https://embryology.med.unsw.edu.au/embryology/api.php?action=feedcontributions&feedformat=atom&user=Z3375390 2026-09-26T18:18:33Z User contributions MediaWiki 1.39.10 https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3375390&diff=107461 2012-10-16T13:52:26Z

<p>Z3375390: /* Lab 11 Assessment */</p> <hr /> <div><br /> == Lab Attendance ==<br /> <br /> <br /> Lab 1 --[[User:Z3375390|Z3375390]] 11:49, 25 July 2012 (EST)<br /> <br /> Lab 2 --[[User:Z3375390|Z3375390]] 10:40, 1 August 2012 (EST)<br /> <br /> Lab 3 --[[User:Z3375390|Z3375390]] 10:07, 8 August 2012 (EST)<br /> <br /> Lab 4 --[[User:Z3375390|Z3375390]] 10:07, 15 August 2012 (EST)<br /> <br /> Lab 5 --[[User:Z3375390|Z3375390]] 10:07, 22 August 2012 (EST)<br /> <br /> Lab 6 --[[User:Z3375390|Z3375390]] 10:07, 29 August 2012 (EST)<br /> <br /> Lab 7 --[[User:Z3375390|Z3375390]] 10:01, 12 September 2012 (EST)<br /> <br /> Lab 8 --[[User:Z3375390|Z3375390]] 10:05, 19 September 2012 (EST)<br /> <br /> Lab 9 --[[User:Z3375390|Z3375390]] 11:21, 26 September 2012 (EST)<br /> <br /> Lab 10 --[[User:Z3375390|Z3375390]] 10:44, 3 October 2012 (EST)<br /> <br /> Lab 11 --[[User:Z3375390|Z3375390]] 10:09, 10 October 2012 (EST)<br /> <br /> ==Lab Assignments==<br /> ===Lab 1 Assessment===<br /> <br /> 1. The idea of In Vitro Fertilisation was influenced by the study of fertilisation of rabbit egg cells in test tubes. However as the cycle of human eggs is different to that of rabbits, further study and experimentation had to be done in order to achieve it. The first successful birth of an IVF baby occurred in 1978. <br /> Robert G. Edwards was awarded the Nobel Prize in 2010 for the development of In Vitro Fertilisation. <br /> [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]<br /> <br /> <br /> ===Lab 2 Assessment===<br /> <br /> An important protein associated with the process of implantation is Rac1. It is of the RhoGTPases family of proteins, and aids the embryonic trophoblast with invasion of the endometrium. Together with a protein known as RhoA, they are able to regulate cell migration and motility. It has been proven that motility is required in order for the trophoblast to invade the endometrium and for the embryo to be implanted within the uterine wall.<br /> Rac1 is needed as it promotes the trophoblast invasion. However, as this process must be tightly controlled, the protein RhoA is needed in order to restrict it. Therefore a balance between the two proteins must be achieved for successful implantation of the embryo in the endometrium.<br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562412/<br /> <br /> ===Lab 3 Assessment===<br /> <br /> 1.Gestational age refers to the time between the end of the mother’s last menstrual cycle and the birth of the baby. It is measured in weeks and determined by the size of the fetus using ultrasound before birth. After birth it is determined by the babies weight, length and other features. Postfertilization age refers to the time passed since fertilization of the egg. The exact time of fertilization however cannot be determined, so therefore it is inferred. Usually, gestational age is two weeks longer than postfertilization age.<br /> <br /> Gestational age is used when describing human development as it can be clearly determined and hence the calculations are more accurate than postfertilizaton age. <br /> <br /> 2.Some of the tissues formed from the somites include skeletal muscle, skin and bone.<br /> <br /> * Skeletal muscle<br /> ** Skeletal muscle cells develop from the myotome<br /> ** Myoblasts undergo frequent division and merging in order to form myotubes<br /> ** As development of the muscle cells continues, the nuclei move from the centre to the periphery of the cell.<br /> * Dermis of the dorsal skin<br /> ** Develops from dermatome and wandering mesenchymal cells<br /> ** Lies between the epidermis and the hypodermis<br /> ** Collagen producing fibroblasts are found in the dermis<br /> ** Composed of two layer: <br /> *** Papillary layer <br /> *** Reticular layer – made of dense irregular connective tissue<br /> * Vertebrae<br /> ** Develops from sclerotome<br /> <br /> ===Lab 4 Assessment===<br /> 1. Invasive prenatal diagnostic techniques:<br /> *Amniocentesis<br /> **This procedure consists of a needle being inserted into the mothers lower abdomen and through to the amniotic cavity<br /> **Usually performed between weeks 14 and 20 when there is enough amniotic fluid present for the procedure to be successful <br /> **Fetal cells acquired from the amniotic fluid are grown in culture for analysis of chromosomes, biochemicals and molecular biology<br /> **Amniotic fluid can also be used to determine the maturity of the fetal lung in the third trimester<br /> **Fetal loss and maternal Rh sensitisation are risks associated with this procedure<br /> **It also increases fetal mortality rate by 0.5%<br /> *Chorionic Villus Sampling<br /> **Consists of a catheter passing through the cervix and into the uterus usualy via the vagina<br /> **Cells acquired from the placental chorionic villi are used in chromosome analysis in order to determine the karyotype of the fetus, can also be used for biochemical and molecular biologic analysis<br /> **Usually performed between weeks 9 and 13 of gestation<br /> **Limb defects in a fetus is an abnormality associated with CVS <br /> **It may also increase the morbidity rate of the fetus<br /> <br /> <br /> 2. Preterm delivered infants are at high risk of developing a chronic lung disease known as Bronchopulmonary Dysplasia (BPD). This abnormality arises after ventilator and oxygen therapy for respiratory failure, which is usually associated with premature birth. Indicators of BPD include arrested alveolar growth and lung vascular growth. These abnormalities continue after childhood, putting lung structure and function at risk. Arrested alveolar growth, onset emphysema and pulmonary hypertension have all been linked to BPD and preterm delivery. Hence it is important to understand the developmental procedure of alveoli and the underlying capillary network in order to develop therapies for lung diseases characterised by impaired alveolarization. Research of stem cells shows that cell-based treatments are possible to repair the damaged organs.<br /> <br /> Stem cells have been found to be capable of self-renewal and have the potential to differentiate into multiple cellular phenotypes. They play a very important role in organ repair and tissue regeneration throughout the life span of an organism. Embryonic stem cells are the most potent form of stem cells as they are able to differentiate into cell types derived from the mesoderm, endoderm and ectoderm. They are also capable extensive self-renewal. Adult stem cells however are very limited in the sense that they can only differentiated into a certain number of cell types and sometimes only one. Embryonic stem cells are therefore very useful in cell-replacement therapy. <br /> <br /> Embryonic stem cells could be used to regenerate lung cells destroyed by disease and injury. BPD could lead to a deficiency of Adult Stem Cells within the lung that contribute to the growth and maintenance of the alveoli, lung matrix and pulmonary microvasculature. Therefore, if these injured and limited cells were to be replaced with EBC's that could repopulate and help with lung growth, the lung can once again carry out its function.<br /> <br /> ===Lab 7 Assessment===<br /> <br /> 1. a) Muscle satellite cells are dormant cells located between the plasma membrane and the basement membrane of the muscle fibres. They function in maintenance, regeneration and growth of skeletal muscle. <br /> <br /> b) Satellite cells are activated after a period of prolonged exercise, their responsiveness influences muscle adaptations. In cases of muscle injury, satellite cells are activated. They then proliferate and fuse together to form new muscle fibres.<br /> <br /> 2. Injury or death of motor neurons generally results in the denervation of the muscle fibres. This means that muscles are no longer able to function as they used to and hence the muscle cells will undergo atrophy and may eventually die. Or, an adjacent neuron may reinnervate the muscle fibres. Muscle atrophy leads to a decrease in muscle mass which results in an increase of fat storage and decrease of metabolic rate.<br /> <br /> ===Lab 8 Assessment===<br /> <br /> Vision:<br /> Good introduction, introduces the main components of the eye that will assumedly be focused on when talking about development. More information is needed in the history section however and the images used also need copyright permission.<br /> <br /> Wording is simple and understandable, it’s also good to see that you guys have a glossary up so to make it easier to comprehend what is being read. However you need more information under current research. Also you should focus on the other components of the eye other than the Optic nerve and the Retina and add more pictures or diagrams to illustrate what it is you’re explaining.<br /> <br /> You should also try using some dot points because reading long paragraphs could get tiring and allow the person to lose focus.<br /> <br /> <br /> Taste:<br /> The overall set up of the page I think is very good. In the introduction there is a balance between pictures and text which makes it a bit easier to read. Also its easy to follow, the text itself isn’t confusing and is understandable.<br /> <br /> There is a good overview of the different types of receptors and their function, also there is a brief section on the adult tongue which is good, however there needs to be more focus on the embryological development rather than just a simple table on that. There also needs to be some images added to that component as well to make it more understandable. <br /> <br /> The sections on abnormalities and current research need to be organised a bit better because they are a little hard to follow, especially with the placing of the images. The glossary is simple and understandable, however there needs to be more work done on the reference list. <br /> <br /> <br /> Olfaction:<br /> The work needs to be spell checked before you submit it, make sure you get all your grammar right as well. I think you should add more to your introduction, and make it a little simpler, easier to follow. Also throughout your project you tend to use a lot of long paragraphs, especially in the current research section.<br /> <br /> Though the developmental timeline that is set up is very detailed, it can be a bit hard to follow and a little confusing. There is too much text and no pictures at all to help demonstrate what is being said about the development. The ratio of images to text in the anatomy and abnormalities sections however is very good and makes it more interesting to read. <br /> <br /> It’s good to see that you have some external links put up on the page and also that you’ve used quite a few references to do your research rather than just a few. <br /> <br /> <br /> Abnormal Vision:<br /> The text on this page is very good, detailed and to the point. However a lot more images are needed on the page to make it more appealing, interesting and easier to follow. <br /> <br /> The section under Ocular Manifestations is a little difficult to keep track of, there needs to be more of an introduction in that section highlighting the two sections that are to be discussed, then there should be a clear division between the two. <br /> <br /> Also the placement of the few images on the page need to be organised a little better. The referencing on this page is done very well and its good to see an extensive use of resources. <br /> <br /> <br /> Hearing:<br /> This whole page I think is done really well. There is a balance between texts and images, it goes through the developmental process in detail, all information is relevant, there is an extensive use of resources and a pretty good glossary as well. <br /> The image right at the beginning of the dog is very smart as it draws attention to the whole page. Also the “Can you hear me” at the beginning gives the expectation that the page as a whole is going to be really good so I thought that was very effective. <br /> More information can be added to the current research section, and also you should try referencing throughout the entire page could be done a little better.<br /> <br /> <br /> ===Lab 9 Assessment===<br /> <br /> 2. The cells that form the tooth bud originate from the ectomesenchyme, the neural crest and the ectoderm. The embryonic development first begins late in stage 18. The tooth buds are formed via interaction between the neural crest and the ectoderm. The ectomesenchume surrounds the tooth bud and forms the dental follicle.<br /> <br /> ===Lab 11 Assessment===<br /> This journal article looks at ways that stem cells could be used in therapeutic cell transplantation and regeneration within the myocardium of the heart. Some studies have shown that adult stem cells have the ability to improve the myocardium though only for a short time. Therefore there is a need for a cell type that is able to provide long-lasting engraftment and myogenesis, such iPS cells.<br /> <br /> It concluded that a combination of surface markers could identify and enrich stem cell derived transcription factors with trilineage cardiovascular potential in vitro and also the ability to fragment and differentiate into mature adult cardiomyocytes.<br /> <br /> &lt;ref&gt;&lt;pubmed&gt;23056209&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;references/&gt;</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3375390&diff=107460 2012-10-16T13:52:06Z

<p>Z3375390: /* Lab 11 Assessment */</p> <hr /> <div><br /> == Lab Attendance ==<br /> <br /> <br /> Lab 1 --[[User:Z3375390|Z3375390]] 11:49, 25 July 2012 (EST)<br /> <br /> Lab 2 --[[User:Z3375390|Z3375390]] 10:40, 1 August 2012 (EST)<br /> <br /> Lab 3 --[[User:Z3375390|Z3375390]] 10:07, 8 August 2012 (EST)<br /> <br /> Lab 4 --[[User:Z3375390|Z3375390]] 10:07, 15 August 2012 (EST)<br /> <br /> Lab 5 --[[User:Z3375390|Z3375390]] 10:07, 22 August 2012 (EST)<br /> <br /> Lab 6 --[[User:Z3375390|Z3375390]] 10:07, 29 August 2012 (EST)<br /> <br /> Lab 7 --[[User:Z3375390|Z3375390]] 10:01, 12 September 2012 (EST)<br /> <br /> Lab 8 --[[User:Z3375390|Z3375390]] 10:05, 19 September 2012 (EST)<br /> <br /> Lab 9 --[[User:Z3375390|Z3375390]] 11:21, 26 September 2012 (EST)<br /> <br /> Lab 10 --[[User:Z3375390|Z3375390]] 10:44, 3 October 2012 (EST)<br /> <br /> Lab 11 --[[User:Z3375390|Z3375390]] 10:09, 10 October 2012 (EST)<br /> <br /> ==Lab Assignments==<br /> ===Lab 1 Assessment===<br /> <br /> 1. The idea of In Vitro Fertilisation was influenced by the study of fertilisation of rabbit egg cells in test tubes. However as the cycle of human eggs is different to that of rabbits, further study and experimentation had to be done in order to achieve it. The first successful birth of an IVF baby occurred in 1978. <br /> Robert G. Edwards was awarded the Nobel Prize in 2010 for the development of In Vitro Fertilisation. <br /> [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]<br /> <br /> <br /> ===Lab 2 Assessment===<br /> <br /> An important protein associated with the process of implantation is Rac1. It is of the RhoGTPases family of proteins, and aids the embryonic trophoblast with invasion of the endometrium. Together with a protein known as RhoA, they are able to regulate cell migration and motility. It has been proven that motility is required in order for the trophoblast to invade the endometrium and for the embryo to be implanted within the uterine wall.<br /> Rac1 is needed as it promotes the trophoblast invasion. However, as this process must be tightly controlled, the protein RhoA is needed in order to restrict it. Therefore a balance between the two proteins must be achieved for successful implantation of the embryo in the endometrium.<br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562412/<br /> <br /> ===Lab 3 Assessment===<br /> <br /> 1.Gestational age refers to the time between the end of the mother’s last menstrual cycle and the birth of the baby. It is measured in weeks and determined by the size of the fetus using ultrasound before birth. After birth it is determined by the babies weight, length and other features. Postfertilization age refers to the time passed since fertilization of the egg. The exact time of fertilization however cannot be determined, so therefore it is inferred. Usually, gestational age is two weeks longer than postfertilization age.<br /> <br /> Gestational age is used when describing human development as it can be clearly determined and hence the calculations are more accurate than postfertilizaton age. <br /> <br /> 2.Some of the tissues formed from the somites include skeletal muscle, skin and bone.<br /> <br /> * Skeletal muscle<br /> ** Skeletal muscle cells develop from the myotome<br /> ** Myoblasts undergo frequent division and merging in order to form myotubes<br /> ** As development of the muscle cells continues, the nuclei move from the centre to the periphery of the cell.<br /> * Dermis of the dorsal skin<br /> ** Develops from dermatome and wandering mesenchymal cells<br /> ** Lies between the epidermis and the hypodermis<br /> ** Collagen producing fibroblasts are found in the dermis<br /> ** Composed of two layer: <br /> *** Papillary layer <br /> *** Reticular layer – made of dense irregular connective tissue<br /> * Vertebrae<br /> ** Develops from sclerotome<br /> <br /> ===Lab 4 Assessment===<br /> 1. Invasive prenatal diagnostic techniques:<br /> *Amniocentesis<br /> **This procedure consists of a needle being inserted into the mothers lower abdomen and through to the amniotic cavity<br /> **Usually performed between weeks 14 and 20 when there is enough amniotic fluid present for the procedure to be successful <br /> **Fetal cells acquired from the amniotic fluid are grown in culture for analysis of chromosomes, biochemicals and molecular biology<br /> **Amniotic fluid can also be used to determine the maturity of the fetal lung in the third trimester<br /> **Fetal loss and maternal Rh sensitisation are risks associated with this procedure<br /> **It also increases fetal mortality rate by 0.5%<br /> *Chorionic Villus Sampling<br /> **Consists of a catheter passing through the cervix and into the uterus usualy via the vagina<br /> **Cells acquired from the placental chorionic villi are used in chromosome analysis in order to determine the karyotype of the fetus, can also be used for biochemical and molecular biologic analysis<br /> **Usually performed between weeks 9 and 13 of gestation<br /> **Limb defects in a fetus is an abnormality associated with CVS <br /> **It may also increase the morbidity rate of the fetus<br /> <br /> <br /> 2. Preterm delivered infants are at high risk of developing a chronic lung disease known as Bronchopulmonary Dysplasia (BPD). This abnormality arises after ventilator and oxygen therapy for respiratory failure, which is usually associated with premature birth. Indicators of BPD include arrested alveolar growth and lung vascular growth. These abnormalities continue after childhood, putting lung structure and function at risk. Arrested alveolar growth, onset emphysema and pulmonary hypertension have all been linked to BPD and preterm delivery. Hence it is important to understand the developmental procedure of alveoli and the underlying capillary network in order to develop therapies for lung diseases characterised by impaired alveolarization. Research of stem cells shows that cell-based treatments are possible to repair the damaged organs.<br /> <br /> Stem cells have been found to be capable of self-renewal and have the potential to differentiate into multiple cellular phenotypes. They play a very important role in organ repair and tissue regeneration throughout the life span of an organism. Embryonic stem cells are the most potent form of stem cells as they are able to differentiate into cell types derived from the mesoderm, endoderm and ectoderm. They are also capable extensive self-renewal. Adult stem cells however are very limited in the sense that they can only differentiated into a certain number of cell types and sometimes only one. Embryonic stem cells are therefore very useful in cell-replacement therapy. <br /> <br /> Embryonic stem cells could be used to regenerate lung cells destroyed by disease and injury. BPD could lead to a deficiency of Adult Stem Cells within the lung that contribute to the growth and maintenance of the alveoli, lung matrix and pulmonary microvasculature. Therefore, if these injured and limited cells were to be replaced with EBC's that could repopulate and help with lung growth, the lung can once again carry out its function.<br /> <br /> ===Lab 7 Assessment===<br /> <br /> 1. a) Muscle satellite cells are dormant cells located between the plasma membrane and the basement membrane of the muscle fibres. They function in maintenance, regeneration and growth of skeletal muscle. <br /> <br /> b) Satellite cells are activated after a period of prolonged exercise, their responsiveness influences muscle adaptations. In cases of muscle injury, satellite cells are activated. They then proliferate and fuse together to form new muscle fibres.<br /> <br /> 2. Injury or death of motor neurons generally results in the denervation of the muscle fibres. This means that muscles are no longer able to function as they used to and hence the muscle cells will undergo atrophy and may eventually die. Or, an adjacent neuron may reinnervate the muscle fibres. Muscle atrophy leads to a decrease in muscle mass which results in an increase of fat storage and decrease of metabolic rate.<br /> <br /> ===Lab 8 Assessment===<br /> <br /> Vision:<br /> Good introduction, introduces the main components of the eye that will assumedly be focused on when talking about development. More information is needed in the history section however and the images used also need copyright permission.<br /> <br /> Wording is simple and understandable, it’s also good to see that you guys have a glossary up so to make it easier to comprehend what is being read. However you need more information under current research. Also you should focus on the other components of the eye other than the Optic nerve and the Retina and add more pictures or diagrams to illustrate what it is you’re explaining.<br /> <br /> You should also try using some dot points because reading long paragraphs could get tiring and allow the person to lose focus.<br /> <br /> <br /> Taste:<br /> The overall set up of the page I think is very good. In the introduction there is a balance between pictures and text which makes it a bit easier to read. Also its easy to follow, the text itself isn’t confusing and is understandable.<br /> <br /> There is a good overview of the different types of receptors and their function, also there is a brief section on the adult tongue which is good, however there needs to be more focus on the embryological development rather than just a simple table on that. There also needs to be some images added to that component as well to make it more understandable. <br /> <br /> The sections on abnormalities and current research need to be organised a bit better because they are a little hard to follow, especially with the placing of the images. The glossary is simple and understandable, however there needs to be more work done on the reference list. <br /> <br /> <br /> Olfaction:<br /> The work needs to be spell checked before you submit it, make sure you get all your grammar right as well. I think you should add more to your introduction, and make it a little simpler, easier to follow. Also throughout your project you tend to use a lot of long paragraphs, especially in the current research section.<br /> <br /> Though the developmental timeline that is set up is very detailed, it can be a bit hard to follow and a little confusing. There is too much text and no pictures at all to help demonstrate what is being said about the development. The ratio of images to text in the anatomy and abnormalities sections however is very good and makes it more interesting to read. <br /> <br /> It’s good to see that you have some external links put up on the page and also that you’ve used quite a few references to do your research rather than just a few. <br /> <br /> <br /> Abnormal Vision:<br /> The text on this page is very good, detailed and to the point. However a lot more images are needed on the page to make it more appealing, interesting and easier to follow. <br /> <br /> The section under Ocular Manifestations is a little difficult to keep track of, there needs to be more of an introduction in that section highlighting the two sections that are to be discussed, then there should be a clear division between the two. <br /> <br /> Also the placement of the few images on the page need to be organised a little better. The referencing on this page is done very well and its good to see an extensive use of resources. <br /> <br /> <br /> Hearing:<br /> This whole page I think is done really well. There is a balance between texts and images, it goes through the developmental process in detail, all information is relevant, there is an extensive use of resources and a pretty good glossary as well. <br /> The image right at the beginning of the dog is very smart as it draws attention to the whole page. Also the “Can you hear me” at the beginning gives the expectation that the page as a whole is going to be really good so I thought that was very effective. <br /> More information can be added to the current research section, and also you should try referencing throughout the entire page could be done a little better.<br /> <br /> <br /> ===Lab 9 Assessment===<br /> <br /> 2. The cells that form the tooth bud originate from the ectomesenchyme, the neural crest and the ectoderm. The embryonic development first begins late in stage 18. The tooth buds are formed via interaction between the neural crest and the ectoderm. The ectomesenchume surrounds the tooth bud and forms the dental follicle.<br /> <br /> ===Lab 11 Assessment===<br /> This journal article looks at ways that stem cells could be used in therapeutic cell transplantation and regeneration within the myocardium of the heart. Some studies have shown that adult stem cells have the ability to improve the myocardium though only for a short time. Therefore there is a need for a cell type that is able to provide long-lasting engraftment and myogenesis, such iPS cells.<br /> <br /> It concluded that a combination of surface markers could identify and enrich stem cell derived transcription factors with trilineage cardiovascular potential in vitro and also the ability to fragment and differentiate into mature adult cardiomyocytes.<br /> <br /> &lt;ref&gt;&lt;pubmed&gt;23056209&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;/references&gt;</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3375390&diff=107459 2012-10-16T13:51:27Z

