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== Introduction ==
 
== Introduction ==
The somatosensory system is an important subdivision of the somatic nervous system comprising of a collection of receptors, tracts and nuclei. The system components convey the sensations of vibrations, light touch, pain and temperature to the consciousness (Creath, Kiemel, Horak, & Jeka, 2008) The system is important in conveying information about the body position and movements with significant influence on the body balance (Wong, Collins, & Kaas, 2010).  The somatosensory system also plays an important role in motor control through conveying of feedback information about the muscular system dynamics including velocity of muscles, tension, length, joint position and movement and contact with the external environment. The system comprises of receptors in the muscles, skin, viscera and joints (Marani, 1994). The following picture shows the general organization of the somatosensory system.
 
  
 +
In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.<ref name="PMID23018205"><pubmed>23018205</pubmed></ref>
 +
These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain.
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Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. <ref name="PMID20956378"><pubmed>20956378 </pubmed></ref>  <ref name="PMID16310064"><pubmed>16310064 </pubmed></ref>
 +
[[File:Touch 2.JPG|thumb|400px| Touch]]
  
(Lagercrantz, Hanson, Evrard & Rodeck, 2001)
+
These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues.<ref name="PMID168272"><pubmed>168272</pubmed></ref>
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).
+
Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>
  
The somatosensory systems development begins during the gestation period specifically the third week into the gestation period. By the end of the 9th week the fetus has a fully developed nervous system with sensory and receptors present at the skin level (Stiles, Reilly, Levine, Trauner, & Nass, 2012). Development of the system entails development of nerve fibers and receptors in the fetus body system. Development of the somatosensory system involves progressive changes in the structural alignment, neurochemical and functional changes with majority of the development changes taking place during the gestation period. Somatosensory receptors develop in the various parts of the body to enable detection and reception of stimuli which is then transmitted through the nerve fibers to the central nervous system (Nakamura & Morrison, 2008). Development of the somatosensory system also entails subsequent development of pathways including the dorsal column-medial lemniscal system.
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Though there is currently little that is known about the embryonic development of the individual receptors of the somatosensory system, the earliest signs of these sensory components are of great interest. Stages from gestation through to embryonic periods of the development of the neural crest were examined. With most developmental activity occurring in the later periods of embryonic development- week 7-8, in relation to survival, innervations, derivatives, differentiation, genetic components and times of first appearance (through light microscopy) of these receptors.  
  
This project looks at the anatomy, function and development of the central somatosensory system and a range peripheral receptors on the skin.
+
To grasp the significance of this system in human survival and progression through life it is important to consider where it all began. Providing an overview of what is currently known about the embryonic development and roots of the somatosensory system and the progression of current scientific and medical research can advance individuals understanding.
  
 
== History of Discoveries ==
 
== History of Discoveries ==
 
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007).  Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion.  The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system.  Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord.  The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).
 
Weber recognized for his role in the study of the nervous system including the establishment of the Weber’s law (Giclu, 2007).  Some of the historical research conducted by Weber concerned the various aspects of nervous system including inhibition of impulse transmission, summation, adaptation and fusion.  The shift from philosophy to physiology can be attributed to Weber’s research work through which he influenced the view on the human system.  Other discoveries that followed Weber’s discoveries about the somatosensory system include the discovery that most receptor endings in the skin, the connection between the system and the spinal cord.  The other important historical discovery about the somatosensory system include the discovery of different kinds of electrical potential in the nervous systems not covered by Weber as the pioneer in the understanding of the nervous system (Deco & Rolls, 2006).
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 +
{| width=600px
 +
|-bgcolor="CEDFF2"
 +
| width=50px|'''Date'''
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| width=300px|'''Description'''
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|-
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| '''1875'''
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| Stimuli (both electrical and mechanical) applied on varies parts of the body was found to induce changes in the electrical activity of the brain - Richard Caton
 +
|-bgcolor="F5FAFF"
 +
| '''1906'''
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| Charles Sherrington demonstrated that different types of stimulation on nerves led to different responses.  Some nerves were found to activate when intense stimuli are applied, causing the sensation of pain. These receptors were given the name nociceptors.
 +
|-
 +
| '''1947'''
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| Somatosensory evoked potentials (SEPs) were recorded by George Dawson in patients with myoclonus
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|-bgcolor="F5FAFF"
 +
| '''1969'''
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| 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
 +
|-
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|placeholder
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|}
  
 
== Central Somatosensory Differentiation ==
 
== Central Somatosensory Differentiation ==
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Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord.  <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>
 
Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord.  <ref name="PMID1127457"><pubmed>1127457</pubmed></ref> From there, fibres go the lateral regions of the ventroposterior nucleus (VP) of the thalamus. From the thalamus, 3rd order neurons project out and into the primary somatosensory cortex so information can be processed. <ref name="PMID1127457"><pubmed>1127457</pubmed></ref>
  
[[File:Somatosensory.png |thumb|450px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]
+
[[File:Somatosensory Map.JPG|thumb|500px| Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts]]
  
 
'''Trigeminal System:'''
 
'''Trigeminal System:'''
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Stage 24:
 
Stage 24:
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>
+
* the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry  
 
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>
 
* the afferents start to grow within the white matter (periphery of Spinal Cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>
  
 
Stage 28 –
 
Stage 28 –
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>
+
* unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn  
 
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>
 
* axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)<ref name="PMID2918087"><pubmed>2918087</pubmed></ref>
  
Stage 29:
+
== Touch & Pressure ==
* afferent fibres have extended 100-200μm into gray matter of the Dorsal Horn  <ref name="PMID2918087"><pubmed>2918087</pubmed></ref>
 
 
 
== Touch ==
 
 
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]
 
[[File:Touch receptors in mammalian skin cartoon.jpg|thumb|450px| Division of Mechanoreceptors in the Skin]]
  
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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.  
 
