessment==

===Task 1===

A recent research review article, which was found in relation to development of the thyroid- endocrine organ, was The thyroid hormone responsive protein (THRP) has a critical role in the embryogenesis of Xenopus laevis. Though this article pertains to embryology of the frog, it highlights the significance THRP has in endocrine, and entire embryology through this animal model.

This article demonstrates the link between the endocrine system and neuronal embryogenesis and the effects that can occur if there are mutations or over expression of protein levels produced/controlled by the thyroid.
THRP normally is controlled and responsive via the thyroid gland. It is also a reading frame for expression of proteins and genes that are involved in c-Abl signaling (such as Abi-2), which contribute significantly to neuronal development. In this article, in vivo tests were performed, whereby THRP was expressed in vectors, during development, in order to establish the effect this neurotoxin protein had upon the neuronal development in Xenopus laevis (frogs). In places where there was over expression of THRP, tadpoles demonstrated severe malformations, which correlated to similar findings in previous mouse model studies mouse models, resulting in spinal chord deformation.

This demonstrates that the thyroid plays a significant role as a control and regulating centre for the expression and release of proteins such as THRP. Without its normal development and function, embryonic, neuronal development can be negatively effected, leading to postnatal deformities of the central nervous system (CNS).

====Reference====
<pubmed> 2109522</pubmed>

===Task 2===

Teeth develop embryonically through a balance between epithelial and ecto-mesenchyme (ectoderm) of the oropharyngeal cavity. Development also involves the neural crest and the first f the pharyngeal arches. Teeth begin development at week 6 (stage 16-17) and postnatal alterations and maturations occur.

Other tissues that are involved in teeth development are odontoblasts, which originate from the neural crest. Which are involved in bud formation of the tooth in initial week 6 developments. Odontoblasts secrete predentin, which when calcified becomes a potein called dentin, which work in conjunction with enamel (secreted by specific cells called ameloblasts), to strengthen and develop teeth.

When teeth form, they progress from an initial lamina layer, then progression to placode (dental) formations, and progress morphologically through bud formation, to cap and then finally to a bell shape; developing into the gum space beneath teeth. At the sites of dental placode formation, there is growth of epithelial cells, which will secrete elements such as enamel teeth strengthening.

Finally, many odontogenic genes are present in these stages, which allow for signaling and transcription factor activation and encoding of genes related to teeth development.

====Reference====
<pubmed>19266065</pubmed>

2012 Group Project 2

2012-10-04T21:50:04Z

Z3330539: /* Introduction */

=Somatosensory Development=

== Introduction ==

In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.<ref name="PMID23018205"><pubmed>23018205</pubmed></ref>
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.
Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. <ref name="PMID20956378"><pubmed>20956378 </pubmed></ref> <ref name="PMID16310064"><pubmed>16310064 </pubmed></ref>
[[File:Touch 2.JPG|thumb|400px| Touch]]

These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues.<ref name="PMID168272"><pubmed>168272</pubmed></ref>
Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.

To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces<ref name="PMID20956378"><pubmed>20956378</pubmed></ref><ref name="PMID16545520"><pubmed>16545520</pubmed></ref>
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.<ref name="PMID6203612"><pubmed>6203612</pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors <ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Cutaneous: Used for describing if a nerve, receptor or cell is affecting or associating with skin.
;Dermis: Layer of skin between the epidermis and subcutaneous tissue
;Dermal Papillae: Most superficial layer of the dermis
;Epidermis: Most exterior/outer layer of skin
;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Neutrophins: Neurotrphic growth factors – proteins supporting the growth and survival of neurons
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Schwann cells: Primary glia, non-neuronal cells. Supporting homeostasis in the body, neuron growth and formation of myelin.

== References ==
<references/>

==External Links==
{{External Links}}

[http://thediagram.com/3_1/pacinian.html Additional Pacinian Corpuscle Image 1]

[http://www.biologymad.com/nervoussystem/nerveimpulses.htm Additional Pacinian Corpuscle Image 2]

[http://www.siumed.edu/~dking2/intro/images/IN038b.jpg Additional Meissner Corpuscel Image 1]

[http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg Additional Meissner Corpuscle Image 2]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez Comparative study between encapsulated and capsulated nerve/receptor cells]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T21:46:53Z

Z3330539: /* External Links */

=Somatosensory Development=

== Introduction ==

In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.<ref name="PMID23018205"><pubmed>23018205</pubmed></ref>
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.
Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. <ref name="PMID20956378"><pubmed>20956378 </pubmed></ref>
[[File:Touch 2.JPG|thumb|400px| Touch]]

These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues.<ref name="PMID168272"><pubmed>168272</pubmed></ref>
Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.