<p>Z3375390: /* Lab 11 Assessment */</p> <hr /> <div><br /> == Lab Attendance ==<br /> <br /> <br /> Lab 1 --[[User:Z3375390|Z3375390]] 11:49, 25 July 2012 (EST)<br /> <br /> Lab 2 --[[User:Z3375390|Z3375390]] 10:40, 1 August 2012 (EST)<br /> <br /> Lab 3 --[[User:Z3375390|Z3375390]] 10:07, 8 August 2012 (EST)<br /> <br /> Lab 4 --[[User:Z3375390|Z3375390]] 10:07, 15 August 2012 (EST)<br /> <br /> Lab 5 --[[User:Z3375390|Z3375390]] 10:07, 22 August 2012 (EST)<br /> <br /> Lab 6 --[[User:Z3375390|Z3375390]] 10:07, 29 August 2012 (EST)<br /> <br /> Lab 7 --[[User:Z3375390|Z3375390]] 10:01, 12 September 2012 (EST)<br /> <br /> Lab 8 --[[User:Z3375390|Z3375390]] 10:05, 19 September 2012 (EST)<br /> <br /> Lab 9 --[[User:Z3375390|Z3375390]] 11:21, 26 September 2012 (EST)<br /> <br /> Lab 10 --[[User:Z3375390|Z3375390]] 10:44, 3 October 2012 (EST)<br /> <br /> Lab 11 --[[User:Z3375390|Z3375390]] 10:09, 10 October 2012 (EST)<br /> <br /> ==Lab Assignments==<br /> ===Lab 1 Assessment===<br /> <br /> 1. The idea of In Vitro Fertilisation was influenced by the study of fertilisation of rabbit egg cells in test tubes. However as the cycle of human eggs is different to that of rabbits, further study and experimentation had to be done in order to achieve it. The first successful birth of an IVF baby occurred in 1978. <br /> Robert G. Edwards was awarded the Nobel Prize in 2010 for the development of In Vitro Fertilisation. <br /> [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]<br /> <br /> <br /> ===Lab 2 Assessment===<br /> <br /> An important protein associated with the process of implantation is Rac1. It is of the RhoGTPases family of proteins, and aids the embryonic trophoblast with invasion of the endometrium. Together with a protein known as RhoA, they are able to regulate cell migration and motility. It has been proven that motility is required in order for the trophoblast to invade the endometrium and for the embryo to be implanted within the uterine wall.<br /> Rac1 is needed as it promotes the trophoblast invasion. However, as this process must be tightly controlled, the protein RhoA is needed in order to restrict it. Therefore a balance between the two proteins must be achieved for successful implantation of the embryo in the endometrium.<br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562412/<br /> <br /> ===Lab 3 Assessment===<br /> <br /> 1.Gestational age refers to the time between the end of the mother’s last menstrual cycle and the birth of the baby. It is measured in weeks and determined by the size of the fetus using ultrasound before birth. After birth it is determined by the babies weight, length and other features. Postfertilization age refers to the time passed since fertilization of the egg. The exact time of fertilization however cannot be determined, so therefore it is inferred. Usually, gestational age is two weeks longer than postfertilization age.<br /> <br /> Gestational age is used when describing human development as it can be clearly determined and hence the calculations are more accurate than postfertilizaton age. <br /> <br /> 2.Some of the tissues formed from the somites include skeletal muscle, skin and bone.<br /> <br /> * Skeletal muscle<br /> ** Skeletal muscle cells develop from the myotome<br /> ** Myoblasts undergo frequent division and merging in order to form myotubes<br /> ** As development of the muscle cells continues, the nuclei move from the centre to the periphery of the cell.<br /> * Dermis of the dorsal skin<br /> ** Develops from dermatome and wandering mesenchymal cells<br /> ** Lies between the epidermis and the hypodermis<br /> ** Collagen producing fibroblasts are found in the dermis<br /> ** Composed of two layer: <br /> *** Papillary layer <br /> *** Reticular layer – made of dense irregular connective tissue<br /> * Vertebrae<br /> ** Develops from sclerotome<br /> <br /> ===Lab 4 Assessment===<br /> 1. Invasive prenatal diagnostic techniques:<br /> *Amniocentesis<br /> **This procedure consists of a needle being inserted into the mothers lower abdomen and through to the amniotic cavity<br /> **Usually performed between weeks 14 and 20 when there is enough amniotic fluid present for the procedure to be successful <br /> **Fetal cells acquired from the amniotic fluid are grown in culture for analysis of chromosomes, biochemicals and molecular biology<br /> **Amniotic fluid can also be used to determine the maturity of the fetal lung in the third trimester<br /> **Fetal loss and maternal Rh sensitisation are risks associated with this procedure<br /> **It also increases fetal mortality rate by 0.5%<br /> *Chorionic Villus Sampling<br /> **Consists of a catheter passing through the cervix and into the uterus usualy via the vagina<br /> **Cells acquired from the placental chorionic villi are used in chromosome analysis in order to determine the karyotype of the fetus, can also be used for biochemical and molecular biologic analysis<br /> **Usually performed between weeks 9 and 13 of gestation<br /> **Limb defects in a fetus is an abnormality associated with CVS <br /> **It may also increase the morbidity rate of the fetus<br /> <br /> <br /> 2. Preterm delivered infants are at high risk of developing a chronic lung disease known as Bronchopulmonary Dysplasia (BPD). This abnormality arises after ventilator and oxygen therapy for respiratory failure, which is usually associated with premature birth. Indicators of BPD include arrested alveolar growth and lung vascular growth. These abnormalities continue after childhood, putting lung structure and function at risk. Arrested alveolar growth, onset emphysema and pulmonary hypertension have all been linked to BPD and preterm delivery. Hence it is important to understand the developmental procedure of alveoli and the underlying capillary network in order to develop therapies for lung diseases characterised by impaired alveolarization. Research of stem cells shows that cell-based treatments are possible to repair the damaged organs.<br /> <br /> Stem cells have been found to be capable of self-renewal and have the potential to differentiate into multiple cellular phenotypes. They play a very important role in organ repair and tissue regeneration throughout the life span of an organism. Embryonic stem cells are the most potent form of stem cells as they are able to differentiate into cell types derived from the mesoderm, endoderm and ectoderm. They are also capable extensive self-renewal. Adult stem cells however are very limited in the sense that they can only differentiated into a certain number of cell types and sometimes only one. Embryonic stem cells are therefore very useful in cell-replacement therapy. <br /> <br /> Embryonic stem cells could be used to regenerate lung cells destroyed by disease and injury. BPD could lead to a deficiency of Adult Stem Cells within the lung that contribute to the growth and maintenance of the alveoli, lung matrix and pulmonary microvasculature. Therefore, if these injured and limited cells were to be replaced with EBC's that could repopulate and help with lung growth, the lung can once again carry out its function.<br /> <br /> ===Lab 7 Assessment===<br /> <br /> 1. a) Muscle satellite cells are dormant cells located between the plasma membrane and the basement membrane of the muscle fibres. They function in maintenance, regeneration and growth of skeletal muscle. <br /> <br /> b) Satellite cells are activated after a period of prolonged exercise, their responsiveness influences muscle adaptations. In cases of muscle injury, satellite cells are activated. They then proliferate and fuse together to form new muscle fibres.<br /> <br /> 2. Injury or death of motor neurons generally results in the denervation of the muscle fibres. This means that muscles are no longer able to function as they used to and hence the muscle cells will undergo atrophy and may eventually die. Or, an adjacent neuron may reinnervate the muscle fibres. Muscle atrophy leads to a decrease in muscle mass which results in an increase of fat storage and decrease of metabolic rate.<br /> <br /> ===Lab 8 Assessment===<br /> <br /> Vision:<br /> Good introduction, introduces the main components of the eye that will assumedly be focused on when talking about development. More information is needed in the history section however and the images used also need copyright permission.<br /> <br /> Wording is simple and understandable, it’s also good to see that you guys have a glossary up so to make it easier to comprehend what is being read. However you need more information under current research. Also you should focus on the other components of the eye other than the Optic nerve and the Retina and add more pictures or diagrams to illustrate what it is you’re explaining.<br /> <br /> You should also try using some dot points because reading long paragraphs could get tiring and allow the person to lose focus.<br /> <br /> <br /> Taste:<br /> The overall set up of the page I think is very good. In the introduction there is a balance between pictures and text which makes it a bit easier to read. Also its easy to follow, the text itself isn’t confusing and is understandable.<br /> <br /> There is a good overview of the different types of receptors and their function, also there is a brief section on the adult tongue which is good, however there needs to be more focus on the embryological development rather than just a simple table on that. There also needs to be some images added to that component as well to make it more understandable. <br /> <br /> The sections on abnormalities and current research need to be organised a bit better because they are a little hard to follow, especially with the placing of the images. The glossary is simple and understandable, however there needs to be more work done on the reference list. <br /> <br /> <br /> Olfaction:<br /> The work needs to be spell checked before you submit it, make sure you get all your grammar right as well. I think you should add more to your introduction, and make it a little simpler, easier to follow. Also throughout your project you tend to use a lot of long paragraphs, especially in the current research section.<br /> <br /> Though the developmental timeline that is set up is very detailed, it can be a bit hard to follow and a little confusing. There is too much text and no pictures at all to help demonstrate what is being said about the development. The ratio of images to text in the anatomy and abnormalities sections however is very good and makes it more interesting to read. <br /> <br /> It’s good to see that you have some external links put up on the page and also that you’ve used quite a few references to do your research rather than just a few. <br /> <br /> <br /> Abnormal Vision:<br /> The text on this page is very good, detailed and to the point. However a lot more images are needed on the page to make it more appealing, interesting and easier to follow. <br /> <br /> The section under Ocular Manifestations is a little difficult to keep track of, there needs to be more of an introduction in that section highlighting the two sections that are to be discussed, then there should be a clear division between the two. <br /> <br /> Also the placement of the few images on the page need to be organised a little better. The referencing on this page is done very well and its good to see an extensive use of resources. <br /> <br /> <br /> Hearing:<br /> This whole page I think is done really well. There is a balance between texts and images, it goes through the developmental process in detail, all information is relevant, there is an extensive use of resources and a pretty good glossary as well. <br /> The image right at the beginning of the dog is very smart as it draws attention to the whole page. Also the “Can you hear me” at the beginning gives the expectation that the page as a whole is going to be really good so I thought that was very effective. <br /> More information can be added to the current research section, and also you should try referencing throughout the entire page could be done a little better.<br /> <br /> <br /> ===Lab 9 Assessment===<br /> <br /> 2. The cells that form the tooth bud originate from the ectomesenchyme, the neural crest and the ectoderm. The embryonic development first begins late in stage 18. The tooth buds are formed via interaction between the neural crest and the ectoderm. The ectomesenchume surrounds the tooth bud and forms the dental follicle.<br /> <br /> ===Lab 11 Assessment===<br /> This journal article looks at ways that stem cells could be used in therapeutic cell transplantation and regeneration within the myocardium of the heart. Some studies have shown that adult stem cells have the ability to improve the myocardium though only for a short time. Therefore there is a need for a cell type that is able to provide long-lasting engraftment and myogenesis, such iPS cells.<br /> <br /> It concluded that a combination of surface markers could identify and enrich stem cell derived transcription factors with trilineage cardiovascular potential in vitro and also the ability to fragment and differentiate into mature adult cardiomyocytes.<br /> <br /> &lt;ref&gt;&lt;pubmed&gt;23056209&lt;/pubmed&gt;&lt;/ref&gt;</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3375390&diff=107458 2012-10-16T13:47:42Z