The receptors that are established throughout embryonic development and are linked to touch are mechanoreceptors or transducers such as Pacinian Corpuscle, Meissner’s Corpuscle, Merkel-cell-neurite complexes, Ruffini endings and hair follicles. Function and development of these various receptors are demonstrated in the table below.  
 
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
 
<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
 +
<br />
 +
<br />
 +
<br />
 +
<br />
 +
<br />
 +
<br />
  
 
<table>
 
<table>
 
{| width=100%
 
{| width=100%
|-bgcolor= "FF9900 "
+
|-bgcolor= "FF9900 " "align="center"  
 
| width= 15%|'''Mechanoreceptors'''
 
| width= 15%|'''Mechanoreceptors'''
| width= 20%|'''Function'''
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| width= 25%|'''Function'''
| width= 15%|'''Embryonic Development'''
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| width= 25%|'''Embryonic Development'''
| width= 10%|'''Temporal Response'''
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| width= 10%|'''Degree/Extent of Response'''
| width= 40%|''Image''
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| width= 25%|'''Image'''  
 
|-bgcolor="FFFF99"
 
|-bgcolor="FFFF99"
  
|'''Pacinian Corpuscles'''
+
|'''Pacinian Corpuscles (lamellar corpuscles)'''
 +
|
 +
*Found in subcutaneous tissue of skin
 +
* Respond to the detection of changes in pressure against the skin in relation to vibrations sensations                                                                                                                             
 +
* Detection between rough and smooth surfaces<ref name="PMID20956378"><pubmed>20956378</pubmed></ref><ref name="PMID16545520"><pubmed>16545520</pubmed></ref>
 +
|Pacinian corpuscles, like other sensory receptors are derived by the dorsal root ganglia neurons of peripheral sensory axons. In embryonic development, these appear E 16.5 (embryonic day) in mice. <ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref> In human embryology, this corresponds to day 58-59, which is satge 23 and week 8 (final week of embryonic development). In order for development, they require tyrosine kinase receptor (TrK) signaling and nerve growth factor (NGF) gene.<ref name="PMID15376326 "><pubmed>15376326 </pubmed></ref>
 +
Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons.
 +
Development is dependent on sensory innervations.<ref name="PMID6203612"><pubmed>6203612</pubmed></ref>
 +
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
 +
|[[File:Pacinian corpuscle histology 03.jpg|thumb|right|200px|alt=Alt|''Histology of a Pacinian Corpuscle-Notice onion like structure''']]
 
|-bgcolor="FFCC66"
 
|-bgcolor="FFCC66"
 
|'''Meissner's Corpuscles'''
 
|'''Meissner's Corpuscles'''
 +
|
 +
*Found in the dermal papillae under the epidermal layer of the skin
 +
*Respond to detection and changes of vibrations
 +
*Very sensitive, detection of light touch sensations<ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
 +
|Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.<ref name="PMID2297894"><pubmed>2297894</pubmed></ref> As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in  the third trimester, which is between weeks 17 & 24, <ref name="PMID2297894"><pubmed>2297894</pubmed></ref> corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development.
 +
| Fast/Rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
 +
|[[File:Meissner corpuscle 01.jpg|thumb|right|200px|alt=Alt|''Histology of a Meissner Corpuscle in subcutaneous layers of the skin''']]
 
|-bgcolor="FFFF99"
 
|-bgcolor="FFFF99"
 
|'''Merkel-cell Neurite Complexes'''
 
|'''Merkel-cell Neurite Complexes'''
 +
|
 +
* Found superficially in epidermal layer of skin in stratum basale
 +
*Responding to light touch sensations
 +
*Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects<ref name="PMID21456507"><pubmed>21456507</pubmed></ref><ref name="PMID19898622"><pubmed>19898622</pubmed></ref>
 +
|Merkel cells are derivatives of the epidermis of the developing embryo. They are able to be seen, with short dendrites, as early as week 8 in embryonic development, within the stratum basale of the epidermis.<ref name="PMID1365319"><pubmed>1365319</pubmed></ref>
 +
Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
 +
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
 +
|[[File:Merkel Cell Neurite Complex.JPG|thumb|right|200px|alt=Alt|''Histology of a Merkel Cell Complex''']]
 
|-bgcolor="FFCC66"  
 
|-bgcolor="FFCC66"  
|'''Ruffine Endings'''
+
|'''Ruffini Endings'''
 +
|
 +
*Found in the deep dermal and subcutaneous layers of hairy and glabous skin
 +
*Large abundance at the joints
 +
*Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
 +
*Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors <ref name="PMID20956378"><pubmed>20956378</pubmed></ref>
 +
|Even more so than the other mechanoreceptors of touch, very little is known about the underlying embryological development of Ruffini endings. Studies have shown the need and role which certain neurotrophic factors play, such as neurotrophin NT3 in differentiation of slow adapting subtype mechanoreceptors from dorsal root ganglia and trigeminal ganglia.<ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
 +
| Slow adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
 +
|[[File:Ruffini Ending.JPG|thumb|right|200px|alt=Alt|''Ruffini Ending''']]   
 
|-bgcolor="FFFF99"
 
|-bgcolor="FFFF99"
 
|'''Hair follicles'''
 
|'''Hair follicles'''
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|
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*Response to movement/displacement of hair on the skin
 +
 +
*Detection of sensation direction<ref name="PMID11685414"><pubmed>11685414</pubmed></ref>
 +
|Hair follicles are derivatives from basal cells, as they proliferate. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref> Basal cells are able to be seen via light microscopy in the developing embryo; approximately on day 60 onwards (stage 23; week 8). As the embryo grows and transitions into the fetal stages, at approximately day 95 and 140, hair pegs and follicles are also able to be seen via light microscopy. <ref name="PMID7517223"><pubmed>7517223</pubmed></ref><ref name="PMID168272"><pubmed>168272</pubmed></ref>
 +
| Fast/rapidly adapting <ref name="PMID20064391"><pubmed>20064391</pubmed></ref><ref name="PMID20064382"><pubmed>20064382</pubmed></ref>
 +
|[[File:Touch Receptor- Hair Follicle.jpg|thumb|right|200px|alt=Alt|''Hair Follicle''']]
 
|-bgcolor="FFCC66"
 
|-bgcolor="FFCC66"
|{
+
</table>
<table>
+
 
 +
 
 +
 
 +
===Pressure===
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 +
The four receptors of the skin that pertain specifically to pressure of the somatosensory system are Pacinian corpuscles, Meissner corpuscles, Merkel discs and Ruffini nerve endings. As seen in the table above, they are categorized into two subtypes, either slow or fast adapting, depending on whether pressure is applied to the skin at low or high frequency rates.
 +
In addition, pressure receptors influencing the function of major body organs (baroreceptors) will be discussed in reference to their similarities with the above mechanoreceptors of the somatosensory system.
 +
 