To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces<ref name="PMID20956378"><pubmed>20956378</pubmed></ref><ref name="PMID16545520"><pubmed>16545520</pubmed></ref>
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.<ref name="PMID6203612"><pubmed>6203612</pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors <ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Cutaneous: Used for describing if a nerve, receptor or cell is affecting or associating with skin.
;Dermis: Layer of skin between the epidermis and subcutaneous tissue
;Dermal Papillae: Most superficial layer of the dermis
;Epidermis: Most exterior/outer layer of skin
;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Neutrophins: Neurotrphic growth factors – proteins supporting the growth and survival of neurons
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Schwann cells: Primary glia, non-neuronal cells. Supporting homeostasis in the body, neuron growth and formation of myelin.

== References ==
<references/>

==External Links==
{{External Links}}

[http://thediagram.com/3_1/pacinian.html Additional Pacinian Corpuscle Image 1]

[http://www.biologymad.com/nervoussystem/nerveimpulses.htm Additional Pacinian Corpuscle Image 2]

[http://www.siumed.edu/~dking2/intro/images/IN038b.jpg Additional Meissner Corpuscel Image 1]

[http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg Additional Meissner Corpuscle Image 2]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez Comparative study between encapsulated and capsulated nerve/receptor cells]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T21:44:35Z

Z3330539: /* External Links */

=Somatosensory Development=

== Introduction ==

In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.<ref name="PMID23018205"><pubmed>23018205</pubmed></ref>
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.
Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. <ref name="PMID20956378"><pubmed>20956378 </pubmed></ref>
[[File:Touch 2.JPG|thumb|400px| Touch]]

These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues.<ref name="PMID168272"><pubmed>168272</pubmed></ref>
Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.

To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces<ref name="PMID20956378"><pubmed>20956378</pubmed></ref><ref name="PMID16545520"><pubmed>16545520</pubmed></ref>
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.<ref name="PMID6203612"><pubmed>6203612</pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors <ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Cutaneous: Used for describing if a nerve, receptor or cell is affecting or associating with skin.
;Dermis: Layer of skin between the epidermis and subcutaneous tissue
;Dermal Papillae: Most superficial layer of the dermis
;Epidermis: Most exterior/outer layer of skin
;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Neutrophins: Neurotrphic growth factors – proteins supporting the growth and survival of neurons
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Schwann cells: Primary glia, non-neuronal cells. Supporting homeostasis in the body, neuron growth and formation of myelin.

== References ==
<references/>

==External Links==
{{External Links}}

[http://thediagram.com/3_1/pacinian.html Additional Pacinian Corpuscle Image 1]

[http://www.biologymad.com/nervoussystem/nerveimpulses.htm Additional Pacinian Corpuscle Image 2]

[http://www.siumed.edu/~dking2/intro/images/IN038b.jpg Additional Meissner Corpuscel Image 1]

[http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg Additional Meissner Corpuscle Image 2]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez Comparative study between encapsulated and capsulated nerve/receptor cells]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T21:42:19Z

Z3330539: /* External Links */

=Somatosensory Development=

== Introduction ==

In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.<ref name="PMID23018205"><pubmed>23018205</pubmed></ref>
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.
Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. <ref name="PMID20956378"><pubmed>20956378 </pubmed></ref>
[[File:Touch 2.JPG|thumb|400px| Touch]]

These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues.<ref name="PMID168272"><pubmed>168272</pubmed></ref>
Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.