<p>Z3375390: </p> <hr /> <div><br /> == Lab Attendance ==<br /> <br /> <br /> Lab 1 --[[User:Z3375390|Z3375390]] 11:49, 25 July 2012 (EST)<br /> <br /> Lab 2 --[[User:Z3375390|Z3375390]] 10:40, 1 August 2012 (EST)<br /> <br /> Lab 3 --[[User:Z3375390|Z3375390]] 10:07, 8 August 2012 (EST)<br /> <br /> Lab 4 --[[User:Z3375390|Z3375390]] 10:07, 15 August 2012 (EST)<br /> <br /> Lab 5 --[[User:Z3375390|Z3375390]] 10:07, 22 August 2012 (EST)<br /> <br /> Lab 6 --[[User:Z3375390|Z3375390]] 10:07, 29 August 2012 (EST)<br /> <br /> Lab 7 --[[User:Z3375390|Z3375390]] 10:01, 12 September 2012 (EST)<br /> <br /> Lab 8 --[[User:Z3375390|Z3375390]] 10:05, 19 September 2012 (EST)<br /> <br /> Lab 9 --[[User:Z3375390|Z3375390]] 11:21, 26 September 2012 (EST)<br /> <br /> Lab 10 --[[User:Z3375390|Z3375390]] 10:44, 3 October 2012 (EST)<br /> <br /> Lab 11 --[[User:Z3375390|Z3375390]] 10:09, 10 October 2012 (EST)<br /> <br /> ==Lab Assignments==<br /> ===Lab 1 Assessment===<br /> <br /> 1. The idea of In Vitro Fertilisation was influenced by the study of fertilisation of rabbit egg cells in test tubes. However as the cycle of human eggs is different to that of rabbits, further study and experimentation had to be done in order to achieve it. The first successful birth of an IVF baby occurred in 1978. <br /> Robert G. Edwards was awarded the Nobel Prize in 2010 for the development of In Vitro Fertilisation. <br /> [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]<br /> <br /> <br /> ===Lab 2 Assessment===<br /> <br /> An important protein associated with the process of implantation is Rac1. It is of the RhoGTPases family of proteins, and aids the embryonic trophoblast with invasion of the endometrium. Together with a protein known as RhoA, they are able to regulate cell migration and motility. It has been proven that motility is required in order for the trophoblast to invade the endometrium and for the embryo to be implanted within the uterine wall.<br /> Rac1 is needed as it promotes the trophoblast invasion. However, as this process must be tightly controlled, the protein RhoA is needed in order to restrict it. Therefore a balance between the two proteins must be achieved for successful implantation of the embryo in the endometrium.<br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562412/<br /> <br /> ===Lab 3 Assessment===<br /> <br /> 1.Gestational age refers to the time between the end of the mother’s last menstrual cycle and the birth of the baby. It is measured in weeks and determined by the size of the fetus using ultrasound before birth. After birth it is determined by the babies weight, length and other features. Postfertilization age refers to the time passed since fertilization of the egg. The exact time of fertilization however cannot be determined, so therefore it is inferred. Usually, gestational age is two weeks longer than postfertilization age.<br /> <br /> Gestational age is used when describing human development as it can be clearly determined and hence the calculations are more accurate than postfertilizaton age. <br /> <br /> 2.Some of the tissues formed from the somites include skeletal muscle, skin and bone.<br /> <br /> * Skeletal muscle<br /> ** Skeletal muscle cells develop from the myotome<br /> ** Myoblasts undergo frequent division and merging in order to form myotubes<br /> ** As development of the muscle cells continues, the nuclei move from the centre to the periphery of the cell.<br /> * Dermis of the dorsal skin<br /> ** Develops from dermatome and wandering mesenchymal cells<br /> ** Lies between the epidermis and the hypodermis<br /> ** Collagen producing fibroblasts are found in the dermis<br /> ** Composed of two layer: <br /> *** Papillary layer <br /> *** Reticular layer – made of dense irregular connective tissue<br /> * Vertebrae<br /> ** Develops from sclerotome<br /> <br /> ===Lab 4 Assessment===<br /> 1. Invasive prenatal diagnostic techniques:<br /> *Amniocentesis<br /> **This procedure consists of a needle being inserted into the mothers lower abdomen and through to the amniotic cavity<br /> **Usually performed between weeks 14 and 20 when there is enough amniotic fluid present for the procedure to be successful <br /> **Fetal cells acquired from the amniotic fluid are grown in culture for analysis of chromosomes, biochemicals and molecular biology<br /> **Amniotic fluid can also be used to determine the maturity of the fetal lung in the third trimester<br /> **Fetal loss and maternal Rh sensitisation are risks associated with this procedure<br /> **It also increases fetal mortality rate by 0.5%<br /> *Chorionic Villus Sampling<br /> **Consists of a catheter passing through the cervix and into the uterus usualy via the vagina<br /> **Cells acquired from the placental chorionic villi are used in chromosome analysis in order to determine the karyotype of the fetus, can also be used for biochemical and molecular biologic analysis<br /> **Usually performed between weeks 9 and 13 of gestation<br /> **Limb defects in a fetus is an abnormality associated with CVS <br /> **It may also increase the morbidity rate of the fetus<br /> <br /> <br /> 2. Preterm delivered infants are at high risk of developing a chronic lung disease known as Bronchopulmonary Dysplasia (BPD). This abnormality arises after ventilator and oxygen therapy for respiratory failure, which is usually associated with premature birth. Indicators of BPD include arrested alveolar growth and lung vascular growth. These abnormalities continue after childhood, putting lung structure and function at risk. Arrested alveolar growth, onset emphysema and pulmonary hypertension have all been linked to BPD and preterm delivery. Hence it is important to understand the developmental procedure of alveoli and the underlying capillary network in order to develop therapies for lung diseases characterised by impaired alveolarization. Research of stem cells shows that cell-based treatments are possible to repair the damaged organs.<br /> <br /> Stem cells have been found to be capable of self-renewal and have the potential to differentiate into multiple cellular phenotypes. They play a very important role in organ repair and tissue regeneration throughout the life span of an organism. Embryonic stem cells are the most potent form of stem cells as they are able to differentiate into cell types derived from the mesoderm, endoderm and ectoderm. They are also capable extensive self-renewal. Adult stem cells however are very limited in the sense that they can only differentiated into a certain number of cell types and sometimes only one. Embryonic stem cells are therefore very useful in cell-replacement therapy. <br /> <br /> Embryonic stem cells could be used to regenerate lung cells destroyed by disease and injury. BPD could lead to a deficiency of Adult Stem Cells within the lung that contribute to the growth and maintenance of the alveoli, lung matrix and pulmonary microvasculature. Therefore, if these injured and limited cells were to be replaced with EBC's that could repopulate and help with lung growth, the lung can once again carry out its function.<br /> <br /> ===Lab 7 Assessment===<br /> <br /> 1. a) Muscle satellite cells are dormant cells located between the plasma membrane and the basement membrane of the muscle fibres. They function in maintenance, regeneration and growth of skeletal muscle. <br /> <br /> b) Satellite cells are activated after a period of prolonged exercise, their responsiveness influences muscle adaptations. In cases of muscle injury, satellite cells are activated. They then proliferate and fuse together to form new muscle fibres.<br /> <br /> 2. Injury or death of motor neurons generally results in the denervation of the muscle fibres. This means that muscles are no longer able to function as they used to and hence the muscle cells will undergo atrophy and may eventually die. Or, an adjacent neuron may reinnervate the muscle fibres. Muscle atrophy leads to a decrease in muscle mass which results in an increase of fat storage and decrease of metabolic rate.<br /> <br /> ===Lab 8 Assessment===<br /> <br /> Vision:<br /> Good introduction, introduces the main components of the eye that will assumedly be focused on when talking about development. More information is needed in the history section however and the images used also need copyright permission.<br /> <br /> Wording is simple and understandable, it’s also good to see that you guys have a glossary up so to make it easier to comprehend what is being read. However you need more information under current research. Also you should focus on the other components of the eye other than the Optic nerve and the Retina and add more pictures or diagrams to illustrate what it is you’re explaining.<br /> <br /> You should also try using some dot points because reading long paragraphs could get tiring and allow the person to lose focus.<br /> <br /> <br /> Taste:<br /> The overall set up of the page I think is very good. In the introduction there is a balance between pictures and text which makes it a bit easier to read. Also its easy to follow, the text itself isn’t confusing and is understandable.<br /> <br /> There is a good overview of the different types of receptors and their function, also there is a brief section on the adult tongue which is good, however there needs to be more focus on the embryological development rather than just a simple table on that. There also needs to be some images added to that component as well to make it more understandable. <br /> <br /> The sections on abnormalities and current research need to be organised a bit better because they are a little hard to follow, especially with the placing of the images. The glossary is simple and understandable, however there needs to be more work done on the reference list. <br /> <br /> <br /> Olfaction:<br /> The work needs to be spell checked before you submit it, make sure you get all your grammar right as well. I think you should add more to your introduction, and make it a little simpler, easier to follow. Also throughout your project you tend to use a lot of long paragraphs, especially in the current research section.<br /> <br /> Though the developmental timeline that is set up is very detailed, it can be a bit hard to follow and a little confusing. There is too much text and no pictures at all to help demonstrate what is being said about the development. The ratio of images to text in the anatomy and abnormalities sections however is very good and makes it more interesting to read. <br /> <br /> It’s good to see that you have some external links put up on the page and also that you’ve used quite a few references to do your research rather than just a few. <br /> <br /> <br /> Abnormal Vision:<br /> The text on this page is very good, detailed and to the point. However a lot more images are needed on the page to make it more appealing, interesting and easier to follow. <br /> <br /> The section under Ocular Manifestations is a little difficult to keep track of, there needs to be more of an introduction in that section highlighting the two sections that are to be discussed, then there should be a clear division between the two. <br /> <br /> Also the placement of the few images on the page need to be organised a little better. The referencing on this page is done very well and its good to see an extensive use of resources. <br /> <br /> <br /> Hearing:<br /> This whole page I think is done really well. There is a balance between texts and images, it goes through the developmental process in detail, all information is relevant, there is an extensive use of resources and a pretty good glossary as well. <br /> The image right at the beginning of the dog is very smart as it draws attention to the whole page. Also the “Can you hear me” at the beginning gives the expectation that the page as a whole is going to be really good so I thought that was very effective. <br /> More information can be added to the current research section, and also you should try referencing throughout the entire page could be done a little better.<br /> <br /> <br /> ===Lab 9 Assessment===<br /> <br /> 2. The cells that form the tooth bud originate from the ectomesenchyme, the neural crest and the ectoderm. The embryonic development first begins late in stage 18. The tooth buds are formed via interaction between the neural crest and the ectoderm. The ectomesenchume surrounds the tooth bud and forms the dental follicle.<br /> <br /> ===Lab 11 Assessment===<br /> This journal article looks at ways that stem cells could be used in therapeutic cell transplantation and regeneration within the myocardium of the heart. Some studies have shown that adult stem cells have the ability to improve the myocardium though only for a short time. Therefore there is a need for a cell type that is able to provide long-lasting engraftment and myogenesis, such iPS cells.<br /> <br /> It concluded that a combination of surface markers could identify and enrich stem cell derived transcription factors with trilineage cardiovascular potential in vitro and also the ability to fragment and differentiate into mature adult cardiomyocytes.</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3375390&diff=106691 2012-10-09T23:09:15Z

<p>Z3375390: </p> <hr /> <div><br /> == Lab Attendance ==<br /> <br /> <br /> Lab 1 --[[User:Z3375390|Z3375390]] 11:49, 25 July 2012 (EST)<br /> <br /> Lab 2 --[[User:Z3375390|Z3375390]] 10:40, 1 August 2012 (EST)<br /> <br /> Lab 3 --[[User:Z3375390|Z3375390]] 10:07, 8 August 2012 (EST)<br /> <br /> Lab 4 --[[User:Z3375390|Z3375390]] 10:07, 15 August 2012 (EST)<br /> <br /> Lab 5 --[[User:Z3375390|Z3375390]] 10:07, 22 August 2012 (EST)<br /> <br /> Lab 6 --[[User:Z3375390|Z3375390]] 10:07, 29 August 2012 (EST)<br /> <br /> Lab 7 --[[User:Z3375390|Z3375390]] 10:01, 12 September 2012 (EST)<br /> <br /> Lab 8 --[[User:Z3375390|Z3375390]] 10:05, 19 September 2012 (EST)<br /> <br /> Lab 9 --[[User:Z3375390|Z3375390]] 11:21, 26 September 2012 (EST)<br /> <br /> Lab 10 --[[User:Z3375390|Z3375390]] 10:44, 3 October 2012 (EST)<br /> <br /> Lab 11 --[[User:Z3375390|Z3375390]] 10:09, 10 October 2012 (EST)<br /> <br /> ==Lab Assignments==<br /> ===Lab 1 Assessment===<br /> <br /> 1. The idea of In Vitro Fertilisation was influenced by the study of fertilisation of rabbit egg cells in test tubes. However as the cycle of human eggs is different to that of rabbits, further study and experimentation had to be done in order to achieve it. The first successful birth of an IVF baby occurred in 1978. <br /> Robert G. Edwards was awarded the Nobel Prize in 2010 for the development of In Vitro Fertilisation. <br /> [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]<br /> <br /> <br /> ===Lab 2 Assessment===<br /> <br /> An important protein associated with the process of implantation is Rac1. It is of the RhoGTPases family of proteins, and aids the embryonic trophoblast with invasion of the endometrium. Together with a protein known as RhoA, they are able to regulate cell migration and motility. It has been proven that motility is required in order for the trophoblast to invade the endometrium and for the embryo to be implanted within the uterine wall.<br /> Rac1 is needed as it promotes the trophoblast invasion. However, as this process must be tightly controlled, the protein RhoA is needed in order to restrict it. Therefore a balance between the two proteins must be achieved for successful implantation of the embryo in the endometrium.<br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562412/<br /> <br /> ===Lab 3 Assessment===<br /> <br /> 1.Gestational age refers to the time between the end of the mother’s last menstrual cycle and the birth of the baby. It is measured in weeks and determined by the size of the fetus using ultrasound before birth. After birth it is determined by the babies weight, length and other features. Postfertilization age refers to the time passed since fertilization of the egg. The exact time of fertilization however cannot be determined, so therefore it is inferred. Usually, gestational age is two weeks longer than postfertilization age.<br /> <br /> Gestational age is used when describing human development as it can be clearly determined and hence the calculations are more accurate than postfertilizaton age. <br /> <br /> 2.Some of the tissues formed from the somites include skeletal muscle, skin and bone.<br /> <br /> * Skeletal muscle<br /> ** Skeletal muscle cells develop from the myotome<br /> ** Myoblasts undergo frequent division and merging in order to form myotubes<br /> ** As development of the muscle cells continues, the nuclei move from the centre to the periphery of the cell.<br /> * Dermis of the dorsal skin<br /> ** Develops from dermatome and wandering mesenchymal cells<br /> ** Lies between the epidermis and the hypodermis<br /> ** Collagen producing fibroblasts are found in the dermis<br /> ** Composed of two layer: <br /> *** Papillary layer <br /> *** Reticular layer – made of dense irregular connective tissue<br /> * Vertebrae<br /> ** Develops from sclerotome<br /> <br /> ===Lab 4 Assessment===<br /> 1. Invasive prenatal diagnostic techniques:<br /> *Amniocentesis<br /> **This procedure consists of a needle being inserted into the mothers lower abdomen and through to the amniotic cavity<br /> **Usually performed between weeks 14 and 20 when there is enough amniotic fluid present for the procedure to be successful <br /> **Fetal cells acquired from the amniotic fluid are grown in culture for analysis of chromosomes, biochemicals and molecular biology<br /> **Amniotic fluid can also be used to determine the maturity of the fetal lung in the third trimester<br /> **Fetal loss and maternal Rh sensitisation are risks associated with this procedure<br /> **It also increases fetal mortality rate by 0.5%<br /> *Chorionic Villus Sampling<br /> **Consists of a catheter passing through the cervix and into the uterus usualy via the vagina<br /> **Cells acquired from the placental chorionic villi are used in chromosome analysis in order to determine the karyotype of the fetus, can also be used for biochemical and molecular biologic analysis<br /> **Usually performed between weeks 9 and 13 of gestation<br /> **Limb defects in a fetus is an abnormality associated with CVS <br /> **It may also increase the morbidity rate of the fetus<br /> <br /> <br /> 2. Preterm delivered infants are at high risk of developing a chronic lung disease known as Bronchopulmonary Dysplasia (BPD). This abnormality arises after ventilator and oxygen therapy for respiratory failure, which is usually associated with premature birth. Indicators of BPD include arrested alveolar growth and lung vascular growth. These abnormalities continue after childhood, putting lung structure and function at risk. Arrested alveolar growth, onset emphysema and pulmonary hypertension have all been linked to BPD and preterm delivery. Hence it is important to understand the developmental procedure of alveoli and the underlying capillary network in order to develop therapies for lung diseases characterised by impaired alveolarization. Research of stem cells shows that cell-based treatments are possible to repair the damaged organs.<br /> <br /> Stem cells have been found to be capable of self-renewal and have the potential to differentiate into multiple cellular phenotypes. They play a very important role in organ repair and tissue regeneration throughout the life span of an organism. Embryonic stem cells are the most potent form of stem cells as they are able to differentiate into cell types derived from the mesoderm, endoderm and ectoderm. They are also capable extensive self-renewal. Adult stem cells however are very limited in the sense that they can only differentiated into a certain number of cell types and sometimes only one. Embryonic stem cells are therefore very useful in cell-replacement therapy. <br /> <br /> Embryonic stem cells could be used to regenerate lung cells destroyed by disease and injury. BPD could lead to a deficiency of Adult Stem Cells within the lung that contribute to the growth and maintenance of the alveoli, lung matrix and pulmonary microvasculature. Therefore, if these injured and limited cells were to be replaced with EBC's that could repopulate and help with lung growth, the lung can once again carry out its function.<br /> <br /> ===Lab 7 Assessment===<br /> <br /> 1. a) Muscle satellite cells are dormant cells located between the plasma membrane and the basement membrane of the muscle fibres. They function in maintenance, regeneration and growth of skeletal muscle. <br /> <br /> b) Satellite cells are activated after a period of prolonged exercise, their responsiveness influences muscle adaptations. In cases of muscle injury, satellite cells are activated. They then proliferate and fuse together to form new muscle fibres.<br /> <br /> 2. Injury or death of motor neurons generally results in the denervation of the muscle fibres. This means that muscles are no longer able to function as they used to and hence the muscle cells will undergo atrophy and may eventually die. Or, an adjacent neuron may reinnervate the muscle fibres. Muscle atrophy leads to a decrease in muscle mass which results in an increase of fat storage and decrease of metabolic rate.<br /> <br /> ===Lab 8 Assessment===<br /> <br /> Vision:<br /> Good introduction, introduces the main components of the eye that will assumedly be focused on when talking about development. More information is needed in the history section however and the images used also need copyright permission.<br /> <br /> Wording is simple and understandable, it’s also good to see that you guys have a glossary up so to make it easier to comprehend what is being read. However you need more information under current research. Also you should focus on the other components of the eye other than the Optic nerve and the Retina and add more pictures or diagrams to illustrate what it is you’re explaining.<br /> <br /> You should also try using some dot points because reading long paragraphs could get tiring and allow the person to lose focus.<br /> <br /> <br /> Taste:<br /> The overall set up of the page I think is very good. In the introduction there is a balance between pictures and text which makes it a bit easier to read. Also its easy to follow, the text itself isn’t confusing and is understandable.<br /> <br /> There is a good overview of the different types of receptors and their function, also there is a brief section on the adult tongue which is good, however there needs to be more focus on the embryological development rather than just a simple table on that. There also needs to be some images added to that component as well to make it more understandable. <br /> <br /> The sections on abnormalities and current research need to be organised a bit better because they are a little hard to follow, especially with the placing of the images. The glossary is simple and understandable, however there needs to be more work done on the reference list. <br /> <br /> <br /> Olfaction:<br /> The work needs to be spell checked before you submit it, make sure you get all your grammar right as well. I think you should add more to your introduction, and make it a little simpler, easier to follow. Also throughout your project you tend to use a lot of long paragraphs, especially in the current research section.<br /> <br /> Though the developmental timeline that is set up is very detailed, it can be a bit hard to follow and a little confusing. There is too much text and no pictures at all to help demonstrate what is being said about the development. The ratio of images to text in the anatomy and abnormalities sections however is very good and makes it more interesting to read. <br /> <br /> It’s good to see that you have some external links put up on the page and also that you’ve used quite a few references to do your research rather than just a few. <br /> <br /> <br /> Abnormal Vision:<br /> The text on this page is very good, detailed and to the point. However a lot more images are needed on the page to make it more appealing, interesting and easier to follow. <br /> <br /> The section under Ocular Manifestations is a little difficult to keep track of, there needs to be more of an introduction in that section highlighting the two sections that are to be discussed, then there should be a clear division between the two. <br /> <br /> Also the placement of the few images on the page need to be organised a little better. The referencing on this page is done very well and its good to see an extensive use of resources. <br /> <br /> <br /> Hearing:<br /> This whole page I think is done really well. There is a balance between texts and images, it goes through the developmental process in detail, all information is relevant, there is an extensive use of resources and a pretty good glossary as well. <br /> The image right at the beginning of the dog is very smart as it draws attention to the whole page. Also the “Can you hear me” at the beginning gives the expectation that the page as a whole is going to be really good so I thought that was very effective. <br /> More information can be added to the current research section, and also you should try referencing throughout the entire page could be done a little better.<br /> <br /> <br /> ===Lab 9 Assessment===<br /> <br /> 2. The cells that form the tooth bud originate from the ectomesenchyme, the neural crest and the ectoderm. The embryonic development first begins late in stage 18. The tooth buds are formed via interaction between the neural crest and the ectoderm. The ectomesenchume surrounds the tooth bud and forms the dental follicle.</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105376 2012-10-03T01:48:23Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |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.&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> ===Genes Involved in Embryonic Development===<br /> <br /> 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 gens that have been considered in recent findings are c-Maf transcription factor and Shox-2. <br /> <br /> <br /> ====c-Maf====<br /> <br /> 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. <br /> <br /> <br /> ====Shox2====<br /> <br /> 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. &lt;ref name=&quot;PMID22103411&quot;&gt;&lt;pubmed&gt;22103411&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors - Summary ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> <br /> <br /> <br /> ====Details of Nociceptor Development====<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Axon growth.JPG|500px|Axon Growth]]<br /> <br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> 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 . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> [[File:Chemical physical phenotype of nociceptors.JPG|500px|Development of Chemical and Physiological phenotype of nociceptors]]<br /> <br /> <br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Increased innervation by nociceptors.JPG|500px|Increased Innervation of peripheral Tissues by Nociceptors]]<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> [[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]<br /> <br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> 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. <br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt; [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptor positions in glabrous skin]]<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;709739&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> ;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105374 2012-10-03T01:46:51Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |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.&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> ===Genes Involved in Embryonic Development===<br /> <br /> 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 gens that have been considered in recent findings are c-Maf transcription factor and Shox-2. <br /> <br /> <br /> ====c-Maf====<br /> <br /> 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. <br /> <br /> <br /> ====Shox2====<br /> <br /> 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. &lt;ref name=&quot;PMID22103411&quot;&gt;&lt;pubmed&gt;22103411&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors - Summary ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> <br /> <br /> <br /> ====Details of Nociceptor Development====<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Axon growth.JPG|500px|Axon Growth]]<br /> <br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> 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 . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> [[File:Chemical physical phenotype of nociceptors.JPG|500px|Development of Chemical and Physiological phenotype of nociceptors]]<br /> <br /> <br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Increased innervation by nociceptors.JPG|500px|Increased Innervation of peripheral Tissues by Nociceptors]]<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> [[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]<br /> <br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> 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. <br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt; [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|300px|alignment|Pressure Receptor positions in glabrous skin]]<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;709739&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> ;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105371 2012-10-03T01:45:01Z