 +
===='''The Slow Adapting Pressure Receptors'''====
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 +
Slow adapting receptors respond to consistent pressure, meaning they continue to respond as long as the stimulus is in contact with the skin.
 +
 
 +
'''Merkel Disc'''
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 +
The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. <ref name="PMID21456507"><pubmed>21456507</pubmed></ref>
 +
 
 +
'''Ruffiini Endings'''
 +
 
 +
Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.<ref name="PMID10759411"><pubmed>10759411</pubmed></ref> In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.
 +
 
 +
 
 +
 
 +
===='''The Rapidly Adapting Pressure Receptors'''====
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Rapidly adapting receptors only respond to changes in pressure, therefore, they respond when the stimulus first touches the skin and when it is removed.
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 +
'''Pacinian Corpuscles'''
 +
 
 +
Pacinian corpuscle are comprised of nerve endings that are wrapped with layers of connecting tissue giving them an ‘onion like’ histological appearance. When this connective tissue that surrounds the nerve ending is deformed, it presses on the nerve endings, triggering an electrical impulse. The receptive fields of the Pacinian corpuscles are relatively large, so the region of sensory space that stimulates and evokes activity in the receptors is wide and therefore the sensations are not very well localised, resulting in low spatial resolution. All of these features determine the rate and extent of response to pressure, elicited via the Pacinian corpuscles.
 +
 
 +
'''Meissner’s Corpuscles'''
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 +
Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.<ref name="PMID15470674"><pubmed>15470674</pubmed></ref>
 +
 
 +
 
 +
[[File:Pressure Receptors in Glabrous Skin.jpg|400px|alignment|"Pressure Receptor positions in glabrous skin"]]
 +
 
 +
 
 +
The development of pressure receptors takes place during the gestation period with the rapidly adapting pressure receptors developing first then followed by the slow adapting pressure receptors. Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults.
 +
 
 +
 
 +
'''Pressure Receptors Influencing Major Organs in The Body'''
 +
 
 +
Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.<ref name="PMID1244282"><pubmed>1244282</pubmed></ref><ref name="PMID709739"><pubmed>709739</pubmed></ref>
 +
 
 +

Different studies have established urinary bladder mechanoreceptors are responsible for detecting changes in bladder volume or intravesical pressure. Such receptors are sensitive to the stretching of the wall. Meaning, as the bladder begins to fill, its walls stretch which, in turn activates the mechanoreceptors present that send a signal to the brain conveying the amount of pressure being exerted.
 +
 
 +
===Genes Involved in Embryonic Development===
 +
 
 +
Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.<ref name="PMID22345400"><pubmed>22345400</pubmed></ref><ref name="PMID22103411"><pubmed>22103411</pubmed></ref>
 +
 
 +
 
 +
'''c-Maf'''
 +
 
 +
This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. <ref name="PMID22345400"><pubmed>22345400</pubmed></ref> <ref name="PMID22889842"><pubmed>22889842</pubmed></ref> <ref name="PMID22516617"><pubmed>22516617</pubmed></ref>
 +
 
 +
 
 +
'''Shox2'''
 +
 
 +
During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. <ref name="PMID22103411"><pubmed>22103411</pubmed></ref><ref name="PMID22516617"><pubmed>22516617</pubmed></ref>
  
 
== Pain ==
 
== Pain ==
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 & 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.
 
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.
 
  
  
==== Development of Nociceptors ====
+
'''Pain-sensing receptors are often referred to as nociceptors.'''  <ref name="PMID9537322"><pubmed>9537322</pubmed></ref>
 +
 
 +
There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor  are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. <ref name="PMID6282398"><pubmed>6282398</pubmed></ref> Nociceptors detect tissue damage, noxious thermal and chemical stimuli. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. <ref name="PMID9109489"><pubmed>9109489</pubmed></ref> <ref name="PMID10392853"><pubmed>10392853</pubmed></ref>
 +
 
 +
==== Development of Nociceptors - Summary ====
  
Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. E stands for embryonic while P stands for postnatal.
+
Nociceptors develop throughout embryonic, fetal and postnatal periods. The table below is a summary of nociceptor development. '''E''' stands for embryonic day while '''P''' stands for postnatal day.
  
 
{| cellpadding="10"
 
{| cellpadding="10"
 
|-style="background:#FF69B4" "align="center"  
 
|-style="background:#FF69B4" "align="center"  
| width= 5%|'''Embryonic Stage in Mice'''  
+
| width= 10%|'''Day of Developmental Day in Mice or Rat'''
 +
| width= 7%|'''Relative Developmental Day and Carnegie Stage in Humans'''  
 
| width=15%|'''Nociceptor Development'''  
 
| width=15%|'''Nociceptor Development'''  
 
|-bgcolor="pink"  
 
|-bgcolor="pink"  
|''' E11.5'''
+
|''' E11.5''' in Mouse
 +
|'''Day 33; Stage 14'''  
 
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
 
|Specification of Nociceptors in the Dorsal Root Ganglia <ref name="PMID490183"><pubmed>490183</pubmed></ref>
|- bgcolor="pink"
+
|- bgcolor="#FFE4E1"
|'''E11-14'''
+
|'''E11-13''' in Mouse
 +
|'''Days 30-42; Stage 13-17'''
 