To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces<ref name="PMID20956378"><pubmed>20956378</pubmed></ref><ref name="PMID16545520"><pubmed>16545520</pubmed></ref>
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.<ref name="PMID6203612"><pubmed>6203612</pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors <ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Cutaneous: Used for describing if a nerve, receptor or cell is affecting or associating with skin.
;Dermis: Layer of skin between the epidermis and subcutaneous tissue
;Dermal Papillae: Most superficial layer of the dermis
;Epidermis: Most exterior/outer layer of skin
;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Neutrophins: Neurotrphic growth factors – proteins supporting the growth and survival of neurons
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Schwann cells: Primary glia, non-neuronal cells. Supporting homeostasis in the body, neuron growth and formation of myelin.

== References ==
<references/>

==External Links==
{{External Links}}

[http://thediagram.com/3_1/pacinian.html Additional Pacinian Corpuscle Image 1]

[http://www.biologymad.com/nervoussystem/nerveimpulses.htm Additional Pacinian Corpuscle Image 2]

Links to Meissner’s Corpuscle Images

[http://www.siumed.edu/~dking2/intro/images/IN038b.jpg Additional Meissner Corpuscel Image 1]

[http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg Additional Meissner Corpuscle Image 2]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T21:32:37Z

Z3330539: /* Touch & Pressure */

=Somatosensory Development=

== Introduction ==

In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.<ref name="PMID23018205"><pubmed>23018205</pubmed></ref>
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.
Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. <ref name="PMID20956378"><pubmed>20956378 </pubmed></ref>
[[File:Touch 2.JPG|thumb|400px| Touch]]

These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues.<ref name="PMID168272"><pubmed>168272</pubmed></ref>
Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.

To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces<ref name="PMID20956378"><pubmed>20956378</pubmed></ref><ref name="PMID16545520"><pubmed>16545520</pubmed></ref>
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.<ref name="PMID6203612"><pubmed>6203612</pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors <ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Cutaneous: Used for describing if a nerve, receptor or cell is affecting or associating with skin.
;Dermis: Layer of skin between the epidermis and subcutaneous tissue
;Dermal Papillae: Most superficial layer of the dermis
;Epidermis: Most exterior/outer layer of skin
;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Neutrophins: Neurotrphic growth factors – proteins supporting the growth and survival of neurons
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Schwann cells: Primary glia, non-neuronal cells. Supporting homeostasis in the body, neuron growth and formation of myelin.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T21:29:39Z

Z3330539: /* Glossary */

=Somatosensory Development=

== Introduction ==

In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.<ref name="PMID23018205"><pubmed>23018205</pubmed></ref>
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.
Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. <ref name="PMID20956378"><pubmed>20956378 </pubmed></ref>
[[File:Touch 2.JPG|thumb|400px| Touch]]

These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues.<ref name="PMID168272"><pubmed>168272</pubmed></ref>
Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.

To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.<ref name="PMID6203612"><pubmed>6203612</pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Cutaneous: Used for describing if a nerve, receptor or cell is affecting or associating with skin.
;Dermis: Layer of skin between the epidermis and subcutaneous tissue
;Dermal Papillae: Most superficial layer of the dermis
;Epidermis: Most exterior/outer layer of skin
;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Neutrophins: Neurotrphic growth factors – proteins supporting the growth and survival of neurons
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Schwann cells: Primary glia, non-neuronal cells. Supporting homeostasis in the body, neuron growth and formation of myelin.

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T16:41:30Z

Z3330539: /* Touch & Pressure */

=Somatosensory Development=

== Introduction ==

In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.<ref name="PMID23018205"><pubmed>23018205</pubmed></ref>
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.
Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. <ref name="PMID20956378"><pubmed>20956378 </pubmed></ref>
[[File:Touch 2.JPG|thumb|400px| Touch]]

These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues.<ref name="PMID168272"><pubmed>168272</pubmed></ref>
Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.

To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.<ref name="PMID6203612"><pubmed>6203612</pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T16:30:33Z

Z3330539: /* Introduction */

=Somatosensory Development=

== Introduction ==

In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.<ref name="PMID23018205"><pubmed>23018205</pubmed></ref>
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.
Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. <ref name="PMID20956378"><pubmed>20956378 </pubmed></ref>
[[File:Touch 2.JPG|thumb|400px| Touch]]

These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues.<ref name="PMID168272"><pubmed>168272</pubmed></ref>
Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.