<p>Z3375390: </p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |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.&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> ===Genes Involved in Embryonic Development===<br /> <br /> 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 gens that have been considered in recent findings are c-Maf transcription factor and Shox-2. <br /> <br /> <br /> ====c-Maf====<br /> <br /> 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. <br /> <br /> <br /> ====Shox2====<br /> <br /> 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. &lt;ref name=&quot;PMID22103411&quot;&gt;&lt;pubmed&gt;22103411&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors - Summary ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> <br /> <br /> <br /> ====Details of Nociceptor Development====<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Axon growth.JPG|500px|Axon Growth]]<br /> <br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> 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 . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> [[File:Chemical physical phenotype of nociceptors.JPG|500px|Development of Chemical and Physiological phenotype of nociceptors]]<br /> <br /> <br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Increased innervation by nociceptors.JPG|500px|Increased Innervation of peripheral Tissues by Nociceptors]]<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> [[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]<br /> <br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|400px|alignment|Pressure Receptors positions in glabrous skin]]<br /> 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. <br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;709739&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> ;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Pressure_Receptors_in_Glabrous_Skin.jpg&diff=105357 2012-10-03T01:31:05Z

<p>Z3375390: </p> <hr /> <div>This image shows the structure and location of the pressure receptors in glabrous skin. a)shows a Meissner corpuscle located between epidermal pegs. b) is a representation of the superficially located Merkel Discs. c) shows the Ruffini endings with their connective tissue lying parallel to the skin. d) represents the location of the Pacinian corpuscles with their 'onion like' structure. e) is a representation on free nerve endings. &lt;ref&gt;&lt;pubmed&gt;15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==Referencing==<br /> &lt;references/&gt;<br /> <br /> <br /> === Copyright===<br /> Copyright © 1999–2012 John Wiley &amp; Sons, Inc. All Rights Reserved.<br /> Wiley Online Library - The online service (or any successor thereto) available from Wiley or its affiliates on the Worldwide Web including all products, services and features offered via the service. Certain products and services under this License may be delivered from other platforms. The terms and conditions hereof are equally applicable to those products and services. <br /> <br /> <br /> ===Original Text===<br /> ''Figure 1. A: Nerve endings of the glabrous digital skin (a) Meissner corpuscles, (b) Merkel disks, (c) Ruffini endings, (d) Pacinian corpuscles, and (e) free nerve endings. Meissner corpuscles connect to and tightly abut the basal surface of the epidermis, just below the basement membrane. B: Cauna's model of an intermediate ridge (IR) and a Meissner corpuscle (MC; a). The intermediate ridge may act as a “magnifying lever mechanism” (Cauna, 1954) because its swing transmits oblique stimuli to the Meissner corpuscle (b and c). The spring-like receptor is fully stimulated by pressure coinciding with its axis (d).''</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Pressure_Receptors_in_Glabrous_Skin.jpg&diff=105348 2012-10-03T01:22:54Z

<p>Z3375390: /* Referencing */</p> <hr /> <div>This image shows the structure and location of the pressure receptors in glabrous skin. a)shows a Meissner corpuscle located between epidermal pegs. b) is a representation of the superficially located Merkel Discs. c) shows the Ruffini endings with their connective tissue lying parallel to the skin. d) represents the location of the Pacinian corpuscles with their 'onion like' structure. e) is a representation on free nerve endings. <br /> <br /> ==Referencing==<br /> &lt;/references&gt;<br /> &lt;ref&gt;&lt;pubmed&gt;15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> === Copyright===<br /> Copyright © 1999–2012 John Wiley &amp; Sons, Inc. All Rights Reserved.<br /> Wiley Online Library - The online service (or any successor thereto) available from Wiley or its affiliates on the Worldwide Web including all products, services and features offered via the service. Certain products and services under this License may be delivered from other platforms. The terms and conditions hereof are equally applicable to those products and services. <br /> <br /> <br /> ===Original Text===<br /> ''Figure 1. A: Nerve endings of the glabrous digital skin (a) Meissner corpuscles, (b) Merkel disks, (c) Ruffini endings, (d) Pacinian corpuscles, and (e) free nerve endings. Meissner corpuscles connect to and tightly abut the basal surface of the epidermis, just below the basement membrane. B: Cauna's model of an intermediate ridge (IR) and a Meissner corpuscle (MC; a). The intermediate ridge may act as a “magnifying lever mechanism” (Cauna, 1954) because its swing transmits oblique stimuli to the Meissner corpuscle (b and c). The spring-like receptor is fully stimulated by pressure coinciding with its axis (d).''</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105343 2012-10-03T01:21:01Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |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.&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> ===Genes Involved in Embryonic Development===<br /> <br /> ====Shox2====<br /> <br /> 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. &lt;ref name=&quot;PMID22103411&quot;&gt;&lt;pubmed&gt;22103411&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors - Summary ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> <br /> <br /> <br /> ====Details of Nociceptor Development====<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Axon growth.JPG|500px|Axon Growth]]<br /> <br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> 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 . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> [[File:Chemical physical phenotype of nociceptors.JPG|500px|Development of Chemical and Physiological phenotype of nociceptors]]<br /> <br /> <br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> [[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]<br /> <br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> [[File:Pressure Receptors in Glabrous Skin.jpg|thumb|alignment|caption]]<br /> 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. <br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;709739&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> ;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105339 2012-10-03T01:19:43Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |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.&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> ===Genes Involved in Embryonic Development===<br /> <br /> ====Shox2====<br /> <br /> 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. &lt;ref name=&quot;PMID22103411&quot;&gt;&lt;pubmed&gt;22103411&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors - Summary ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> <br /> <br /> <br /> ====Details of Nociceptor Development====<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Axon growth.JPG|500px|Axon Growth]]<br /> <br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> 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 . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> [[File:Chemical physical phenotype of nociceptors.JPG|500px|Development of Chemical and Physiological phenotype of nociceptors]]<br /> <br /> <br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> [[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]<br /> <br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> [[File:Pressure Receptors in Glabrous Skin.jpg]]<br /> 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. <br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;709739&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> ;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Pressure_Receptors_in_Glabrous_Skin.jpg&diff=105334 2012-10-03T01:17:02Z

<p>Z3375390: </p> <hr /> <div>This image shows the structure and location of the pressure receptors in glabrous skin. a)shows a Meissner corpuscle located between epidermal pegs. b) is a representation of the superficially located Merkel Discs. c) shows the Ruffini endings with their connective tissue lying parallel to the skin. d) represents the location of the Pacinian corpuscles with their 'onion like' structure. e) is a representation on free nerve endings. <br /> <br /> ==Referencing==<br /> Hoffmann JN, Montag AG, '''Dominy NJ.Meissner corpuscles and somatosensory acuity: The prehensile appendages of primates and elephants'''Anat Rec A Discov Mol Cell Evol Biol. 2004 Nov;281(1):1138-47. &lt;ref&gt;&lt;pubmed&gt;15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> === Copyright===<br /> Copyright © 1999–2012 John Wiley &amp; Sons, Inc. All Rights Reserved.<br /> Wiley Online Library - The online service (or any successor thereto) available from Wiley or its affiliates on the Worldwide Web including all products, services and features offered via the service. Certain products and services under this License may be delivered from other platforms. The terms and conditions hereof are equally applicable to those products and services. <br /> <br /> <br /> ===Original Text===<br /> ''Figure 1. A: Nerve endings of the glabrous digital skin (a) Meissner corpuscles, (b) Merkel disks, (c) Ruffini endings, (d) Pacinian corpuscles, and (e) free nerve endings. Meissner corpuscles connect to and tightly abut the basal surface of the epidermis, just below the basement membrane. B: Cauna's model of an intermediate ridge (IR) and a Meissner corpuscle (MC; a). The intermediate ridge may act as a “magnifying lever mechanism” (Cauna, 1954) because its swing transmits oblique stimuli to the Meissner corpuscle (b and c). The spring-like receptor is fully stimulated by pressure coinciding with its axis (d).''</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Pressure_Receptors_in_Glabrous_Skin.jpg&diff=105330 2012-10-03T01:14:01Z

<p>Z3375390: </p> <hr /> <div>This image shows the structure and location of the pressure receptors in glabrous skin. a)shows a Meissner corpuscle located between epidermal pegs. b) is a representation of the superficially located Merkel Discs. c) shows the Ruffini endings with their connective tissue lying parallel to the skin. d) represents the location of the Pacinian corpuscles with their 'onion like' structure. e) is a representation on free nerve endings. <br /> <br /> ==Referencing==<br /> Hoffmann JN, Montag AG, ;Dominy NJ.Meissner corpuscles and somatosensory acuity: The prehensile appendages of primates and elephants:Anat Rec A Discov Mol Cell Evol Biol. 2004 Nov;281(1):1138-47. &lt;ref&gt;&lt;pubmed&gt;15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> === Copyright===<br /> Copyright © 1999–2012 John Wiley &amp; Sons, Inc. All Rights Reserved.<br /> Wiley Online Library - The online service (or any successor thereto) available from Wiley or its affiliates on the Worldwide Web including all products, services and features offered via the service. Certain products and services under this License may be delivered from other platforms. The terms and conditions hereof are equally applicable to those products and services. <br /> <br /> <br /> ==Original Text==<br /> 'Figure 1. A: Nerve endings of the glabrous digital skin (a) Meissner corpuscles, (b) Merkel disks, (c) Ruffini endings, (d) Pacinian corpuscles, and (e) free nerve endings. Meissner corpuscles connect to and tightly abut the basal surface of the epidermis, just below the basement membrane. B: Cauna's model of an intermediate ridge (IR) and a Meissner corpuscle (MC; a). The intermediate ridge may act as a “magnifying lever mechanism” (Cauna, 1954) because its swing transmits oblique stimuli to the Meissner corpuscle (b and c). The spring-like receptor is fully stimulated by pressure coinciding with its axis (d).'</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Pressure_Receptors_in_Glabrous_Skin.jpg&diff=105327 2012-10-03T01:12:47Z

<p>Z3375390: </p> <hr /> <div>This image shows the structure and location of the pressure receptors in glabrous skin. a)shows a Meissner corpuscle located between epidermal pegs. b) is a representation of the superficially located Merkel Discs. c) shows the Ruffini endings with their connective tissue lying parallel to the skin. d) represents the location of the Pacinian corpuscles with their 'onion like' structure. e) is a representation on free nerve endings. <br /> <br /> ==Referencing==<br /> Hoffmann JN, Montag AG, ;Dominy NJ.Meissner corpuscles and somatosensory acuity: The prehensile appendages of primates and elephants:Anat Rec A Discov Mol Cell Evol Biol. 2004 Nov;281(1):1138-47.<br /> URL: http://www.ncbi.nlm.nih.gov/pubmed/15470674<br /> <br /> === Copyright===<br /> Copyright © 1999–2012 John Wiley &amp; Sons, Inc. All Rights Reserved.<br /> Wiley Online Library - The online service (or any successor thereto) available from Wiley or its affiliates on the Worldwide Web including all products, services and features offered via the service. Certain products and services under this License may be delivered from other platforms. The terms and conditions hereof are equally applicable to those products and services. <br /> <br /> <br /> ==Original Text==<br /> 'Figure 1. A: Nerve endings of the glabrous digital skin (a) Meissner corpuscles, (b) Merkel disks, (c) Ruffini endings, (d) Pacinian corpuscles, and (e) free nerve endings. Meissner corpuscles connect to and tightly abut the basal surface of the epidermis, just below the basement membrane. B: Cauna's model of an intermediate ridge (IR) and a Meissner corpuscle (MC; a). The intermediate ridge may act as a “magnifying lever mechanism” (Cauna, 1954) because its swing transmits oblique stimuli to the Meissner corpuscle (b and c). The spring-like receptor is fully stimulated by pressure coinciding with its axis (d).'</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Pressure_Receptors_in_Glabrous_Skin.jpg&diff=105312 2012-10-03T01:04:31Z

<p>Z3375390: </p> <hr /> <div></div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3375390&diff=105276 2012-10-03T00:44:22Z