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref>  <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
 
|Axons of Nociceptors begin extending to the periphery and towards the spinal cord <ref name="PMID9920667"><pubmed>9920667</pubmed></ref>  <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
|- bgcolor="pink"
+
|- bgcolor="pink"
|''' E14.5 '''
+
|'''E14''' in Rat
 +
|'''Day 40; Stage 16'''
 +
|Axons have reached their peripheral target <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
 +
|- bgcolor="#FFE4E1"
 +
|''' E14.5''' in Mouse
 +
|'''Day 52; Stage 20'''
 
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5  <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
 
|Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5  <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
 
|-bgcolor="pink"
 
|-bgcolor="pink"
|''' E15-17'''
+
|''' E15-17''' in Rat
 +
|'''Days 44-55; Stage 21-22'''  
 
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
 
|Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
+
|-bgcolor="#FFE4E1"
|'''E17'''
+
|'''E17''' in Rat
 +
|'''Day 55; Stage 22'''
 
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors,  are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>  
 
|TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors,  are expressed <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>  
 
|-bgcolor="pink"
 
|-bgcolor="pink"
|'''E18.5'''
+
|'''E18.5''' in Rat
 +
|'''Fetal Stages'''
 
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
 
|Axons reach their peripheral Tissue <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
|-bgcolor="pink"
+
|-bgcolor="#FFE4E1"
|'''E18-20'''
+
|'''E18-20''' in Mouse
 +
|'''Fetal Stages'''
 
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
 
|Axons reach dorsal horn of the spinal cord <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>
 
|-bgcolor="pink"
 
|-bgcolor="pink"
|'''P2'''
+
|'''P2''' in Mouse
 +
|'''Fetal Stages'''
 
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
 
|TRPV1 capsaicin receptor expressed <ref name="PMID16630838"><pubmed>16630838</pubmed></ref>
|-bgcolor="pink"
+
|-bgcolor="#FFE4E1"
|'''P4-10'''
+
|'''P4-10''' in Rat
 +
|'''Fetal Stages'''  
 
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
 
|NGF increases the sensitivity of Nociceptors <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
 
|}
 
|}
  
'''Details of Nociceptor Development'''
 
  
'''Nociceptor Specification:'''
+
 
 +
====Details of Nociceptor Development====
 +
 
 +
'''1. Nociceptor Specification:'''
  
 
Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>
 
Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. <ref name="PMID490183"><pubmed>490183</pubmed></ref> Much of sensory neuron differentiation is done via neurotrophin signalling. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Neurotrophin are growth factors that act by binding to neurotrophin receptors called Tyrosine kinase (Trk) receptors. Expression of Tyrosine kinase A (TrkA) receptors in Dorsal Root Ganglion (DRG) cells determines their fate as unmyelinated Nociceptors. <ref name="PMID8835730"><pubmed>8835730</pubmed></ref> This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. <ref name="PMID15247919"><pubmed>15247919</pubmed></ref> TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. <ref name="PMID22787056"><pubmed>22787056</pubmed></ref> One study has shown that mice without TrkA receptor are born without nociceptors. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref> Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref> Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. <ref name="PMID16429136"><pubmed>16429136</pubmed></ref>
 +
 +
[[File:One Nociceptor Specification.JPG|500px|Nociceptor Specification]]
  
  
'''Nociceptor Survival'''
+
'''2. Nociceptor Survival'''
  
 
Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>
 
Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. <ref name="PMID9283812"><pubmed>9283812</pubmed></ref> <ref name="PMID8126547"><pubmed>8126547</pubmed></ref> Nociceptors that do not receive enough NGF will not survive. <ref name="PMID8145823"><pubmed>8145823</pubmed></ref>
  
 +
[[File:Nociceptor survival.JPG|500px|Nociceptor Survival]]
  
  
'''Growth of Axons - to the Spinal Cord and Periphery'''
+
'''3. Growth of Axons - to the Spinal Cord and Periphery'''
  
Increases in axon length, width and branching are all controlled by neurotrophins such as NGF.  <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref>  <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>  After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
+
Increases in axon length, width and branching are all controlled by neurotrophins such as NGF.  <ref name="PMID9920667"><pubmed>9920667</pubmed></ref> These processes begin at embryonic day 11 to 13 in mice. <ref name="PMID9920667"><pubmed>9920667</pubmed></ref>  <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref>  After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. <ref name="PMID12123609"><pubmed>12123609</pubmed></ref> These molecules include:
 
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons  
 
* Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons  
 
* PIK3 and Akt – increase the Diameter of the Axons  
 
* PIK3 and Akt – increase the Diameter of the Axons  
 
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>
 
* Akt – can also increase the branching of the axon <ref name="PMID12123609"><pubmed>12123609</pubmed></ref>
  
During embryonic days 18-20, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>
+
During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. <ref name="PMID10701827"><pubmed>10701827</pubmed></ref> The axons project into the dorsal horn while maintaining in a somatotopic pattern. <ref name="PMID2442203"><pubmed>2442203</pubmed></ref> Similarly, as axons of sensory neurons such as nociceptors grow from the dorsal root ganglia to the periphery, the axons travel via specific pathways so that 1 spinal nerve innervates 1 region of skin. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref> This gives rise to the dermatomes. <ref name="PMID7175742"><pubmed>7175742</pubmed></ref>
 +
 
 +
Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth.  <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5 in rat, neurons reach their peripheral target tissues.  <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
 +
 
 +
[[File:Axon growth.JPG|500px|Axon Growth]]
 +
 
 +
 
 +
 
 +
'''4. Determination of the  Physiological Phenotype of Nociceptors'''
 +
 
 +
A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors .  <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand,  tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
  
Extracellular signalling molecules direct the growth of the axons to ensure they reach their correct targets. NGF increases sprouting of axons but this may lead to excessive nociceptive innervation of the peripheral tissue. <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth.  <ref name="PMID14749426"><pubmed>14749426</pubmed></ref> By embryonic day 18.5, neurons reach their peripheral target tissues.  <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>
 
  
 +
'''5. Development of the Chemical Phenotype of Nociceptors'''
  
'''Determination of the Physiological Phenotype of Nociceptors'''
+
In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>  Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.
  