To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T16:29:21Z

Z3330539: /* Introduction */

=Somatosensory Development=

== Introduction ==

In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.<ref name="PMID23018205"><pubmed>23018205</pubmed></ref>
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.
Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. <ref name="PMID20956378"><pubmed>20956378 </pubmed></ref>
[[File:Touch 2.JPG|thumb|390px| Touch]]

These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues.<ref name="PMID168272"><pubmed>168272</pubmed></ref>
Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.

To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T16:19:54Z

Z3330539: /* Introduction */

=Somatosensory Development=

== Introduction ==

In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.<ref name="PMID23018205"><pubmed>23018205</pubmed></ref>
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.
Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. <ref name="PMID20956378"><pubmed>20956378 </pubmed></ref>

These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues.<ref name="PMID168272"><pubmed>168272</pubmed></ref>
Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.

To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

File:Touch 2.JPG

2012-10-04T16:15:06Z

Z3330539: Somatosensory: Touch Student Image -~~~~ I,~~~~, will not allow this image to be reproduced in any way without written permission/consent.

Somatosensory: Touch

Student Image -[[User:Z3330539|Z3330539]] 02:15, 5 October 2012 (EST)

I,[[User:Z3330539|Z3330539]] 02:15, 5 October 2012 (EST), will not allow this image to be reproduced in any way without written permission/consent.

File:Touch1.JPG

2012-10-04T16:11:08Z

Z3330539:

'''Somatosensory: Touch'''

Student Image -[[User:Z3330539|Z3330539]] 02:10, 5 October 2012 (EST)-

I, [[User:Z3330539|Z3330539]] 02:10, 5 October 2012 (EST), will not allow this image to be reproduced in any way without written permission/consent.

File:Touch1.JPG

2012-10-04T16:10:20Z

Z3330539: "Somatosensory: Touch" Student Image -~~~~- I, ~~~~, will not allow this image to be reproduced in any way without written permission/consent.

"Somatosensory: Touch"

Student Image -[[User:Z3330539|Z3330539]] 02:10, 5 October 2012 (EST)-

I, [[User:Z3330539|Z3330539]] 02:10, 5 October 2012 (EST), will not allow this image to be reproduced in any way without written permission/consent.

2012 Group Project 2

2012-10-04T16:04:25Z

Z3330539: /* Introduction */

=Somatosensory Development=

== Introduction ==

In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.<ref name="PMID23018205"><pubmed>23018205</pubmed></ref>
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.
Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. <ref name="PMID20956378"><pubmed>20956378 </pubmed></ref>

These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues. PMID:168272
Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.

To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T16:03:17Z

Z3330539: /* Introduction */

=Somatosensory Development=

== Introduction ==

In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.<ref name="PMID23018205"><pubmed>23018205</pubmed></ref>
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.
Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. <ref name="PMID20956378"><pubmed>20956378 </pubmed></ref>

These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues. PMID:168272
Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.

To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T15:59:22Z

Z3330539: /* Introduction */

=Somatosensory Development=

== Introduction ==

In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.<ref name="PMID23018205"><pubmed>23018205</pubmed></ref>
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.
Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. <ref name="PMID20956378"><pubmed>20956378 </pubmed></ref>

These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues. PMID:168272
Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.

To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T15:57:00Z

Z3330539: /* Introduction */

=Somatosensory Development=

== Introduction ==

In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.<ref name="PMID23018205"><pubmed>23018205</pubmed></ref>
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.
Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. <ref name="PMID20956378"><pubmed>20956378 </pubmed></ref>

These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues. PMID:168272
Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.
To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T15:53:20Z

Z3330539: /* Introduction */

=Somatosensory Development=

== Introduction ==
In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system.

The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature. PMID: 23018205
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.

Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. PMID:20956378
These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues. PMID:168272

Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS) PMID:2918087

Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.