<p>Z3375390: </p> <hr /> <div><br /> == Lab Attendance ==<br /> <br /> <br /> Lab 1 --[[User:Z3375390|Z3375390]] 11:49, 25 July 2012 (EST)<br /> <br /> Lab 2 --[[User:Z3375390|Z3375390]] 10:40, 1 August 2012 (EST)<br /> <br /> Lab 3 --[[User:Z3375390|Z3375390]] 10:07, 8 August 2012 (EST)<br /> <br /> Lab 4 --[[User:Z3375390|Z3375390]] 10:07, 15 August 2012 (EST)<br /> <br /> Lab 5 --[[User:Z3375390|Z3375390]] 10:07, 22 August 2012 (EST)<br /> <br /> Lab 6 --[[User:Z3375390|Z3375390]] 10:07, 29 August 2012 (EST)<br /> <br /> Lab 7 --[[User:Z3375390|Z3375390]] 10:01, 12 September 2012 (EST)<br /> <br /> Lab 8 --[[User:Z3375390|Z3375390]] 10:05, 19 September 2012 (EST)<br /> <br /> Lab 9 --[[User:Z3375390|Z3375390]] 11:21, 26 September 2012 (EST)<br /> <br /> Lab 10 --[[User:Z3375390|Z3375390]] 10:44, 3 October 2012 (EST)<br /> <br /> ==Lab Assignments==<br /> ===Lab 1 Assessment===<br /> <br /> 1. The idea of In Vitro Fertilisation was influenced by the study of fertilisation of rabbit egg cells in test tubes. However as the cycle of human eggs is different to that of rabbits, further study and experimentation had to be done in order to achieve it. The first successful birth of an IVF baby occurred in 1978. <br /> Robert G. Edwards was awarded the Nobel Prize in 2010 for the development of In Vitro Fertilisation. <br /> [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]<br /> <br /> <br /> ===Lab 2 Assessment===<br /> <br /> An important protein associated with the process of implantation is Rac1. It is of the RhoGTPases family of proteins, and aids the embryonic trophoblast with invasion of the endometrium. Together with a protein known as RhoA, they are able to regulate cell migration and motility. It has been proven that motility is required in order for the trophoblast to invade the endometrium and for the embryo to be implanted within the uterine wall.<br /> Rac1 is needed as it promotes the trophoblast invasion. However, as this process must be tightly controlled, the protein RhoA is needed in order to restrict it. Therefore a balance between the two proteins must be achieved for successful implantation of the embryo in the endometrium.<br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562412/<br /> <br /> ===Lab 3 Assessment===<br /> <br /> 1.Gestational age refers to the time between the end of the mother’s last menstrual cycle and the birth of the baby. It is measured in weeks and determined by the size of the fetus using ultrasound before birth. After birth it is determined by the babies weight, length and other features. Postfertilization age refers to the time passed since fertilization of the egg. The exact time of fertilization however cannot be determined, so therefore it is inferred. Usually, gestational age is two weeks longer than postfertilization age.<br /> <br /> Gestational age is used when describing human development as it can be clearly determined and hence the calculations are more accurate than postfertilizaton age. <br /> <br /> 2.Some of the tissues formed from the somites include skeletal muscle, skin and bone.<br /> <br /> * Skeletal muscle<br /> ** Skeletal muscle cells develop from the myotome<br /> ** Myoblasts undergo frequent division and merging in order to form myotubes<br /> ** As development of the muscle cells continues, the nuclei move from the centre to the periphery of the cell.<br /> * Dermis of the dorsal skin<br /> ** Develops from dermatome and wandering mesenchymal cells<br /> ** Lies between the epidermis and the hypodermis<br /> ** Collagen producing fibroblasts are found in the dermis<br /> ** Composed of two layer: <br /> *** Papillary layer <br /> *** Reticular layer – made of dense irregular connective tissue<br /> * Vertebrae<br /> ** Develops from sclerotome<br /> <br /> ===Lab 4 Assessment===<br /> 1. Invasive prenatal diagnostic techniques:<br /> *Amniocentesis<br /> **This procedure consists of a needle being inserted into the mothers lower abdomen and through to the amniotic cavity<br /> **Usually performed between weeks 14 and 20 when there is enough amniotic fluid present for the procedure to be successful <br /> **Fetal cells acquired from the amniotic fluid are grown in culture for analysis of chromosomes, biochemicals and molecular biology<br /> **Amniotic fluid can also be used to determine the maturity of the fetal lung in the third trimester<br /> **Fetal loss and maternal Rh sensitisation are risks associated with this procedure<br /> **It also increases fetal mortality rate by 0.5%<br /> *Chorionic Villus Sampling<br /> **Consists of a catheter passing through the cervix and into the uterus usualy via the vagina<br /> **Cells acquired from the placental chorionic villi are used in chromosome analysis in order to determine the karyotype of the fetus, can also be used for biochemical and molecular biologic analysis<br /> **Usually performed between weeks 9 and 13 of gestation<br /> **Limb defects in a fetus is an abnormality associated with CVS <br /> **It may also increase the morbidity rate of the fetus<br /> <br /> <br /> 2. Preterm delivered infants are at high risk of developing a chronic lung disease known as Bronchopulmonary Dysplasia (BPD). This abnormality arises after ventilator and oxygen therapy for respiratory failure, which is usually associated with premature birth. Indicators of BPD include arrested alveolar growth and lung vascular growth. These abnormalities continue after childhood, putting lung structure and function at risk. Arrested alveolar growth, onset emphysema and pulmonary hypertension have all been linked to BPD and preterm delivery. Hence it is important to understand the developmental procedure of alveoli and the underlying capillary network in order to develop therapies for lung diseases characterised by impaired alveolarization. Research of stem cells shows that cell-based treatments are possible to repair the damaged organs.<br /> <br /> Stem cells have been found to be capable of self-renewal and have the potential to differentiate into multiple cellular phenotypes. They play a very important role in organ repair and tissue regeneration throughout the life span of an organism. Embryonic stem cells are the most potent form of stem cells as they are able to differentiate into cell types derived from the mesoderm, endoderm and ectoderm. They are also capable extensive self-renewal. Adult stem cells however are very limited in the sense that they can only differentiated into a certain number of cell types and sometimes only one. Embryonic stem cells are therefore very useful in cell-replacement therapy. <br /> <br /> Embryonic stem cells could be used to regenerate lung cells destroyed by disease and injury. BPD could lead to a deficiency of Adult Stem Cells within the lung that contribute to the growth and maintenance of the alveoli, lung matrix and pulmonary microvasculature. Therefore, if these injured and limited cells were to be replaced with EBC's that could repopulate and help with lung growth, the lung can once again carry out its function.<br /> <br /> ===Lab 7 Assessment===<br /> <br /> 1. a) Muscle satellite cells are dormant cells located between the plasma membrane and the basement membrane of the muscle fibres. They function in maintenance, regeneration and growth of skeletal muscle. <br /> <br /> b) Satellite cells are activated after a period of prolonged exercise, their responsiveness influences muscle adaptations. In cases of muscle injury, satellite cells are activated. They then proliferate and fuse together to form new muscle fibres.<br /> <br /> 2. Injury or death of motor neurons generally results in the denervation of the muscle fibres. This means that muscles are no longer able to function as they used to and hence the muscle cells will undergo atrophy and may eventually die. Or, an adjacent neuron may reinnervate the muscle fibres. Muscle atrophy leads to a decrease in muscle mass which results in an increase of fat storage and decrease of metabolic rate.<br /> <br /> ===Lab 8 Assessment===<br /> <br /> Vision:<br /> Good introduction, introduces the main components of the eye that will assumedly be focused on when talking about development. More information is needed in the history section however and the images used also need copyright permission.<br /> <br /> Wording is simple and understandable, it’s also good to see that you guys have a glossary up so to make it easier to comprehend what is being read. However you need more information under current research. Also you should focus on the other components of the eye other than the Optic nerve and the Retina and add more pictures or diagrams to illustrate what it is you’re explaining.<br /> <br /> You should also try using some dot points because reading long paragraphs could get tiring and allow the person to lose focus.<br /> <br /> <br /> Taste:<br /> The overall set up of the page I think is very good. In the introduction there is a balance between pictures and text which makes it a bit easier to read. Also its easy to follow, the text itself isn’t confusing and is understandable.<br /> <br /> There is a good overview of the different types of receptors and their function, also there is a brief section on the adult tongue which is good, however there needs to be more focus on the embryological development rather than just a simple table on that. There also needs to be some images added to that component as well to make it more understandable. <br /> <br /> The sections on abnormalities and current research need to be organised a bit better because they are a little hard to follow, especially with the placing of the images. The glossary is simple and understandable, however there needs to be more work done on the reference list. <br /> <br /> <br /> Olfaction:<br /> The work needs to be spell checked before you submit it, make sure you get all your grammar right as well. I think you should add more to your introduction, and make it a little simpler, easier to follow. Also throughout your project you tend to use a lot of long paragraphs, especially in the current research section.<br /> <br /> Though the developmental timeline that is set up is very detailed, it can be a bit hard to follow and a little confusing. There is too much text and no pictures at all to help demonstrate what is being said about the development. The ratio of images to text in the anatomy and abnormalities sections however is very good and makes it more interesting to read. <br /> <br /> It’s good to see that you have some external links put up on the page and also that you’ve used quite a few references to do your research rather than just a few. <br /> <br /> <br /> Abnormal Vision:<br /> The text on this page is very good, detailed and to the point. However a lot more images are needed on the page to make it more appealing, interesting and easier to follow. <br /> <br /> The section under Ocular Manifestations is a little difficult to keep track of, there needs to be more of an introduction in that section highlighting the two sections that are to be discussed, then there should be a clear division between the two. <br /> <br /> Also the placement of the few images on the page need to be organised a little better. The referencing on this page is done very well and its good to see an extensive use of resources. <br /> <br /> <br /> Hearing:<br /> This whole page I think is done really well. There is a balance between texts and images, it goes through the developmental process in detail, all information is relevant, there is an extensive use of resources and a pretty good glossary as well. <br /> The image right at the beginning of the dog is very smart as it draws attention to the whole page. Also the “Can you hear me” at the beginning gives the expectation that the page as a whole is going to be really good so I thought that was very effective. <br /> More information can be added to the current research section, and also you should try referencing throughout the entire page could be done a little better.<br /> <br /> <br /> ===Lab 9 Assessment===<br /> <br /> 2. The cells that form the tooth bud originate from the ectomesenchyme, the neural crest and the ectoderm. The embryonic development first begins late in stage 18. The tooth buds are formed via interaction between the neural crest and the ectoderm. The ectomesenchume surrounds the tooth bud and forms the dental follicle.</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105241 2012-10-03T00:18:32Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |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.&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID20064382&quot;&gt;&lt;pubmed&gt;20064382&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> ===Genes Involved in Embryonic Development===<br /> <br /> ====Shox- 2====<br /> <br /> 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. &lt;ref name=&quot;PMID22103411&quot;&gt;&lt;pubmed&gt;22103411&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;709739&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> ;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3375390&diff=105054 2012-10-02T15:42:07Z

<p>Z3375390: </p> <hr /> <div><br /> == Lab Attendance ==<br /> <br /> <br /> Lab 1 --[[User:Z3375390|Z3375390]] 11:49, 25 July 2012 (EST)<br /> <br /> Lab 2 --[[User:Z3375390|Z3375390]] 10:40, 1 August 2012 (EST)<br /> <br /> Lab 3 --[[User:Z3375390|Z3375390]] 10:07, 8 August 2012 (EST)<br /> <br /> Lab 4 --[[User:Z3375390|Z3375390]] 10:07, 15 August 2012 (EST)<br /> <br /> Lab 5 --[[User:Z3375390|Z3375390]] 10:07, 22 August 2012 (EST)<br /> <br /> Lab 6 --[[User:Z3375390|Z3375390]] 10:07, 29 August 2012 (EST)<br /> <br /> Lab 7 --[[User:Z3375390|Z3375390]] 10:01, 12 September 2012 (EST)<br /> <br /> Lab 8 --[[User:Z3375390|Z3375390]] 10:05, 19 September 2012 (EST)<br /> <br /> Lab 9 --[[User:Z3375390|Z3375390]] 11:21, 26 September 2012 (EST)<br /> <br /> ==Lab Assignments==<br /> ===Lab 1 Assessment===<br /> <br /> 1. The idea of In Vitro Fertilisation was influenced by the study of fertilisation of rabbit egg cells in test tubes. However as the cycle of human eggs is different to that of rabbits, further study and experimentation had to be done in order to achieve it. The first successful birth of an IVF baby occurred in 1978. <br /> Robert G. Edwards was awarded the Nobel Prize in 2010 for the development of In Vitro Fertilisation. <br /> [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]<br /> <br /> <br /> ===Lab 2 Assessment===<br /> <br /> An important protein associated with the process of implantation is Rac1. It is of the RhoGTPases family of proteins, and aids the embryonic trophoblast with invasion of the endometrium. Together with a protein known as RhoA, they are able to regulate cell migration and motility. It has been proven that motility is required in order for the trophoblast to invade the endometrium and for the embryo to be implanted within the uterine wall.<br /> Rac1 is needed as it promotes the trophoblast invasion. However, as this process must be tightly controlled, the protein RhoA is needed in order to restrict it. Therefore a balance between the two proteins must be achieved for successful implantation of the embryo in the endometrium.<br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562412/<br /> <br /> ===Lab 3 Assessment===<br /> <br /> 1.Gestational age refers to the time between the end of the mother’s last menstrual cycle and the birth of the baby. It is measured in weeks and determined by the size of the fetus using ultrasound before birth. After birth it is determined by the babies weight, length and other features. Postfertilization age refers to the time passed since fertilization of the egg. The exact time of fertilization however cannot be determined, so therefore it is inferred. Usually, gestational age is two weeks longer than postfertilization age.<br /> <br /> Gestational age is used when describing human development as it can be clearly determined and hence the calculations are more accurate than postfertilizaton age. <br /> <br /> 2.Some of the tissues formed from the somites include skeletal muscle, skin and bone.<br /> <br /> * Skeletal muscle<br /> ** Skeletal muscle cells develop from the myotome<br /> ** Myoblasts undergo frequent division and merging in order to form myotubes<br /> ** As development of the muscle cells continues, the nuclei move from the centre to the periphery of the cell.<br /> * Dermis of the dorsal skin<br /> ** Develops from dermatome and wandering mesenchymal cells<br /> ** Lies between the epidermis and the hypodermis<br /> ** Collagen producing fibroblasts are found in the dermis<br /> ** Composed of two layer: <br /> *** Papillary layer <br /> *** Reticular layer – made of dense irregular connective tissue<br /> * Vertebrae<br /> ** Develops from sclerotome<br /> <br /> ===Lab 4 Assessment===<br /> 1. Invasive prenatal diagnostic techniques:<br /> *Amniocentesis<br /> **This procedure consists of a needle being inserted into the mothers lower abdomen and through to the amniotic cavity<br /> **Usually performed between weeks 14 and 20 when there is enough amniotic fluid present for the procedure to be successful <br /> **Fetal cells acquired from the amniotic fluid are grown in culture for analysis of chromosomes, biochemicals and molecular biology<br /> **Amniotic fluid can also be used to determine the maturity of the fetal lung in the third trimester<br /> **Fetal loss and maternal Rh sensitisation are risks associated with this procedure<br /> **It also increases fetal mortality rate by 0.5%<br /> *Chorionic Villus Sampling<br /> **Consists of a catheter passing through the cervix and into the uterus usualy via the vagina<br /> **Cells acquired from the placental chorionic villi are used in chromosome analysis in order to determine the karyotype of the fetus, can also be used for biochemical and molecular biologic analysis<br /> **Usually performed between weeks 9 and 13 of gestation<br /> **Limb defects in a fetus is an abnormality associated with CVS <br /> **It may also increase the morbidity rate of the fetus<br /> <br /> <br /> 2. Preterm delivered infants are at high risk of developing a chronic lung disease known as Bronchopulmonary Dysplasia (BPD). This abnormality arises after ventilator and oxygen therapy for respiratory failure, which is usually associated with premature birth. Indicators of BPD include arrested alveolar growth and lung vascular growth. These abnormalities continue after childhood, putting lung structure and function at risk. Arrested alveolar growth, onset emphysema and pulmonary hypertension have all been linked to BPD and preterm delivery. Hence it is important to understand the developmental procedure of alveoli and the underlying capillary network in order to develop therapies for lung diseases characterised by impaired alveolarization. Research of stem cells shows that cell-based treatments are possible to repair the damaged organs.<br /> <br /> Stem cells have been found to be capable of self-renewal and have the potential to differentiate into multiple cellular phenotypes. They play a very important role in organ repair and tissue regeneration throughout the life span of an organism. Embryonic stem cells are the most potent form of stem cells as they are able to differentiate into cell types derived from the mesoderm, endoderm and ectoderm. They are also capable extensive self-renewal. Adult stem cells however are very limited in the sense that they can only differentiated into a certain number of cell types and sometimes only one. Embryonic stem cells are therefore very useful in cell-replacement therapy. <br /> <br /> Embryonic stem cells could be used to regenerate lung cells destroyed by disease and injury. BPD could lead to a deficiency of Adult Stem Cells within the lung that contribute to the growth and maintenance of the alveoli, lung matrix and pulmonary microvasculature. Therefore, if these injured and limited cells were to be replaced with EBC's that could repopulate and help with lung growth, the lung can once again carry out its function.<br /> <br /> ===Lab 7 Assessment===<br /> <br /> 1. a) Muscle satellite cells are dormant cells located between the plasma membrane and the basement membrane of the muscle fibres. They function in maintenance, regeneration and growth of skeletal muscle. <br /> <br /> b) Satellite cells are activated after a period of prolonged exercise, their responsiveness influences muscle adaptations. In cases of muscle injury, satellite cells are activated. They then proliferate and fuse together to form new muscle fibres.<br /> <br /> 2. Injury or death of motor neurons generally results in the denervation of the muscle fibres. This means that muscles are no longer able to function as they used to and hence the muscle cells will undergo atrophy and may eventually die. Or, an adjacent neuron may reinnervate the muscle fibres. Muscle atrophy leads to a decrease in muscle mass which results in an increase of fat storage and decrease of metabolic rate.<br /> <br /> ===Lab 8 Assessment===<br /> <br /> Vision:<br /> Good introduction, introduces the main components of the eye that will assumedly be focused on when talking about development. More information is needed in the history section however and the images used also need copyright permission.<br /> <br /> Wording is simple and understandable, it’s also good to see that you guys have a glossary up so to make it easier to comprehend what is being read. However you need more information under current research. Also you should focus on the other components of the eye other than the Optic nerve and the Retina and add more pictures or diagrams to illustrate what it is you’re explaining.<br /> <br /> You should also try using some dot points because reading long paragraphs could get tiring and allow the person to lose focus.<br /> <br /> <br /> Taste:<br /> The overall set up of the page I think is very good. In the introduction there is a balance between pictures and text which makes it a bit easier to read. Also its easy to follow, the text itself isn’t confusing and is understandable.<br /> <br /> There is a good overview of the different types of receptors and their function, also there is a brief section on the adult tongue which is good, however there needs to be more focus on the embryological development rather than just a simple table on that. There also needs to be some images added to that component as well to make it more understandable. <br /> <br /> The sections on abnormalities and current research need to be organised a bit better because they are a little hard to follow, especially with the placing of the images. The glossary is simple and understandable, however there needs to be more work done on the reference list. <br /> <br /> <br /> Olfaction:<br /> The work needs to be spell checked before you submit it, make sure you get all your grammar right as well. I think you should add more to your introduction, and make it a little simpler, easier to follow. Also throughout your project you tend to use a lot of long paragraphs, especially in the current research section.<br /> <br /> Though the developmental timeline that is set up is very detailed, it can be a bit hard to follow and a little confusing. There is too much text and no pictures at all to help demonstrate what is being said about the development. The ratio of images to text in the anatomy and abnormalities sections however is very good and makes it more interesting to read. <br /> <br /> It’s good to see that you have some external links put up on the page and also that you’ve used quite a few references to do your research rather than just a few. <br /> <br /> <br /> Abnormal Vision:<br /> The text on this page is very good, detailed and to the point. However a lot more images are needed on the page to make it more appealing, interesting and easier to follow. <br /> <br /> The section under Ocular Manifestations is a little difficult to keep track of, there needs to be more of an introduction in that section highlighting the two sections that are to be discussed, then there should be a clear division between the two. <br /> <br /> Also the placement of the few images on the page need to be organised a little better. The referencing on this page is done very well and its good to see an extensive use of resources. <br /> <br /> <br /> Hearing:<br /> This whole page I think is done really well. There is a balance between texts and images, it goes through the developmental process in detail, all information is relevant, there is an extensive use of resources and a pretty good glossary as well. <br /> The image right at the beginning of the dog is very smart as it draws attention to the whole page. Also the “Can you hear me” at the beginning gives the expectation that the page as a whole is going to be really good so I thought that was very effective. <br /> More information can be added to the current research section, and also you should try referencing throughout the entire page could be done a little better.<br /> <br /> <br /> ===Lab 9 Assessment===<br /> <br /> 2. The cells that form the tooth bud originate from the ectomesenchyme, the neural crest and the ectoderm. The embryonic development first begins late in stage 18. The tooth buds are formed via interaction between the neural crest and the ectoderm. The ectomesenchume surrounds the tooth bud and forms the dental follicle.</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3375390&diff=105053 2012-10-02T15:41:06Z