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 .  <ref name="PMID16630838"><pubmed>16630838</pubmed></ref> These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand,  tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref> These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7). <ref name="PMID11487631"><pubmed>11487631</pubmed></ref>
 
  
 +
[[File:Chemical physiological phenotype of nociceptors.JPG|500px|File:Chemical physiological phenotype of nociceptors.JPG]]
  
'''Development of the Chemical Phenotype of Nociceptors'''
 
  
In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref>  Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 – at this stage nociceptors have not made contact with their target tissues. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> Thus nociceptors do not require contact with peripheral target tissues to express some levels of SP and CGRP. However, studies also show that number of CGRP expressing nociceptors increased under the influence of epidermal cells. <ref name="PMID9092599"><pubmed>9092599</pubmed></ref> <ref name="PMID12733058"><pubmed>12733058</pubmed></ref> Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.
 
  
  
'''Increase in the Nociceptor Innervation Density '''
+
'''6. Increase in the Nociceptor Innervation Density '''
  
 
Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>
 
Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref> This increase in innervation density involves an increase in both the innervation of the tissue by the endings of an individual sensory neuron and the number of neurons. <ref name="PMID10407031"><pubmed>10407031</pubmed></ref>
 +
 +
[[File:Nociceptor Innervation Increases.JPG|400px|File:Nociceptor Innervation Increases.JPG]]
  
 
      
 
      
'''Increase in Nociceptor Sensitivity'''
+
'''7. Increase in Nociceptor Sensitivity'''
  
Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
+
Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> This process involves NGF activating TrkA receptor which initiates a signalling pathway that results in the sensitisation of the receptor, TRPV1 to heat and capsaicin. <ref name="PMID12815188"><pubmed>12815188</pubmed></ref> It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref> NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. <ref name="PMID15201308"><pubmed>15201308</pubmed></ref>
  
 
== Hot/Cold ==
 
== Hot/Cold ==
Line 190: Line 345:
 
===Warm===
 
===Warm===
  
There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor 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.
+
There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious<ref name="PMID19822171"><pubmed>19822171</pubmed></ref>. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.
  
* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperatures rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system.
+
* ''TRPV1''. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C<ref name="PMID19822171"/>. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.  
 
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
 
*''TRPV2''. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C <ref name="PMID12838328"/> <ref name="PMID19822171"/>.
 
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
 
*''TRPV3''. Activated strongly by temperatures in the 34-38 ˚C range.
Line 206: Line 361:
 
===Embryology and Development===
 
===Embryology and Development===
  
Stay tuned!
+
[[File:Thermoreceptor development diagram.JPG|thumb|450px|right|Diagram of thermosensation development]]
 +
 
 +
 
 +
The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system<ref name="PMID22787056"><pubmed>22787056</pubmed></ref>. The actual expression of thermoTRP channels, the functional unit of thermosensation, occurs quite late. TRPM8, the receptor for cold and menthol stimuli, is first seen in the mouse embryo at day 16.5 post conception <ref name="PMID16446141"><pubmed>16446141</pubmed></ref>. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.
 +
 
 +
One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor <ref name="PMID20888752"><pubmed>20888752</pubmed></ref>. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 <ref name="PMID10398684"><pubmed>10398684</pubmed></ref>. The TrkA lineage neurons are an important source of sensory nerves. Approximately half of them continue to express TrkA during development, the other half ceasing TrkA expression and beginning to produce RET<ref name="PMID22787056"/>. These RET+ neurons are important as it is from them that the thermosensory nerves are derived <ref name="PMID22787056"/>. This switching is not complete at birth, only finishing at postnatal day 30 <ref name="PMID16446141"/>.
 +
 
 +
RET is an important receptor for glial-cell-derived neurotrophic factor <ref name="PMID9354331"><pubmed>9354331</pubmed></ref>. It is in these neurons that another important protein is present called Runx1. Runx1 is a runt domain protein. These proteins are involved in mediating many developmental processes <ref name="PMID16446141"/>. The role of Runx1 in controlling the development of the thermoTRP channels used in thermosensation can be observed by breeding Runx1 deficient mice. These mice do not express TRPM8, and the expression of heat sensors TRPV1 and TRPV2 is very deficient <ref name="PMID16446141"/>.
 +
 
 +
A more broadly acting protein, but just as important as those already mentioned, is Brn3a. This is a protein that is involved in the differentiation of neurons into peripheral sensory neurons <ref name="PMID15253936"><pubmed>15253936</pubmed></ref>. It is an example of a homeodomain proteins, that is, it controls the transcription of a range of genes. When Brn3a is deficient, the axonal growth of the sensory neurons is impaired and they also go through apoptosis at a more rapid rate <ref name="PMID15253936"/>.  This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.
 +
 
 +
== Abnormalities of the Somatosensory Development ==
  
== Pressure ==
 
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 (Kinkelin, Stucky, L & Koltzenburg, 1999). Although these pressure receptors are present throughout the fetal life to adulthood, their depolarization responses to chemical irritants, mechanical injury and inflammatory mediators are been found to be similar in both the fetus and adults. Pressure-sensitive receptors of different types found in the skin where they detect changes in pressures. They respond to physical contact such as brushing against a wall, mosquito landing site or any form of touch on the skin.
 
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 & 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 & 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 & Hashimoto, 2008). 
 
Different studies have established urinary bladder mechanoreceptors as responsible for detecting changes in bladder volume or intravesical pressure (Downie & 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).
 
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 & Athanasios, 1999).
 