To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T14:15:38Z

Z3330539: /* The Rapidly Adapting Pressure Receptors */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T14:06:27Z

Z3330539: /* Touch & Pressure */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
Development is dependent on sensory innervations.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T13:59:53Z

Z3330539: /* Touch & Pressure */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found superficially in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
*Large abundance at the joints
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T13:56:57Z

Z3330539: /* Touch & Pressure */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T13:49:07Z

Z3330539: /* Touch & Pressure */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T13:47:39Z

Z3330539: /* The Rapidly Adapting Pressure Receptors */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|Pressure Receptor positions in glabrous skin]]

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T13:44:02Z

Z3330539: /* Pressure */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|Pressure Receptor positions in glabrous skin]]

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T13:41:51Z

Z3330539: /* The Rapidly Adapting Pressure Receptors */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|Pressure Receptor positions in glabrous skin]]

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T13:40:56Z

Z3330539: /* The Rapidly Adapting Pressure Receptors */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>
[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|Pressure Receptor positions in glabrous skin]]

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T13:38:13Z

Z3330539: /* Pressure */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T13:34:37Z

Z3330539: /* The Rapidly Adapting Pressure Receptors */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T13:31:32Z

Z3330539: /* The Rapidly Adapting Pressure Receptors */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref>

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T13:28:46Z

Z3330539: /* Pressure */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. [53] All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref>

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T13:24:54Z

Z3330539: /* Pressure */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin.

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. [53] All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref>

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T13:21:51Z

Z3330539: /* Touch & Pressure */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin.

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. [53] All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref>

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change. [57]

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T13:17:06Z

Z3330539: /* The Rapidly Adapting Pressure Receptors */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin.

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.[55] In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. [53] All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref><pubmed>1244282</pubmed></ref>

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change. [57]

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 2

2012-10-04T13:10:22Z

Z3330539: /* Pressure */

=Somatosensory Development=

== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010). The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.

(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
Understanding the development of this systems both structurally and functionally during the fetal life is crucial in understanding how a fetus develops the capacity to receive and experience sensations delivered by thermal, mechanical, tactile and noxious stimuli (Willis, 2007).

The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.

This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.

== History of Discoveries ==
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007). Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion. The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system. Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord. The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).

{| width=600px
|-bgcolor="CEDFF2"
| width=50px|'''Date'''
| width=300px|'''Description'''
|-
| '''1875'''
| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
|-bgcolor="F5FAFF"
| '''1906'''
| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses. Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
|-
| '''1947'''
| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
|-bgcolor="F5FAFF"
| '''1969'''
| Two types of fibres responsible for nociception were identied. Afferent fibres with myelinated axons that give sharp pains were named A delta fibres (Aδ). Unmyelinated fibres that produced slow burning pain were named type C fibres
|-
|placeholder
|}

== Central Somatosensory Differentiation ==

====Adult Central Somatosensory systems:====

Ascending components of the Central Somatosensory system include;
* the primary somatosensory cortex of the brain,
* the trigeminal system: – receives sensory signals from the face; <ref name="PMID8440772"><pubmed> 8440772</pubmed></ref>
* the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. <ref name="PMID14485390"><pubmed> 14485390</pubmed></ref> <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

'''Dorsal column system and Lateral Spinothalamic tract:'''

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>

[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]

'''Trigeminal System:'''

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.<ref name="PMID7962713"><pubmed>7962713</pubmed></ref>

==== Development of the Primary Somatosensory Cortex:====

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. <ref name="PMID10764649"><pubmed>10764649</pubmed></ref> Development of this region begins in late embryonic period and continues post-natally. The primary somatosensory cortex has separate functional groups of layer IV neurons called ‘barrels’. <ref name="PMID4141363"><pubmed>4141363</pubmed></ref> In the adult, the barrels are arranged in a pattern, isomorphic to the pattern of somatosensory receptors on the face and body surface (see figure). <ref name="PMID7721983"><pubmed>7721983</pubmed></ref> This patterning of the somatosensory cortex is the key step in its development. These layer IV neuron barrels receive inputs from the afferents coming from the ventroposterior nucleus (VP) thalamus and the posterior thalamic complex (POm). <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref> The extrinsic signalling by the VP and POm afferents from the thalamus may cause graded gene expression in the cortical neurons to pattern the somatosensory cortex. <ref name="PMID2461788"><pubmed>2461788</pubmed></ref>

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> The VP afferents receiving information from the face and jaw differentiate before birth. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Then the lateral regions of the somatosensory cortex develop. Within 24hrs after birth, the VP afferents receiving sensory information from the rest of the body develops. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. <ref name="PMID7962713"><pubmed>7962713</pubmed></ref> Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 23;
* Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>

== Touch & Pressure ==
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]

The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>

The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
<br />
<br />
<br />
<br />
<br />
<br />