<p>Z3375390: </p> <hr /> <div><br /> == Lab Attendance ==<br /> <br /> <br /> Lab 1 --[[User:Z3375390|Z3375390]] 11:49, 25 July 2012 (EST)<br /> <br /> Lab 2 --[[User:Z3375390|Z3375390]] 10:40, 1 August 2012 (EST)<br /> <br /> Lab 3 --[[User:Z3375390|Z3375390]] 10:07, 8 August 2012 (EST)<br /> <br /> Lab 4 --[[User:Z3375390|Z3375390]] 10:07, 15 August 2012 (EST)<br /> <br /> Lab 5 --[[User:Z3375390|Z3375390]] 10:07, 22 August 2012 (EST)<br /> <br /> Lab 6 --[[User:Z3375390|Z3375390]] 10:07, 29 August 2012 (EST)<br /> <br /> Lab 7 --[[User:Z3375390|Z3375390]] 10:01, 12 September 2012 (EST)<br /> <br /> Lab 8 --[[User:Z3375390|Z3375390]] 10:05, 19 September 2012 (EST)<br /> <br /> Lab 9 --[[User:Z3375390|Z3375390]] 11:21, 26 September 2012 (EST)<br /> <br /> ==Lab Assignments==<br /> ===Lab 1 Assessment===<br /> <br /> 1. The idea of In Vitro Fertilisation was influenced by the study of fertilisation of rabbit egg cells in test tubes. However as the cycle of human eggs is different to that of rabbits, further study and experimentation had to be done in order to achieve it. The first successful birth of an IVF baby occurred in 1978. <br /> Robert G. Edwards was awarded the Nobel Prize in 2010 for the development of In Vitro Fertilisation. <br /> [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]<br /> <br /> <br /> ===Lab 2 Assessment===<br /> <br /> An important protein associated with the process of implantation is Rac1. It is of the RhoGTPases family of proteins, and aids the embryonic trophoblast with invasion of the endometrium. Together with a protein known as RhoA, they are able to regulate cell migration and motility. It has been proven that motility is required in order for the trophoblast to invade the endometrium and for the embryo to be implanted within the uterine wall.<br /> Rac1 is needed as it promotes the trophoblast invasion. However, as this process must be tightly controlled, the protein RhoA is needed in order to restrict it. Therefore a balance between the two proteins must be achieved for successful implantation of the embryo in the endometrium.<br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562412/<br /> <br /> ===Lab 3 Assessment===<br /> <br /> 1.Gestational age refers to the time between the end of the mother’s last menstrual cycle and the birth of the baby. It is measured in weeks and determined by the size of the fetus using ultrasound before birth. After birth it is determined by the babies weight, length and other features. Postfertilization age refers to the time passed since fertilization of the egg. The exact time of fertilization however cannot be determined, so therefore it is inferred. Usually, gestational age is two weeks longer than postfertilization age.<br /> <br /> Gestational age is used when describing human development as it can be clearly determined and hence the calculations are more accurate than postfertilizaton age. <br /> <br /> 2.Some of the tissues formed from the somites include skeletal muscle, skin and bone.<br /> <br /> * Skeletal muscle<br /> ** Skeletal muscle cells develop from the myotome<br /> ** Myoblasts undergo frequent division and merging in order to form myotubes<br /> ** As development of the muscle cells continues, the nuclei move from the centre to the periphery of the cell.<br /> * Dermis of the dorsal skin<br /> ** Develops from dermatome and wandering mesenchymal cells<br /> ** Lies between the epidermis and the hypodermis<br /> ** Collagen producing fibroblasts are found in the dermis<br /> ** Composed of two layer: <br /> *** Papillary layer <br /> *** Reticular layer – made of dense irregular connective tissue<br /> * Vertebrae<br /> ** Develops from sclerotome<br /> <br /> ===Lab 4 Assessment===<br /> 1. Invasive prenatal diagnostic techniques:<br /> *Amniocentesis<br /> **This procedure consists of a needle being inserted into the mothers lower abdomen and through to the amniotic cavity<br /> **Usually performed between weeks 14 and 20 when there is enough amniotic fluid present for the procedure to be successful <br /> **Fetal cells acquired from the amniotic fluid are grown in culture for analysis of chromosomes, biochemicals and molecular biology<br /> **Amniotic fluid can also be used to determine the maturity of the fetal lung in the third trimester<br /> **Fetal loss and maternal Rh sensitisation are risks associated with this procedure<br /> **It also increases fetal mortality rate by 0.5%<br /> *Chorionic Villus Sampling<br /> **Consists of a catheter passing through the cervix and into the uterus usualy via the vagina<br /> **Cells acquired from the placental chorionic villi are used in chromosome analysis in order to determine the karyotype of the fetus, can also be used for biochemical and molecular biologic analysis<br /> **Usually performed between weeks 9 and 13 of gestation<br /> **Limb defects in a fetus is an abnormality associated with CVS <br /> **It may also increase the morbidity rate of the fetus<br /> <br /> <br /> 2. Preterm delivered infants are at high risk of developing a chronic lung disease known as Bronchopulmonary Dysplasia (BPD). This abnormality arises after ventilator and oxygen therapy for respiratory failure, which is usually associated with premature birth. Indicators of BPD include arrested alveolar growth and lung vascular growth. These abnormalities continue after childhood, putting lung structure and function at risk. Arrested alveolar growth, onset emphysema and pulmonary hypertension have all been linked to BPD and preterm delivery. Hence it is important to understand the developmental procedure of alveoli and the underlying capillary network in order to develop therapies for lung diseases characterised by impaired alveolarization. Research of stem cells shows that cell-based treatments are possible to repair the damaged organs.<br /> <br /> Stem cells have been found to be capable of self-renewal and have the potential to differentiate into multiple cellular phenotypes. They play a very important role in organ repair and tissue regeneration throughout the life span of an organism. Embryonic stem cells are the most potent form of stem cells as they are able to differentiate into cell types derived from the mesoderm, endoderm and ectoderm. They are also capable extensive self-renewal. Adult stem cells however are very limited in the sense that they can only differentiated into a certain number of cell types and sometimes only one. Embryonic stem cells are therefore very useful in cell-replacement therapy. <br /> <br /> Embryonic stem cells could be used to regenerate lung cells destroyed by disease and injury. BPD could lead to a deficiency of Adult Stem Cells within the lung that contribute to the growth and maintenance of the alveoli, lung matrix and pulmonary microvasculature. Therefore, if these injured and limited cells were to be replaced with EBC's that could repopulate and help with lung growth, the lung can once again carry out its function.<br /> <br /> ===Lab 7 Assessment===<br /> <br /> 1. a) Muscle satellite cells are dormant cells located between the plasma membrane and the basement membrane of the muscle fibres. They function in maintenance, regeneration and growth of skeletal muscle. <br /> <br /> b) Satellite cells are activated after a period of prolonged exercise, their responsiveness influences muscle adaptations. In cases of muscle injury, satellite cells are activated. They then proliferate and fuse together to form new muscle fibres.<br /> <br /> 2. Injury or death of motor neurons generally results in the denervation of the muscle fibres. This means that muscles are no longer able to function as they used to and hence the muscle cells will undergo atrophy and may eventually die. Or, an adjacent neuron may reinnervate the muscle fibres. Muscle atrophy leads to a decrease in muscle mass which results in an increase of fat storage and decrease of metabolic rate.<br /> <br /> ===Lab 8 Assessment===<br /> <br /> Vision:<br /> Good introduction, introduces the main components of the eye that will assumedly be focused on when talking about development. More information is needed in the history section however and the images used also need copyright permission.<br /> <br /> Wording is simple and understandable, it’s also good to see that you guys have a glossary up so to make it easier to comprehend what is being read. However you need more information under current research. Also you should focus on the other components of the eye other than the Optic nerve and the Retina and add more pictures or diagrams to illustrate what it is you’re explaining.<br /> <br /> You should also try using some dot points because reading long paragraphs could get tiring and allow the person to lose focus.<br /> <br /> <br /> Taste:<br /> The overall set up of the page I think is very good. In the introduction there is a balance between pictures and text which makes it a bit easier to read. Also its easy to follow, the text itself isn’t confusing and is understandable.<br /> <br /> There is a good overview of the different types of receptors and their function, also there is a brief section on the adult tongue which is good, however there needs to be more focus on the embryological development rather than just a simple table on that. There also needs to be some images added to that component as well to make it more understandable. <br /> <br /> The sections on abnormalities and current research need to be organised a bit better because they are a little hard to follow, especially with the placing of the images. The glossary is simple and understandable, however there needs to be more work done on the reference list. <br /> <br /> <br /> Olfaction:<br /> The work needs to be spell checked before you submit it, make sure you get all your grammar right as well. I think you should add more to your introduction, and make it a little simpler, easier to follow. Also throughout your project you tend to use a lot of long paragraphs, especially in the current research section.<br /> <br /> Though the developmental timeline that is set up is very detailed, it can be a bit hard to follow and a little confusing. There is too much text and no pictures at all to help demonstrate what is being said about the development. The ratio of images to text in the anatomy and abnormalities sections however is very good and makes it more interesting to read. <br /> <br /> It’s good to see that you have some external links put up on the page and also that you’ve used quite a few references to do your research rather than just a few. <br /> <br /> <br /> Abnormal Vision:<br /> The text on this page is very good, detailed and to the point. However a lot more images are needed on the page to make it more appealing, interesting and easier to follow. <br /> <br /> The section under Ocular Manifestations is a little difficult to keep track of, there needs to be more of an introduction in that section highlighting the two sections that are to be discussed, then there should be a clear division between the two. <br /> <br /> Also the placement of the few images on the page need to be organised a little better. The referencing on this page is done very well and its good to see an extensive use of resources. <br /> <br /> <br /> Hearing:<br /> This whole page I think is done really well. There is a balance between texts and images, it goes through the developmental process in detail, all information is relevant, there is an extensive use of resources and a pretty good glossary as well. <br /> The image right at the beginning of the dog is very smart as it draws attention to the whole page. Also the “Can you hear me” at the beginning gives the expectation that the page as a whole is going to be really good so I thought that was very effective. <br /> More information can be added to the current research section, and also you should try referencing throughout the entire page could be done a little better.<br /> <br /> <br /> ===Lab 8 Assessment===<br /> <br /> 2. The cells that form the tooth bud originate from the ectomesenchyme, the neural crest and the ectoderm. The embryonic development first begins late in stage 18. The tooth buds are formed via interaction between the neural crest and the ectoderm. The ectomesenchume surrounds the tooth bud and forms the dental follicle.</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105047 2012-10-02T15:26:05Z