  
* Pressure receptors consists of nerve endings encapsulated by specialized connective tissue
+
'''This table shows diseases that can affect the development of the somatosensory development. These abnormalities are not diseases of the somatosensory system specifically but they do affect the development of the somatosensory cortex or the peripheral touch receptors.'''
* A-beta receptors:
 
** Ruffini endings respond to pressure in both hairy and glabrous skin (slow adapting receptor)
 
** Krause corpuscle respond to pressure in lips, tongue and genitals
 
* Merkel cells respond to pressure of the skin, epidermis of globrous skin
 
* Pacinian corpuscles:
 
** Found in the deeper layers of the skin
 
** Rapidly adapting receptors
 
** Consists of a nerve ending with layers of connective tissue wrapped around it
 
** When the connective tissue is deformed due to pressure, it presses on the nerve endings which trigger an electrical impulse
 
** Respond to transient pressure
 
** Development is dependent on sensory innervations
 
** Corpuscles form in the dermis, hypodermis, surfaces of muscles, tendons and aponeuroses
 
** First appear during the fourth foetal month of development
 
  
  
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1244282/?page=2
 
  
http://onlinelibrary.wiley.com/doi/10.1002/dvdy.20156/full#sec1-4
+
{| cellpadding="10"
+
|-style="background:#00FFFF" "align="center"
 +
| width= 5%|'''Disease'''
 +
| width= 15%|'''Description of Disease'''
 +
| width= 20%|'''Cause of Disease and Link to Embryology'''
 +
|- bgcolor="#AFEEEE"
 +
|'''Minamata disease (Methylmercury poisoning) related Somatosensory Disorders'''
 +
| MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. <ref name="PMID19819550"><pubmed>19819550</pubmed></ref>
 +
|Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. <ref name="PMID 16087068"><pubmed>16087068</pubmed></ref> This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref> Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. <ref name="PMID16087068"><pubmed>16087068</pubmed></ref>
 +
|- bgcolor="#E0FFFF"
 +
|'''Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex'''
 +
| Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. <ref name="PMID3623561"><pubmed>3623561</pubmed></ref> Similar results were found in a swedish study. <ref name="PMID3953668"><pubmed>3953668</pubmed></ref>
 +
|As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. <ref name="PMID12691840"><pubmed>12691840</pubmed></ref>
 +
|-bgcolor="#AFEEEE"
 +
|'''Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia'''
 +
|In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
 +
|Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. <ref name="PMID9818942"><pubmed>9818942</pubmed></ref>
 +
|}
  
 
== Current Research ==
 
== Current Research ==
Line 252: Line 415:
 
== Glossary ==
 
== Glossary ==
  
 +
;Apraxia: a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [http://dictionary.reference.com/browse/apraxia]
 +
;Astereognosis: the inability to determine the shape of an object by touching or feeling it [http://dictionary.reference.com/browse/astereognosis]
 +
;Cutaneous: Used for describing if a nerve, receptor or cell is affecting or associating with skin.
 +
;Dermis: Layer of skin between the epidermis and subcutaneous tissue
 +
;Dermal Papillae: Most superficial layer of the dermis
 +
;Epidermis: Most exterior/outer layer of skin
 
;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
 
;Innocuous: A stimulus that poses no threat of harming the tissues and structures of the body.
 +
;Neutrophins: Neurotrphic growth factors – proteins supporting the growth and survival of neurons
 
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
 
;Noxious: A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
 +
;Receptive Field: an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
 +
;Schwann cells: Primary glia, non-neuronal cells. Supporting homeostasis in the body, neuron growth and formation of myelin.
  
 
== References ==
 
== References ==
Line 262: Line 434:
 
{{External Links}}
 
{{External Links}}
  
Link to Pacinian Corpuscle image
 
 
1. http://thediagram.com/3_1/pacinian.html
 
 
2. http://www.biologymad.com/nervoussystem/nerveimpulses.htm
 
  
Links to Meissner’s Corpuscle Images
+
[http://thediagram.com/3_1/pacinian.html Additional Pacinian Corpuscle Image 1]
  
1. http://www.siumed.edu/~dking2/intro/images/IN038b.jpg
+
[http://www.biologymad.com/nervoussystem/nerveimpulses.htm Additional Pacinian Corpuscle Image 2]
  
2. http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg
+
[http://www.siumed.edu/~dking2/intro/images/IN038b.jpg Additional Meissner Corpuscel Image 1]
  
[http://neuroscience.uth.tmc.edu/s2/chapter02.html]
+
[http://www.virtualworldlets.net/Worlds/Listings/BodySenses/Texture-MeissnerCorpuscle.jpg Additional Meissner Corpuscle Image 2]
  
[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez]
+
[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705296/?tool=pmcentrez Comparative study between encapsulated and capsulated nerve/receptor cells]
  
[http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0190962205027027]
 
  
  

Latest revision as of 18:30, 5 October 2012


Somatosensory Development

Introduction

In the beginning of life and development, knowledge and discovery of surroundings is initiated through the somatosensory system. The somatosensory system has multiple components contributing to the ‘natural’ senses/responses to mechanical or external stimuli. When skin is altered, for example through stretch, receptors and neural processes become activated and lead to responses of sensory modalities. These include touch, pressure, pain and temperature.[1] These modalities allow for individuals to distinguish and recognize textures, shape, changes in temperature and degrees/levels of pain. Receptors that stimulate the sensory modalities are mechanoreceptors, nocioreceptors and thermoreceptors. [2] [3]

Touch

These somatosensory receptors are found mainly within layers of the skin, from superficial to deep dermal layers and some, which are found within joints and muscle tissues.[4] Information is passed through these receptors, as a result of action potentials, via sensory nerves and ganglia (dosal root). Through afferent neuron synapses the periphery is able to communicate with the spinal cord, somatosensory cortex and facial regions, causing sensory recognition of stimulus. Thus creating a communication bridge between peripheral innervation by external stimulus and the central nervous system (CNS). [5]

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

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

History of Discoveries

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

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

Central Somatosensory Differentiation

Adult Central Somatosensory systems:

Ascending components of the Central Somatosensory system include;