<table>
{| width=100%
|-bgcolor= "FF9900 " "align="center"
| width= 15%|'''Mechanoreceptors'''
| width= 25%|'''Function'''
| width= 25%|'''Embryonic Development'''
| width= 10%|'''Degree/Extent of Response'''
| width= 25%|'''Image'''
|-bgcolor="FFFF99"

|'''Pacinian Corpuscles (lamellar corpuscles)'''
|
*Found in subcutaneous tissue of skin
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
* Detection between rough and smooth surfaces
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
|-bgcolor="FFCC66"
|'''Meissner's Corpuscles'''
|
*Found in the dermal papillae under the epidermal layer of the skin
*Respond to detection and changes of vibrations
*Very sensitive, detection of light touch sensations
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
|-bgcolor="FFFF99"
|'''Merkel-cell Neurite Complexes'''
|
* Found in epidermal layer of skin in stratum basale
*Responding to light touch sensations
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
|-bgcolor="FFCC66"
|'''Ruffini Endings'''
|
*Found in the dermal and subcutaneous layers of skin
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]
|-bgcolor="FFFF99"
|'''Hair follicles'''
|
*Response to movement/displacement of hair on the skin

*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
|-bgcolor="FFCC66"
</table>

===Pressure===

The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.

===='''The Slow Adapting Pressure Receptors'''====

Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.

'''Merkel Disc'''

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin.

'''Ruffiini Endings'''

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.[55] In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.

===='''The Rapidly Adapting Pressure Receptors'''====

Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.

'''Pacinian Corpuscles'''

Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. [53] All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.

'''Meissner’s Corpuscles'''

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle. [54]

'''Pressure Receptors Influencing Major Organs in The Body'''

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change. [57]

 Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

===Genes Involved in Embryonic Development===

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>

'''c-Maf'''

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

'''Shox2'''

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>

== Pain ==

'''Pain-sensing receptors are often referred to as nociceptors.''' <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>

==== Development of Nociceptors - Summary ====

Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.

{| cellpadding="10"
|-style="background:#FF69B4" "align="center"
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''
| width=15%|'''Nociceptor Development'''
|-bgcolor="pink"
|''' E11.5''' in Mouse
|'''Day 33; Stage 14'''
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="#FFE4E1"
|'''E11-13''' in Mouse
|'''Days 30-42; Stage 13-17'''
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
|'''E14''' in Rat
|'''Day 40; Stage 16'''
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="#FFE4E1"
|''' E14.5''' in Mouse
|'''Day 52; Stage 20'''
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
|''' E15-17''' in Rat
|'''Days 44-55; Stage 21-22'''
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E17''' in Rat
|'''Day 55; Stage 22'''
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
|-bgcolor="pink"
|'''E18.5''' in Rat
|'''Fetal Stages'''
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''E18-20''' in Mouse
|'''Fetal Stages'''
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|-bgcolor="pink"
|'''P2''' in Mouse
|'''Fetal Stages'''
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="#FFE4E1"
|'''P4-10''' in Rat
|'''Fetal Stages'''
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
|}

====Details of Nociceptor Development====

'''1. Nociceptor Specification:'''

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>

[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]

'''2. Nociceptor Survival'''

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>

[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]

'''3. Growth of Axons - to the Spinal Cord and Periphery'''

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
* PIK3 and Akt – increase the Diameter of the Axons
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>

Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>

[[File:Axon growth.JPG|500px|Axon Growth]]

'''4. Determination of the Physiological Phenotype of Nociceptors'''

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>

'''5. Development of the Chemical Phenotype of Nociceptors'''

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.

[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]

'''6. Increase in the Nociceptor Innervation Density '''

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>

[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]

'''7. Increase in Nociceptor Sensitivity'''

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>

== Hot/Cold ==

In addition to sensory modalities such as pressure and pain, the human body is able to detect the temperature of its surrounding environment. This is called thermoreception, and is extremely important for a variety of reasons. The ability to sense temperature is important for maintaining homeostasis in many biological processes. It is also of practical safety use, we are able to reliably avoid stimuli that are either too hot or too cold and may do us harm.