<p>Z3375390: /* Glossary */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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 globrous 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;709739&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> ;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105037 2012-10-02T15:02:20Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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 globrous 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;709739&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105035 2012-10-02T15:00:06Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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 globrous 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;709739&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> <br /> <br /> Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105033 2012-10-02T14:52:20Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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 globrous 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;709739&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105022 2012-10-02T14:26:01Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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 globrous 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> <br /> 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105021 2012-10-02T14:20:40Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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 globrous 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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.<br /> <br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105019 2012-10-02T14:19:22Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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 globrous 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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.<br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105018 2012-10-02T14:17:56Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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 globrous 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> 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. <br /> <br /> 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.<br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105014 2012-10-02T14:10:19Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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 globrous 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> 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. <br /> <br /> 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.<br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105008 2012-10-02T13:54:02Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> 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. &lt;ref&gt;&lt;pubmed&gt;1244282&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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 globrous 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> * Merkel cells respond to pressure of the skin, epidermis of globrous skin<br /> ** Located superficially<br /> ** Slow adapting<br /> ** Respond to very low frequency pressure changes<br /> ** Very small receptive fields<br /> <br /> 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.<br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=105004 2012-10-02T13:51:15Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> 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. <br /> <br /> 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 globrous 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt; 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. <br /> <br /> <br /> * Merkel cells respond to pressure of the skin, epidermis of globrous skin<br /> ** Located superficially<br /> ** Slow adapting<br /> ** Respond to very low frequency pressure changes<br /> ** Very small receptive fields<br /> <br /> 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.<br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104997 2012-10-02T13:36:30Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> 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. <br /> <br /> 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 globrous 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> * Merkel cells respond to pressure of the skin, epidermis of globrous skin<br /> ** Located superficially<br /> ** Slow adapting<br /> ** Respond to very low frequency pressure changes<br /> ** Very small receptive fields<br /> <br /> 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.<br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104996 2012-10-02T13:30:44Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> 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. <br /> <br /> 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 globrous 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Ruffini endings are encapsulated, 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.&lt;ref&gt;&lt;pubmed&gt; 10759411&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> * Merkel cells respond to pressure of the skin, epidermis of globrous skin<br /> ** Located superficially<br /> ** Slow adapting<br /> ** Respond to very low frequency pressure changes<br /> ** Very small receptive fields<br /> <br /> 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.<br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104995 2012-10-02T13:29:34Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> 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. <br /> <br /> 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 globrous 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. &lt;ref&gt;&lt;pubmed&gt; 15470674&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Ruffini endings are encapsulated, 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. <br /> <br /> <br /> * Merkel cells respond to pressure of the skin, epidermis of globrous skin<br /> ** Located superficially<br /> ** Slow adapting<br /> ** Respond to very low frequency pressure changes<br /> ** Very small receptive fields<br /> <br /> 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.<br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104989 2012-10-02T13:23:09Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> {| width=600px<br /> |-bgcolor=&quot;CEDFF2&quot; <br /> | width=50px|'''Date'''<br /> | width=300px|'''Description''' <br /> |-<br /> | '''1875'''<br /> | 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<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1906''' <br /> | 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. <br /> |-<br /> | '''1947''' <br /> | Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus<br /> |-bgcolor=&quot;F5FAFF&quot; <br /> | '''1969''' <br /> | 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<br /> |- <br /> |placeholder<br /> |}<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |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. &lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt; 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.&lt;ref name=&quot;PMID15376326 &quot;&gt;&lt;pubmed&gt;15376326 &lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> | Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.&lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 &amp; 24, &lt;ref name=&quot;PMID2297894&quot;&gt;&lt;pubmed&gt;2297894&lt;/pubmed&gt;&lt;/ref&gt; corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. <br /> | Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> | Slow adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Fast/rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]<br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> 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&lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;&gt;&lt;pubmed&gt;16446141&lt;/pubmed&gt;&lt;/ref&gt;. 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.<br /> <br /> One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor &lt;ref name=&quot;PMID20888752&quot;&gt;&lt;pubmed&gt;20888752&lt;/pubmed&gt;&lt;/ref&gt;. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 &lt;ref name=&quot;PMID10398684&quot;&gt;&lt;pubmed&gt;10398684&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID22787056&quot;/&gt;. These RET+ neurons are important as it is from them that the thermosensory nerves are derived &lt;ref name=&quot;PMID22787056&quot;/&gt;. This switching is not complete at birth, only finishing at postnatal day 30 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> RET is an important receptor for glial-cell-derived neurotrophic factor &lt;ref name=&quot;PMID9354331&quot;&gt;&lt;pubmed&gt;9354331&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;. 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 &lt;ref name=&quot;PMID16446141&quot;/&gt;.<br /> <br /> 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 &lt;ref name=&quot;PMID15253936&quot;&gt;&lt;pubmed&gt;15253936&lt;/pubmed&gt;&lt;/ref&gt;. 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 &lt;ref name=&quot;PMID15253936&quot;/&gt;. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> 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. <br /> <br /> 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 globrous 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.<br /> <br /> Ruffini endings are encapsulated, 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. <br /> <br /> <br /> * Merkel cells respond to pressure of the skin, epidermis of globrous skin<br /> ** Located superficially<br /> ** Slow adapting<br /> ** Respond to very low frequency pressure changes<br /> ** Very small receptive fields<br /> <br /> 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.<br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104871 2012-10-02T11:14:19Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 29:<br /> * afferent fibres have extended 100-200μm into gray matter of the Dorsal Horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |<br /> |Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> |<br /> |Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> |Fast/rapidly adapting<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> Stay tuned!<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> 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. <br /> <br /> 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 globrous 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.<br /> <br /> <br /> * Ruffini endings respond to pressure in both hairy and glabrous skin (slow adapting receptor)<br /> ** Deeply located<br /> ** Innervated by A-beta fibres<br /> ** Large receptive fields<br /> ** Encapsulated<br /> ** Also respond to temperatures above 45 degrees <br /> * Merkel cells respond to pressure of the skin, epidermis of globrous skin<br /> ** Located superficially<br /> ** Slow adapting<br /> ** Respond to very low frequency pressure changes<br /> ** Very small receptive fields<br /> <br /> 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.<br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104868 2012-10-02T11:12:04Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 29:<br /> * afferent fibres have extended 100-200μm into gray matter of the Dorsal Horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |<br /> |Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> |<br /> |Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> |Fast/rapidly adapting<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 10%|'''Day of Developmental Day in Mice or Rat''' <br /> | width= 7%|'''Relative Developmental Day in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5''' in Mouse<br /> |'''Day 33''' <br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-13''' in Mouse<br /> |'''Days 30-42'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot; <br /> |'''E14''' in Rat<br /> |'''Day 40'''<br /> |Axons have reached their peripheral target &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5''' in Mouse<br /> |'''Day 52'''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17''' in Rat<br /> |'''Days 44-55''' <br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17''' in Rat<br /> |'''Day 55'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5''' in Rat<br /> |'''NA'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20''' in Mouse<br /> |'''NA'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2''' in Mouse<br /> |''' NA'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10''' in Rat<br /> |'''NA''' <br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> Stay tuned!<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> 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. <br /> <br /> Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to changes in pressure 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 globrous 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.<br /> <br /> <br /> * Ruffini endings respond to pressure in both hairy and glabrous skin (slow adapting receptor)<br /> ** Deeply located<br /> ** Innervated by A-beta fibres<br /> ** Large receptive fields<br /> ** Encapsulated<br /> ** Also respond to temperatures above 45 degrees <br /> * Merkel cells respond to pressure of the skin, epidermis of globrous skin<br /> ** Located superficially<br /> ** Slow adapting<br /> ** Respond to very low frequency pressure changes<br /> ** Very small receptive fields<br /> <br /> 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.<br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104813 2012-10-02T10:21:26Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory.png |thumb|450px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 29:<br /> * afferent fibres have extended 100-200μm into gray matter of the Dorsal Horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |<br /> |Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> |<br /> |Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> |Fast/rapidly adapting<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 5%|'''Embryonic Stage in Mice or Rat''' <br /> | width= 5%|'''Relative Embryonic Stage in Humans''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5'''<br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-14'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5 '''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17'''<br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10'''<br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> Stay tuned!<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> 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. <br /> <br /> Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to changes in pressure 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 globrous skin. This means they are mainly located within the extremities such as the palms and soles of feet. <br /> <br /> <br /> * Ruffini endings respond to pressure in both hairy and glabrous skin (slow adapting receptor)<br /> ** Deeply located<br /> ** Innervated by A-beta fibres<br /> ** Large receptive fields<br /> ** Encapsulated<br /> ** Also respond to temperatures above 45 degrees <br /> * Merkel cells respond to pressure of the skin, epidermis of globrous skin<br /> ** Located superficially<br /> ** Slow adapting<br /> ** Respond to very low frequency pressure changes<br /> ** Very small receptive fields<br /> <br /> 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.<br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104809 2012-10-02T10:12:05Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory.png |thumb|450px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 29:<br /> * afferent fibres have extended 100-200μm into gray matter of the Dorsal Horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |<br /> |Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> |<br /> |Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> |Fast/rapidly adapting<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 5%|'''Embryonic Stage in Mice''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5'''<br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-14'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5 '''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17'''<br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10'''<br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> Stay tuned!<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> 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. <br /> <br /> Meissner Corpuscles are also rapidly adapting pressure receptors, so they only respond to changes in pressure 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. <br /> <br /> <br /> * Ruffini endings respond to pressure in both hairy and glabrous skin (slow adapting receptor)<br /> ** Deeply located<br /> ** Innervated by A-beta fibres<br /> ** Large receptive fields<br /> ** Encapsulated<br /> ** Also respond to temperatures above 45 degrees <br /> * Merkel cells respond to pressure of the skin, epidermis of globrous skin<br /> ** Located superficially<br /> ** Slow adapting<br /> ** Respond to very low frequency pressure changes<br /> ** Very small receptive fields<br /> <br /> 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.<br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104805 2012-10-02T09:53:42Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory.png |thumb|450px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 29:<br /> * afferent fibres have extended 100-200μm into gray matter of the Dorsal Horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |<br /> |Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> |<br /> |Fast/Rapidly adapting &lt;ref name=&quot;PMID20064391&quot;&gt;&lt;pubmed&gt;20064391&lt;/pubmed&gt;&lt;/ref&gt;<br /> |[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']] <br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> | 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.&lt;ref name=&quot;PMID1365319&quot;&gt;&lt;pubmed&gt;1365319&lt;/pubmed&gt;&lt;/ref&gt; <br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> | Hair follicles are derivatives from basal cells, as they proliferate. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7517223&quot;&gt;&lt;pubmed&gt;7517223&lt;/pubmed&gt;&lt;/ref&gt;&lt;ref name=&quot;PMID168272&quot;&gt;&lt;pubmed&gt;168272&lt;/pubmed&gt;&lt;/ref&gt;<br /> |Fast/rapidly adapting<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 5%|'''Embryonic Stage in Mice''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5'''<br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-14'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5 '''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17'''<br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10'''<br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> Stay tuned!<br /> <br /> == Pressure ==<br /> <br /> 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. <br /> <br /> 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. <br /> <br /> * Ruffini endings respond to pressure in both hairy and glabrous skin (slow adapting receptor)<br /> ** Deeply located<br /> ** Innervated by A-beta fibres<br /> ** Large receptive fields<br /> ** Encapsulated<br /> ** Also respond to temperatures above 45 degrees <br /> * Merkel cells respond to pressure of the skin, epidermis of globrous skin<br /> ** Located superficially<br /> ** Slow adapting<br /> ** Respond to very low frequency pressure changes<br /> ** Very small receptive fields<br /> * Meisenrs corpuscles<br /> ** Located superficially<br /> ** Rapidly adapting with small receptive fields<br /> ** Small receptive fields spatial resolution is high <br /> <br /> 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.<br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104496 2012-10-01T14:38:05Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory.png |thumb|450px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 29:<br /> * afferent fibres have extended 100-200μm into gray matter of the Dorsal Horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Fast/rapidly adapting<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 5%|'''Embryonic Stage in Mice''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5'''<br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-14'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5 '''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17'''<br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10'''<br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> Stay tuned!<br /> <br /> == Pressure ==<br /> <br /> 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, Meissener corpuscles, Merkel discs and Ruffini nerve endings. <br /> <br /> 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. <br /> <br /> * Ruffini endings respond to pressure in both hairy and glabrous skin (slow adapting receptor)<br /> ** Deeply located<br /> ** Innervated by A-beta fibres<br /> ** Large receptive fields<br /> ** Encapsulated<br /> ** Also respond to temperatures above 45 degrees <br /> * Merkel cells respond to pressure of the skin, epidermis of globrous skin<br /> ** Located superficially<br /> ** Slow adapting<br /> ** Respond to very low frequency pressure changes<br /> ** Very small receptive fields<br /> * Meiseners corpuscles<br /> ** Located superficially<br /> ** Rapidly adapting with small receptive fields<br /> ** Small receptive fields spatial resolution is high <br /> <br /> 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.<br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> <br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104495 2012-10-01T14:36:45Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory.png |thumb|450px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 29:<br /> * afferent fibres have extended 100-200μm into gray matter of the Dorsal Horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Fast/rapidly adapting<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 5%|'''Embryonic Stage in Mice''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5'''<br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-14'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5 '''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17'''<br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10'''<br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> Stay tuned!<br /> <br /> == Pressure ==<br /> 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.<br /> <br /> 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, Meissener corpuscles, Merkel discs and Ruffini nerve endings. <br /> <br /> 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. <br /> <br /> * Ruffini endings respond to pressure in both hairy and glabrous skin (slow adapting receptor)<br /> ** Deeply located<br /> ** Innervated by A-beta fibres<br /> ** Large receptive fields<br /> ** Encapsulated<br /> ** Also respond to temperatures above 45 degrees <br /> * Merkel cells respond to pressure of the skin, epidermis of globrous skin<br /> ** Located superficially<br /> ** Slow adapting<br /> ** Respond to very low frequency pressure changes<br /> ** Very small receptive fields<br /> * Meiseners corpuscles<br /> ** Located superficially<br /> ** Rapidly adapting with small receptive fields<br /> ** Small receptive fields spatial resolution is high <br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> <br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1244282/?page=2<br /> <br /> http://onlinelibrary.wiley.com/doi/10.1002/dvdy.20156/full#sec1-4<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104494 2012-10-01T14:35:17Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory.png |thumb|450px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 29:<br /> * afferent fibres have extended 100-200μm into gray matter of the Dorsal Horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Fast/rapidly adapting<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 5%|'''Embryonic Stage in Mice''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5'''<br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-14'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5 '''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17'''<br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10'''<br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> Stay tuned!<br /> <br /> == Pressure ==<br /> 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.<br /> <br /> 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, Meissener corpuscles, Merkel discs and Ruffini nerve endings. <br /> <br /> 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. <br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> <br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1244282/?page=2<br /> <br /> http://onlinelibrary.wiley.com/doi/10.1002/dvdy.20156/full#sec1-4<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104493 2012-10-01T14:32:16Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory.png |thumb|450px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 29:<br /> * afferent fibres have extended 100-200μm into gray matter of the Dorsal Horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Fast/rapidly adapting<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 5%|'''Embryonic Stage in Mice''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5'''<br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-14'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5 '''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17'''<br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10'''<br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> Stay tuned!<br /> <br /> == Pressure ==<br /> 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.<br /> <br /> 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, Meissener corpuscles, Merkel discs and Ruffini nerve endings. <br /> <br /> 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. 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. <br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> <br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1244282/?page=2<br /> <br /> http://onlinelibrary.wiley.com/doi/10.1002/dvdy.20156/full#sec1-4<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104492 2012-10-01T14:30:12Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory.png |thumb|450px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 29:<br /> * afferent fibres have extended 100-200μm into gray matter of the Dorsal Horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Fast/rapidly adapting<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 5%|'''Embryonic Stage in Mice''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5'''<br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-14'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5 '''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17'''<br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10'''<br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> Stay tuned!<br /> <br /> == Pressure ==<br /> 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.<br /> <br /> 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, Meissener corpuscles, Merkel discs and Ruffini nerve endings. <br /> <br /> 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. <br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> <br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1244282/?page=2<br /> <br /> http://onlinelibrary.wiley.com/doi/10.1002/dvdy.20156/full#sec1-4<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104491 2012-10-01T14:28:18Z

<p>Z3375390: /* Pressure */</p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory.png |thumb|450px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 29:<br /> * afferent fibres have extended 100-200μm into gray matter of the Dorsal Horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Fast/rapidly adapting<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 5%|'''Embryonic Stage in Mice''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5'''<br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-14'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5 '''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17'''<br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10'''<br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> Stay tuned!<br /> <br /> == Pressure ==<br /> 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.<br /> <br /> 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, Meissener corpuscles, Merkel discs and Ruffini nerve endings. <br /> <br /> 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. 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. <br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> <br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1244282/?page=2<br /> <br /> http://onlinelibrary.wiley.com/doi/10.1002/dvdy.20156/full#sec1-4<br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104490 2012-10-01T14:23:25Z

<p>Z3375390: </p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory.png |thumb|450px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 29:<br /> * afferent fibres have extended 100-200μm into gray matter of the Dorsal Horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Fast/rapidly adapting<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 5%|'''Embryonic Stage in Mice''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5'''<br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-14'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5 '''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17'''<br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10'''<br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> Stay tuned!<br /> <br /> == Pressure ==<br /> 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.<br /> <br /> 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, Meissener corpuscles, Merkel discs and Ruffini nerve endings. <br /> <br /> 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. <br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> <br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1244282/?page=2<br /> <br /> http://onlinelibrary.wiley.com/doi/10.1002/dvdy.20156/full#sec1-4<br /> <br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104489 2012-10-01T14:21:23Z

<p>Z3375390: </p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory.png |thumb|450px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 29:<br /> * afferent fibres have extended 100-200μm into gray matter of the Dorsal Horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Fast/rapidly adapting<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 5%|'''Embryonic Stage in Mice''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5'''<br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-14'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5 '''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17'''<br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10'''<br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> Stay tuned!<br /> <br /> == Pressure ==<br /> 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.<br /> <br /> 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, Meissener corpuscles, Merkel discs and Ruffini nerve endings. <br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> <br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1244282/?page=2<br /> <br /> http://onlinelibrary.wiley.com/doi/10.1002/dvdy.20156/full#sec1-4<br /> <br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=2012_Group_Project_2&diff=104488 2012-10-01T14:19:42Z