  • the primary somatosensory cortex of the brain,
  • the trigeminal system: – receives sensory signals from the face; [6]
  • the dorsal column system and lateral spinothalamic tract:– receive signals from the rest of the body. [7] [8]

Dorsal column system and Lateral Spinothalamic tract:

Peripheral sensory neurons enter the spinal cord via the dorsal root ganglion. The sensory signal then get passed onto collateral fibres in the spinal cord which ascend via the dorsal column or lateral spinothalamic tract up the spinal cord. [8] 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. [8]

Somatosensory pathway involving Dorsal Column and Lateral Spinothalamic tracts

Trigeminal System:

Sensory signals from the face are passed through the trigeminal nerve which passes signals to the trigeminal sensory nucleus. Axons from this trigeminal sensory nucleus go to the medial regions of the VP of the thalamus. From there fibres conduct the signals to the primary somatosensory cortex.[9]

Development of the Primary Somatosensory Cortex:

Development of the primary somatosensory cortex is thought be controlled by both intrinsic factors and extrinsic factors. [10] 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’. [11] 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). [12] 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). [13] These thalamocortical afferents of the VP and POm provide information that patterns the developing primary somatosensory cortex. [13] 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. [13]

VP afferents develop just prior to the development of the area of the somatosensory cortex that will process the information from these VP afferents. [9] The VP afferents receiving information from the face and jaw differentiate before birth. [9] 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. [9] This will be followed by the development of the medial regions of the somatosensory cortex that processes the information from the body. [9] Consequently, there’s a lateral to medial gradient of somatosensory cortex development which controlled by the VP afferents from the thalamus.

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

This is the process where sensory afferents synapse the neurons in the spinal cord so peripheral somatosensory information can be transmitted through the spinal reflex arc or up to the primary somatosensory cortex where the information can be processed. Sensory afferents from the periphery, with their cell bodies (soma) in the dorsal root ganglion, grow towards the spinal cord in stages to make these connections with the CNS.[5]

Stage 23;

  • Axons of primary afferent neurons extend to the spinal cord. When these afferent neurons reach the CNS, axons of these afferent neurons bifurcate and begin to extend into the Primordium of the dorsal funiculus [5]


Stage 24:

  • the afferent axons have extended 1 segment rostrally and 1 segment caudally relative to the axons' point of entry
  • the afferents start to grow within the white matter (periphery of Spinal Cord)[5]

Stage 28 –

  • unbranched afferent axonal fibres invade gray matter at the border of Dorsal horn
  • axonal fibres extend rostrally and caudally and start sending fine collateral fibres into the gray matter of spinal cord (the cellular, central region of spinal cord)[5]

Touch & Pressure

Division of Mechanoreceptors in the Skin



The sense of touch allows individuals to perform a myriad of functions through the receptors deep within dermal and epidermal layers of the skin. This sensory modality, though its' development is not greatly understood among the five acknowledged sense subsets, it is essential for survival and development throughout life.[2]


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. [2]





Mechanoreceptors Function Embryonic Development Degree/Extent of Response Image
Pacinian Corpuscles (lamellar corpuscles)
  • Found in subcutaneous tissue of skin
  • Respond to the detection of changes in pressure against the skin in relation to vibrations sensations
  • Detection between rough and smooth surfaces[2][14]
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. [15] 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.[15]

Formation occurs in the dermis, hypodermis, the surfaces of muscle and tendons. Development is dependent on sensory innervations.[16]

Fast/Rapidly adapting [17][18]
Alt
Histology of a Pacinian Corpuscle-Notice onion like structure'
Meissner's Corpuscles
  • Found in the dermal papillae under the epidermal layer of the skin
  • Respond to detection and changes of vibrations
  • Very sensitive, detection of light touch sensations[2]
Mechanoreceptors hypothesized to be derived from Schwann cells, through monkey and mouse models.[19] As embryo grows, these receptors mature, axons ascend and are restricted to the dermal papillae. [19] In a monkey model, Meissner’s corpuscles begin/first show signs of differentiation in the third trimester, which is between weeks 17 & 24, [19] corresponding to human development by plus/minus 10 days (1week-18-25weeks), which is well passed embryonic and into fetal development. Fast/Rapidly adapting [17][18]
Alt
Histology of a Meissner Corpuscle in subcutaneous layers of the skin'
Merkel-cell Neurite Complexes
  • Found superficially in epidermal layer of skin in stratum basale
  • Responding to light touch sensations
  • Involved in spatial differentiation through touch; establishment of shapes, sizes and textures of objects[20][21]
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.[22]

Further studies suggest that they have originated from the neural crest, or possibly differentiated from the fetal epidermal keratinocyte. [20]

Slow adapting [17][18]
Alt
Histology of a Merkel Cell Complex'
Ruffini Endings
  • Found in the deep dermal and subcutaneous layers of hairy and glabous skin
  • Large abundance at the joints
  • Responds to changes in joint movement; stretching and application of pressure to the skin surfaces
  • Contributes in holding/gripping objects. E.g. sensation of an object slipping though fingers is recognized by these receptors [2]
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.[18] Slow adapting [17][18]
Alt
Ruffini Ending'
Hair follicles
  • Response to movement/displacement of hair on the skin
  • Detection of sensation direction[23]
Hair follicles are derivatives from basal cells, as they proliferate. [24] 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. [24][4] Fast/rapidly adapting [17][18]
Alt
Hair Follicle'


Pressure

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

The Slow Adapting Pressure Receptors

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

Merkel Disc

The most abundant pressure receptor in the body would be the Merkel disc. They are found in both hairy and glabrous skin, as well as some mucosa. They only respond to very low frequency pressure changes. They are unencapsulated receptors with very small receptive fields that are able to localise the sensation very well as they are closer to the surface of the skin. [20]

Ruffiini Endings

Ruffini endings are encapsulated, slow adapting type II receptors that respond to consistent pressure. They are known to be innervated by A-beta fibres and to have large receptive fields similar to that of Pacinian Corpuscles. The pressure sensations detected by the Ruffini endings are therefore not very well localised.[25] In addition, Ruffini endings are surrounded by collagen fibres, parallel to the skin and therefore are highly sensitive to stretch sensation.