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels<ref name="PMID12838328"><pubmed>12838328</pubmed></ref>. We will refer to them as ThermoTRP’s. These receptors are able to generate action potentials in response to changes in temperatures in the environment surrounding the nerve ending in the skin. The nerve impulse generated by these receptors is conveyed along the nerve fibre and into the dorsal root ganglion. There are two main types of ThermoTRP, those that are activated by warm stimuli and those that are activated by cold stimuli<ref name="PMID12838328"/>.

===Warm===

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
*''TRPV4''. Activated at 27 – 34 ˚C.

===Cold===

Cold thermoreceptors essentially work in an identical manner to warm thermoreceptors. Instead of being activating by rising temperatures, they are stimulated by falling temperatures. There are two main receptors responsible for perception of cold stimuli.

*''TRPM8''. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
*''ANKTM1''. Noxious or damaging cold temperatures are those at or below the 17 ˚C mark. These extreme temperatures are able to activate the ANKTM1 receptor<ref name="PMID12838328"/>.

===Embryology and Development===

[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]

The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.

RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.

A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

== Pressure ==
Pressure receptors can be categorized into two groups, the slow adapting receptors and rapidly adapting receptors. Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin. Rapidly adapting receptors, however, only respond to changes in pressure, so they respond when the stimulus first touches the skin and when it is removed. There are four types of pressure receptors in the skin, Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings.

Pacinian corpuscles are rapidly adapting receptors found in the deeper layers of the skin. Their nerve endings are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. These particular corpuscles form in the dermis, hypodermis, the surfaces of muscle and tendons. Their development is dependent on sensory innervations and they begin to appear during the fourth fetal month of development. <ref><pubmed>1244282</pubmed></ref> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]

Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well-localised and specific. They are superficially located, found in the dermal papillae, between the epidermal pegs of glabrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the subepidermal nerve plexus that lose their myelination as they enter the corpuscle. <ref><pubmed> 15470674</pubmed></ref>

Ruffini endings are encapsulated,cutaneous, slow adapting type II receptors that respond to consistent pressure. They are located deeply within the dermis of both hairy and glabrous skin. They are known to be innervated by A-beta fibres and to have large receptive fields similar to the Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref><pubmed> 10759411</pubmed></ref> They are most abundant at the joints, where they convey signals dealing with both pressure and angle of the joints. Ruffini endings however, though dealing with pressure, their main focus would be stretch of the skin, as their surrounding collagen fibres are parallel to the skin and therefore are highly affected by such a sensation.

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They are superficially located in the epidermal basal layer of the skin, and only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. The development of Merkel cells however is still unclear. Theories suggest that they may have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocytes.<ref><pubmed>21456507</pubmed></ref>

The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hering from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall which in turn activates the baroreceptors which send a signal conveying this change. <ref><pubmed>709739</pubmed></ref>

Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.

== Abnormalities of the Somatosensory Development ==

'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''

{| cellpadding="10"
|-style="background:#00FFFF" "align="center"
| width= 5%|'''Disease'''
| width= 15%|'''Description of Disease'''
| width= 20%|'''Cause of Disease and Link to Embryology'''
|- bgcolor="#AFEEEE"
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
|- bgcolor="#E0FFFF"
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
|-bgcolor="#AFEEEE"
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
|}

== Current Research ==

==== Somatosensory Activation by Corneal Pain:====

[[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]

Investigation is currently done on to localize somatotopic representation of pain from the cornea. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This type of research gives insight into the mechanism of chronic pain development in various eye conditions. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. <ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> The region of the somatosensory cortex that deals with corneal pain, also deals with blinking or photophobia. Such finding has been achieved using functional Magnetic Resonance Imaging (fMRI).<ref name="PMIDPMC3433421"><pubmed>PMC3433421</pubmed></ref> See figure

==== Sleep can Remodel the Somatosensory Cortex ====

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref> It was found that elimination of these filopodia occurred at a higher rate during sleep. <ref name="PMID22058046"><pubmed>22058046</pubmed></ref>

== Glossary ==

;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]

== References ==
<references/>

==External Links==
{{External Links}}

Link to Pacinian Corpuscle image

1. http://thediagram.com/3_1/pacinian.html

2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm

Links to Meissner’s Corpuscle Images

1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg

2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg

[http://neuroscience.uth.tmc.edu/s2/chapter02.html]

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]

[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}