<p>Z3375390: </p> <hr /> <div><br /> <br /> =Somatosensory Development=<br /> <br /> == Introduction ==<br /> 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, &amp; Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, &amp; 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.<br /> <br /> <br /> (Lagercrantz, Hanson, Evrard &amp; Rodeck, 2001)<br /> 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). <br /> <br /> 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, &amp; 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 &amp; Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.<br /> <br /> This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.<br /> <br /> == History of Discoveries ==<br /> 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 &amp; Rolls, 2006).<br /> <br /> == Central Somatosensory Differentiation ==<br /> <br /> ====Adult Central Somatosensory systems:====<br /> <br /> Ascending components of the Central Somatosensory system include; <br /> * the primary somatosensory cortex of the brain, <br /> * the trigeminal system: – receives sensory signals from the face; &lt;ref name=&quot;PMID8440772&quot;&gt;&lt;pubmed&gt; 8440772&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. &lt;ref name=&quot;PMID14485390&quot;&gt;&lt;pubmed&gt; 14485390&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> '''Dorsal column system and Lateral Spinothalamic tract:'''<br /> <br /> 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID1127457&quot;&gt;&lt;pubmed&gt;1127457&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> [[File:Somatosensory.png |thumb|450px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]<br /> <br /> '''Trigeminal System:'''<br /> <br /> 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.&lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> ==== Development of the Primary Somatosensory Cortex:====<br /> <br /> Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. &lt;ref name=&quot;PMID10764649&quot;&gt;&lt;pubmed&gt;10764649&lt;/pubmed&gt;&lt;/ref&gt; 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’. &lt;ref name=&quot;PMID4141363&quot;&gt;&lt;pubmed&gt;4141363&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID7721983&quot;&gt;&lt;pubmed&gt;7721983&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID2461788&quot;&gt;&lt;pubmed&gt;2461788&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; The VP afferents receiving information from the face and jaw differentiate before birth. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. &lt;ref name=&quot;PMID7962713&quot;&gt;&lt;pubmed&gt;7962713&lt;/pubmed&gt;&lt;/ref&gt; Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.<br /> <br /> ==== Making Connections between Afferent Sensory Fibres and the Central Nervous System (CNS)====<br /> <br /> 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.&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 23; <br /> * 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 &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> Stage 24:<br /> * the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * the afferents start to grow within the white matter (periphery of Spinal Cord)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 28 –<br /> * unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> * 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)&lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> Stage 29:<br /> * afferent fibres have extended 100-200μm into gray matter of the Dorsal Horn &lt;ref name=&quot;PMID2918087&quot;&gt;&lt;pubmed&gt;2918087&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Touch ==<br /> [[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]<br /> <br /> <br /> <br /> <br /> 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.&lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> 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. <br /> &lt;ref name=&quot;PMID20956378&quot;&gt;&lt;pubmed&gt;20956378&lt;/pubmed&gt;&lt;/ref&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> &lt;br /&gt;<br /> <br /> &lt;table&gt;<br /> {| width=100%<br /> |-bgcolor= &quot;FF9900 &quot;<br /> | width= 15%|'''Mechanoreceptors'''<br /> | width= 25%|'''Function'''<br /> | width= 25%|'''Embryonic Development'''<br /> | width= 10%|'''Degree/Extent of Response'''<br /> | width= 25%|'''Image''' <br /> |-bgcolor=&quot;FFFF99&quot;<br /> <br /> |'''Pacinian Corpuscles (lamellar corpuscles)'''<br /> | <br /> *Found in subcutaneous tissue of skin<br /> * Respond to the detection of changes in pressure against the skin in relation to vibrations sensations <br /> * Detection between rough and smooth surfaces<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot;<br /> |'''Meissner's Corpuscles'''<br /> |<br /> *Found in the dermal papillae under the epidermal layer of the skin<br /> *Respond to detection and changes of vibrations<br /> *Very sensitive, detection of light touch sensations<br /> |<br /> |Fast/Rapidly adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Merkel-cell Neurite Complexes'''<br /> |<br /> * Found in epidermal layer of skin in stratum basale<br /> *Responding to light touch sensations<br /> *Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects&lt;ref name=&quot;PMID21456507&quot;&gt;&lt;pubmed&gt;21456507&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFCC66&quot; <br /> |'''Ruffini Endings'''<br /> |<br /> *Found in the dermal and subcutaneous layers of skin<br /> *Responds to changes in joint movement; stretching and application of pressure to the skin surfaces<br /> *Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors<br /> |<br /> |Slow adapting<br /> |<br /> |-bgcolor=&quot;FFFF99&quot;<br /> |'''Hair follicles'''<br /> |<br /> *Response to movement/displacement of hair on the skin<br /> <br /> *Detection of sensation direction&lt;ref name=&quot;PMID11685414&quot;&gt;&lt;pubmed&gt;11685414&lt;/pubmed&gt;&lt;/ref&gt;<br /> |<br /> |Fast/rapidly adapting<br /> |[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']] <br /> |-bgcolor=&quot;FFCC66&quot;<br /> &lt;/table&gt;<br /> <br /> == Pain ==<br /> With the current advancements in study and research on the nervous system, the mechanisms responsible for the sensation or the sensory component of pain are now well understood. Different nerve fibres involved in the transmission of the pain impulse have been identified including the A-delta fibres, C fibres and A-beta fibres (Nakamura &amp; Morrison, 2008). The A-delta fibres have been identified with response to mechanical or thermal stimulation such as pin prick or scald while C fibres respond to thermal, mechanical and chemical stimulation (Silberstein, 2003). The C fibres are slower in response to simulation and particularly transmit the dull, thudding pain of injury, inflammation or disease. <br /> On the other hand, the A-beta fibres transmit touch and play a crucial role in the sensation of pain. Current research in the development of pain fibres has seen the classification of pain into fast and slow pain and the pain fibres responsible for transmission of the pain. Fast pain is transmitted by the A-delta fibers with the stimulus being more superficial stimulus. Slow pain starts one second or more after stimulation and increases slowly over seconds or minutes and has been found to be associated with tissue distraction as well as being felt in both superficial and deep tissues. The various nerve fibers carry somatosensory information from the body periphery to the spinal cord. According to Medina and Lebovic (2009), studies have revealed that some nerve fibers present in the endometriotic tissues are responsible for pain severity.<br /> <br /> <br /> ==== Development of Nociceptors ====<br /> <br /> Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.<br /> <br /> {| cellpadding=&quot;10&quot;<br /> |-style=&quot;background:#FF69B4&quot; &quot;align=&quot;center&quot; <br /> | width= 5%|'''Embryonic Stage in Mice''' <br /> | width=15%|'''Nociceptor Development''' <br /> |-bgcolor=&quot;pink&quot; <br /> |''' E11.5'''<br /> |Specification of Nociceptors in the Dorsal Root Ganglia &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |'''E11-14'''<br /> |Axons of Nociceptors begin extending to the periphery and towards the spinal cord &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |- bgcolor=&quot;pink&quot;<br /> |''' E14.5 '''<br /> |Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |''' E15-17'''<br /> |Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E17'''<br /> |TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; <br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18.5'''<br /> |Axons reach their peripheral Tissue &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''E18-20'''<br /> |Axons reach dorsal horn of the spinal cord &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P2'''<br /> |TRPV1 capsaicin receptor expressed &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt;<br /> |-bgcolor=&quot;pink&quot;<br /> |'''P4-10'''<br /> |NGF increases the sensitivity of Nociceptors &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> |}<br /> <br /> '''Details of Nociceptor Development'''<br /> <br /> '''Nociceptor Specification:'''<br /> <br /> Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. &lt;ref name=&quot;PMID490183&quot;&gt;&lt;pubmed&gt;490183&lt;/pubmed&gt;&lt;/ref&gt; Much of sensory neuron differentiation is done via neurotrophin signalling. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID8835730&quot;&gt;&lt;pubmed&gt;8835730&lt;/pubmed&gt;&lt;/ref&gt; This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. &lt;ref name=&quot;PMID15247919&quot;&gt;&lt;pubmed&gt;15247919&lt;/pubmed&gt;&lt;/ref&gt; TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. &lt;ref name=&quot;PMID22787056&quot;&gt;&lt;pubmed&gt;22787056&lt;/pubmed&gt;&lt;/ref&gt; One study has shown that mice without TrkA receptor are born without nociceptors. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt; Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt; Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. &lt;ref name=&quot;PMID16429136&quot;&gt;&lt;pubmed&gt;16429136&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Nociceptor Survival'''<br /> <br /> 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. &lt;ref name=&quot;PMID9283812&quot;&gt;&lt;pubmed&gt;9283812&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID8126547&quot;&gt;&lt;pubmed&gt;8126547&lt;/pubmed&gt;&lt;/ref&gt; Nociceptors that do not receive enough NGF will not survive. &lt;ref name=&quot;PMID8145823&quot;&gt;&lt;pubmed&gt;8145823&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> <br /> '''Growth of Axons - to the Spinal Cord and Periphery'''<br /> <br /> Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; These processes begin at embryonic day 11 to 13. &lt;ref name=&quot;PMID9920667&quot;&gt;&lt;pubmed&gt;9920667&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt; These molecules include:<br /> * Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons <br /> * PIK3 and Akt – increase the Diameter of the Axons <br /> * Akt – can also increase the branching of the axon &lt;ref name=&quot;PMID12123609&quot;&gt;&lt;pubmed&gt;12123609&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. &lt;ref name=&quot;PMID10701827&quot;&gt;&lt;pubmed&gt;10701827&lt;/pubmed&gt;&lt;/ref&gt; The axons project into the dorsal horn while maintaining in a somatotopic pattern. &lt;ref name=&quot;PMID2442203&quot;&gt;&lt;pubmed&gt;2442203&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt; This gives rise to the dermatomes. &lt;ref name=&quot;PMID7175742&quot;&gt;&lt;pubmed&gt;7175742&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> 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. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. &lt;ref name=&quot;PMID14749426&quot;&gt;&lt;pubmed&gt;14749426&lt;/pubmed&gt;&lt;/ref&gt; By embryonic day 18.5, neurons reach their peripheral target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Determination of the Physiological Phenotype of Nociceptors'''<br /> <br /> A lot of this functional development occurs postnatally. For example, TRPA1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . &lt;ref name=&quot;PMID16630838&quot;&gt;&lt;pubmed&gt;16630838&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt; 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). &lt;ref name=&quot;PMID11487631&quot;&gt;&lt;pubmed&gt;11487631&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Development of the Chemical Phenotype of Nociceptors'''<br /> <br /> In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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 – at this stage nociceptors have not made contact with their target tissues. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID9092599&quot;&gt;&lt;pubmed&gt;9092599&lt;/pubmed&gt;&lt;/ref&gt; &lt;ref name=&quot;PMID12733058&quot;&gt;&lt;pubmed&gt;12733058&lt;/pubmed&gt;&lt;/ref&gt; Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.<br /> <br /> <br /> '''Increase in the Nociceptor Innervation Density '''<br /> <br /> 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID10407031&quot;&gt;&lt;pubmed&gt;10407031&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> <br /> '''Increase in Nociceptor Sensitivity'''<br /> <br /> Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; 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. &lt;ref name=&quot;PMID12815188&quot;&gt;&lt;pubmed&gt;12815188&lt;/pubmed&gt;&lt;/ref&gt; It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt; NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. &lt;ref name=&quot;PMID15201308&quot;&gt;&lt;pubmed&gt;15201308&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Hot/Cold ==<br /> <br /> 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. <br /> <br /> 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&lt;ref name=&quot;PMID12838328&quot;&gt;&lt;pubmed&gt;12838328&lt;/pubmed&gt;&lt;/ref&gt;. 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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Warm===<br /> <br /> There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious&lt;ref name=&quot;PMID19822171&quot;&gt;&lt;pubmed&gt;19822171&lt;/pubmed&gt;&lt;/ref&gt;. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor unresponsive to mechanical stimuli, but can be excited by some chemicals such as the capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.<br /> <br /> * ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C&lt;ref name=&quot;PMID19822171&quot;/&gt;. 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.<br /> *''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.<br /> *''TRPV4''. Activated at 27 – 34 ˚C. <br /> <br /> ===Cold===<br /> <br /> 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. <br /> <br /> *''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. &lt;ref name=&quot;PMID12838328&quot;/&gt; &lt;ref name=&quot;PMID19822171&quot;/&gt;.<br /> *''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&lt;ref name=&quot;PMID12838328&quot;/&gt;.<br /> <br /> ===Embryology and Development===<br /> <br /> Stay tuned!<br /> <br /> == Pressure ==<br /> 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.<br /> <br /> <br /> <br /> Bunched receptors known as Merkel’s discs have been found to specialize in conveying information about continuous pressure exerted on the surface of the skin (Ragert, Nierhaus, Cohen &amp; Villringer, 2008). Pacinian corpuscles respond to quick changes in touch or pressure by firing off rapid bursts of signals before they decrease with time (Irie, Kato, Yakushji, Hirose &amp; Mizuta, 2011). 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 (Ino-Oka, Sekino, Kajikawa, Inooka, Imai &amp; Hashimoto, 2008). <br /> Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie &amp; Armour, 1992). Discovery of the pressure receptor locations in human bodies has been exploited in nursing interventions including the touch therapy or massage (Field, 1998). Massage therapy has been found to be effective in enhancing various clinical conditions including reduction of pain, diminishing of depression, enhancing attentiveness, promotion of immune function as well as promotion of growth and development of pre-term infants (Sanders, 2010).<br /> According to Field (1998), intentional stimulation of pressure receptors during massage therapy results in enhanced vagal activity associated with the diverse benefits accrued from massage therapy. Understanding of pressure receptors has been discovered to be important in the treatment of balance disorders. The pressure receptors in the skin detect bodily contact with the environment enabling control of the contact during treatment of balance disorders (George &amp; Athanasios, 1999).<br /> <br /> <br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1244282/?page=2<br /> <br /> http://onlinelibrary.wiley.com/doi/10.1002/dvdy.20156/full#sec1-4<br /> <br /> <br /> == Current Research ==<br /> <br /> ==== Somatosensory Activation by Corneal Pain:====<br /> <br /> <br /> <br /> [[File:Somatotopic Activation by corneal pain and eye blink.png |thumb|450px|Somatotopic Activation by corneal pain and eye blink]]<br /> <br /> Investigation is currently done on to localize somatotopic representation of pain from the cornea. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This type of research gives insight into the mechanism of chronic pain development in various eye conditions. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. &lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; 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).&lt;ref name=&quot;PMIDPMC3433421&quot;&gt;&lt;pubmed&gt;PMC3433421&lt;/pubmed&gt;&lt;/ref&gt; See figure<br /> <br /> <br /> ==== Sleep can Remodel the Somatosensory Cortex ====<br /> <br /> 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. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt; It was found that elimination of these filopodia occurred at a higher rate during sleep. &lt;ref name=&quot;PMID22058046&quot;&gt;&lt;pubmed&gt;22058046&lt;/pubmed&gt;&lt;/ref&gt;<br /> <br /> == Glossary ==<br /> <br /> ;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.<br /> ;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.<br /> <br /> == References ==<br /> &lt;references/&gt;<br /> <br /> <br /> ==External Links==<br /> {{External Links}}<br /> <br /> Link to Pacinian Corpuscle image<br /> <br /> 1. http://thediagram.com/3_1/pacinian.html<br /> <br /> 2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm<br /> <br /> Links to Meissner’s Corpuscle Images<br /> <br /> 1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg<br /> <br /> 2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg<br /> <br /> [http://neuroscience.uth.tmc.edu/s2/chapter02.html]<br /> <br /> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]<br /> <br /> [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]<br /> <br /> <br /> --[[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.<br /> <br /> ----<br /> <br /> {{2012Projects}}</div>

Z3375390 https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3375390&diff=103798 2012-09-26T01:21:15Z

<p>Z3375390: </p> <hr /> <div><br /> == Lab Attendance ==<br /> <br /> <br /> Lab 1 --[[User:Z3375390|Z3375390]] 11:49, 25 July 2012 (EST)<br /> <br /> Lab 2 --[[User:Z3375390|Z3375390]] 10:40, 1 August 2012 (EST)<br /> <br /> Lab 3 --[[User:Z3375390|Z3375390]] 10:07, 8 August 2012 (EST)<br /> <br /> Lab 4 --[[User:Z3375390|Z3375390]] 10:07, 15 August 2012 (EST)<br /> <br /> Lab 5 --[[User:Z3375390|Z3375390]] 10:07, 22 August 2012 (EST)<br /> <br /> Lab 6 --[[User:Z3375390|Z3375390]] 10:07, 29 August 2012 (EST)<br /> <br /> Lab 7 --[[User:Z3375390|Z3375390]] 10:01, 12 September 2012 (EST)<br /> <br /> Lab 8 --[[User:Z3375390|Z3375390]] 10:05, 19 September 2012 (EST)<br /> <br /> Lab 9 --[[User:Z3375390|Z3375390]] 11:21, 26 September 2012 (EST)<br /> <br /> ==Lab Assignments==<br /> ===Lab 1 Assessment===<br /> <br /> 1. The idea of In Vitro Fertilisation was influenced by the study of fertilisation of rabbit egg cells in test tubes. However as the cycle of human eggs is different to that of rabbits, further study and experimentation had to be done in order to achieve it. The first successful birth of an IVF baby occurred in 1978. <br /> Robert G. Edwards was awarded the Nobel Prize in 2010 for the development of In Vitro Fertilisation. <br /> [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/]<br /> <br /> <br /> ===Lab 2 Assessment===<br /> <br /> An important protein associated with the process of implantation is Rac1. It is of the RhoGTPases family of proteins, and aids the embryonic trophoblast with invasion of the endometrium. Together with a protein known as RhoA, they are able to regulate cell migration and motility. It has been proven that motility is required in order for the trophoblast to invade the endometrium and for the embryo to be implanted within the uterine wall.<br /> Rac1 is needed as it promotes the trophoblast invasion. However, as this process must be tightly controlled, the protein RhoA is needed in order to restrict it. Therefore a balance between the two proteins must be achieved for successful implantation of the embryo in the endometrium.<br /> <br /> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562412/<br /> <br /> ===Lab 3 Assessment===<br /> <br /> 1.Gestational age refers to the time between the end of the mother’s last menstrual cycle and the birth of the baby. It is measured in weeks and determined by the size of the fetus using ultrasound before birth. After birth it is determined by the babies weight, length and other features. Postfertilization age refers to the time passed since fertilization of the egg. The exact time of fertilization however cannot be determined, so therefore it is inferred. Usually, gestational age is two weeks longer than postfertilization age.<br /> <br /> Gestational age is used when describing human development as it can be clearly determined and hence the calculations are more accurate than postfertilizaton age. <br /> <br /> 2.Some of the tissues formed from the somites include skeletal muscle, skin and bone.<br /> <br /> * Skeletal muscle<br /> ** Skeletal muscle cells develop from the myotome<br /> ** Myoblasts undergo frequent division and merging in order to form myotubes<br /> ** As development of the muscle cells continues, the nuclei move from the centre to the periphery of the cell.<br /> * Dermis of the dorsal skin<br /> ** Develops from dermatome and wandering mesenchymal cells<br /> ** Lies between the epidermis and the hypodermis<br /> ** Collagen producing fibroblasts are found in the dermis<br /> ** Composed of two layer: <br /> *** Papillary layer <br /> *** Reticular layer – made of dense irregular connective tissue<br /> * Vertebrae<br /> ** Develops from sclerotome<br /> <br /> ===Lab 4 Assessment===<br /> 1. Invasive prenatal diagnostic techniques:<br /> *Amniocentesis<br /> **This procedure consists of a needle being inserted into the mothers lower abdomen and through to the amniotic cavity<br /> **Usually performed between weeks 14 and 20 when there is enough amniotic fluid present for the procedure to be successful <br /> **Fetal cells acquired from the amniotic fluid are grown in culture for analysis of chromosomes, biochemicals and molecular biology<br /> **Amniotic fluid can also be used to determine the maturity of the fetal lung in the third trimester<br /> **Fetal loss and maternal Rh sensitisation are risks associated with this procedure<br /> **It also increases fetal mortality rate by 0.5%<br /> *Chorionic Villus Sampling<br /> **Consists of a catheter passing through the cervix and into the uterus usualy via the vagina<br /> **Cells acquired from the placental chorionic villi are used in chromosome analysis in order to determine the karyotype of the fetus, can also be used for biochemical and molecular biologic analysis<br /> **Usually performed between weeks 9 and 13 of gestation<br /> **Limb defects in a fetus is an abnormality associated with CVS <br /> **It may also increase the morbidity rate of the fetus<br /> <br /> <br /> 2. Preterm delivered infants are at high risk of developing a chronic lung disease known as Bronchopulmonary Dysplasia (BPD). This abnormality arises after ventilator and oxygen therapy for respiratory failure, which is usually associated with premature birth. Indicators of BPD include arrested alveolar growth and lung vascular growth. These abnormalities continue after childhood, putting lung structure and function at risk. Arrested alveolar growth, onset emphysema and pulmonary hypertension have all been linked to BPD and preterm delivery. Hence it is important to understand the developmental procedure of alveoli and the underlying capillary network in order to develop therapies for lung diseases characterised by impaired alveolarization. Research of stem cells shows that cell-based treatments are possible to repair the damaged organs.<br /> <br /> Stem cells have been found to be capable of self-renewal and have the potential to differentiate into multiple cellular phenotypes. They play a very important role in organ repair and tissue regeneration throughout the life span of an organism. Embryonic stem cells are the most potent form of stem cells as they are able to differentiate into cell types derived from the mesoderm, endoderm and ectoderm. They are also capable extensive self-renewal. Adult stem cells however are very limited in the sense that they can only differentiated into a certain number of cell types and sometimes only one. Embryonic stem cells are therefore very useful in cell-replacement therapy. <br /> <br /> Embryonic stem cells could be used to regenerate lung cells destroyed by disease and injury. BPD could lead to a deficiency of Adult Stem Cells within the lung that contribute to the growth and maintenance of the alveoli, lung matrix and pulmonary microvasculature. Therefore, if these injured and limited cells were to be replaced with EBC's that could repopulate and help with lung growth, the lung can once again carry out its function.<br /> <br /> ===Lab 7 Assessment===<br /> <br /> 1. a) Muscle satellite cells are dormant cells located between the plasma membrane and the basement membrane of the muscle fibres. They function in maintenance, regeneration and growth of skeletal muscle. <br /> <br /> b) Satellite cells are activated after a period of prolonged exercise, their responsiveness influences muscle adaptations. In cases of muscle injury, satellite cells are activated. They then proliferate and fuse together to form new muscle fibres.<br /> <br /> 2. Injury or death of motor neurons generally results in the denervation of the muscle fibres. This means that muscles are no longer able to function as they used to and hence the muscle cells will undergo atrophy and may eventually die. Or, an adjacent neuron may reinnervate the muscle fibres. Muscle atrophy leads to a decrease in muscle mass which results in an increase of fat storage and decrease of metabolic rate.<br /> <br /> ===Lab 8 Assessment===<br /> <br /> Vision:<br /> Good introduction, introduces the main components of the eye that will assumedly be focused on when talking about development. More information is needed in the history section however and the images used also need copyright permission.<br /> <br /> Wording is simple and understandable, it’s also good to see that you guys have a glossary up so to make it easier to comprehend what is being read. However you need more information under current research. Also you should focus on the other components of the eye other than the Optic nerve and the Retina and add more pictures or diagrams to illustrate what it is you’re explaining.<br /> <br /> You should also try using some dot points because reading long paragraphs could get tiring and allow the person to lose focus.<br /> <br /> <br /> Taste:<br /> The overall set up of the page I think is very good. In the introduction there is a balance between pictures and text which makes it a bit easier to read. Also its easy to follow, the text itself isn’t confusing and is understandable.<br /> <br /> There is a good overview of the different types of receptors and their function, also there is a brief section on the adult tongue which is good, however there needs to be more focus on the embryological development rather than just a simple table on that. There also needs to be some images added to that component as well to make it more understandable. <br /> <br /> The sections on abnormalities and current research need to be organised a bit better because they are a little hard to follow, especially with the placing of the images. The glossary is simple and understandable, however there needs to be more work done on the reference list. <br /> <br /> <br /> Olfaction:<br /> The work needs to be spell checked before you submit it, make sure you get all your grammar right as well. I think you should add more to your introduction, and make it a little simpler, easier to follow. Also throughout your project you tend to use a lot of long paragraphs, especially in the current research section.<br /> <br /> Though the developmental timeline that is set up is very detailed, it can be a bit hard to follow and a little confusing. There is too much text and no pictures at all to help demonstrate what is being said about the development. The ratio of images to text in the anatomy and abnormalities sections however is very good and makes it more interesting to read. <br /> <br /> It’s good to see that you have some external links put up on the page and also that you’ve used quite a few references to do your research rather than just a few. <br /> <br /> <br /> Abnormal Vision:<br /> The text on this page is very good, detailed and to the point. However a lot more images are needed on the page to make it more appealing, interesting and easier to follow. <br /> <br /> The section under Ocular Manifestations is a little difficult to keep track of, there needs to be more of an introduction in that section highlighting the two sections that are to be discussed, then there should be a clear division between the two. <br /> <br /> Also the placement of the few images on the page need to be organised a little better. The referencing on this page is done very well and its good to see an extensive use of resources. <br /> <br /> <br /> Hearing:<br /> This whole page I think is done really well. There is a balance between texts and images, it goes through the developmental process in detail, all information is relevant, there is an extensive use of resources and a pretty good glossary as well. <br /> The image right at the beginning of the dog is very smart as it draws attention to the whole page. Also the “Can you hear me” at the beginning gives the expectation that the page as a whole is going to be really good so I thought that was very effective. <br /> More information can be added to the current research section, and also you should try referencing throughout the entire page could be done a little better.</div>

Z3375390