The Rapidly Adapting Pressure Receptors

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

Pacinian Corpuscles

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

Meissner’s Corpuscles

Meissner Corpuscles respond to transient and phasic pressures rather than constant pressure. Unlike Pacinian corpuscles however, their receptive field is small, so the sensations are well localised and specific. As a result of being superficially located in the glabious skin they are mainly within the extremities such as the palms and soles of feet. These corpuscles are innervated via myelinated fibres from the sub-epidermal nerve plexus that lose their myelination as they enter the corpuscle.[26]


"Pressure Receptor positions in glabrous skin"


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


Pressure Receptors Influencing Major Organs in The Body

Baroreceptors are special pressure receptors found in the right atrium of the heart and play the role of detecting changes in blood pressure enabling the body to control the pressure and the amount of blood flowing into the heart. They are also quite abundant in the Aortic Arch, where they are innervated by the Aortic Nerve, a branch of the Vagus nerve, as well as in the Carotid Sinus, where the Nerve of Hearing from the Glossopharyngeal nerve innervates the receptors. Baroreceptors are similar to Ruffini nerve endings in the sense that they respond to stretch. Changes in pressure within the vessels affect the stretch of the wall, which in turn activates the baroreceptors which sending a signal conveying this change.[27][28]


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

Genes Involved in Embryonic Development

Due to the limited understanding of the differentiation and development of the above mechanoreceptors, current literature is aimed at the transcription factors and genes that code for these particular receptors within the skin. Two genes that have been considered in recent findings are c-Maf transcription factor and Shox2.[29][30]


c-Maf

This proto-oncogene is closely related to development and function of rapidly adapting mechanoreceptors, especially Pacinian corpuscle. Mutations of c-Maf gene, in mouse models showed a decrease in the ability of Pacinian corpuscles to detect high frequency vibrations, due to receptor atrophy. C-Maf genes were found to regulate the expression of Ret+/MafA+ signaling pathways, which directly contribute to expression and innervation of Pacinian corpuscles. [29] [31] [32]


Shox2

During embryonic development Short stature homeobox 2 (SHox2) is expressed in various sensory receptors/neurons. In particular, they play a role in encoding for the development and function of Meissner’s corpuscle and Merkel cells. When tested in mutant mice, in vivo, this gene was responsible for the diversification of various mechanoreceptors. Due to the balance of suppression and expression pathways between Shox 2 and other genes such as Ret and/or tyrosine kinase receptors (TrkB and TrkC), subtypes develop. Specifically, Shox2 was found to be responsible for the differentiation of subclasses that expressed TrkB in relation to skin sensation/touch involving changes in vibration and those responsible for spatial awareness of shape and texture. [30][32]

Pain

Pain-sensing receptors are often referred to as nociceptors. [33]

There are mainly 2 types of afferent nociceptor fibres which are classified based on the degree of axon myelination. Nociceptor are mainly C-fibres that have unmyelinated axons. This means C-fibre nociceptors are slowly conducting fibres and responsible for dull, delayed pain. [34] Some nociceptors are thinly myelinated, rapidly adapting Aδ fibres which are responsible for conducting rapid and acute pain. [34] Nociceptors detect tissue damage, noxious thermal and chemical stimuli. [35] Once activated by these stimuli, they can release neuropeptides such as substance P (SP) and inflammatory mediators like prostaglandin E2 to stimulate inflammation. [35] [36]

Development of Nociceptors - Summary

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

Day of Developmental Day in Mice or Rat Relative Developmental Day and Carnegie Stage in Humans Nociceptor Development
E11.5 in Mouse Day 33; Stage 14 Specification of Nociceptors in the Dorsal Root Ganglia [37]
E11-13 in Mouse Days 30-42; Stage 13-17 Axons of Nociceptors begin extending to the periphery and towards the spinal cord [38] [39] [40]
E14 in Rat Day 40; Stage 16 Axons have reached their peripheral target [40]
E14.5 in Mouse Day 52; Stage 20 Substance P and CGRP are produced. Levels increase after nociceptors make contact with their target tissue in E18.5 [41]
E15-17 in Rat Days 44-55; Stage 21-22 Functional synaptic junctions form between nociceptors and interneurons as part of the reflex arc [41]
E17 in Rat Day 55; Stage 22 TTX resistant voltage-gated sodium channel Nav1.8, responsible for hyperexcitability of nociceptors, are expressed [42]
E18.5 in Rat Fetal Stages Axons reach their peripheral Tissue [41]
E18-20 in Mouse Fetal Stages Axons reach dorsal horn of the spinal cord [40]
P2 in Mouse Fetal Stages TRPV1 capsaicin receptor expressed [43]
P4-10 in Rat Fetal Stages NGF increases the sensitivity of Nociceptors [44]


Details of Nociceptor Development

1. Nociceptor Specification:

Birth of nociceptors occurs in the DRG at E11.5 (embryonic day 11.5) in mice. [37] Much of sensory neuron differentiation is done via neurotrophin signalling. [45] 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. [46] This because TrkA enables TrkA+ neurons to respond to certain neurotrophins, called nerve growth factor (NGF), that enable nociceptor differentiation. [47] TrkA signalling promotes the development of sensory channels in the nociceptors and this allows the nociceptors to respond to noxious stimuli. [48] One study has shown that mice without TrkA receptor are born without nociceptors. [45] Expression of TrkA receptors in nociceptors is up-regulated by the transcription factor Runx1. [49] Cells without the Runx1 gene result in an absence of TrkA receptors and were unable to develop to mature nociceptors. [49]

Nociceptor Specification


2. Nociceptor Survival

Once nociceptors are specified, receiving nerve growth factors (NGF) via the TrkA receptors increase the chance of their survival. This was shown by a study where NFG levels were over-expressed in transgenic mice and this caused the number of TrkA+ neurons to double. [50] [51] Nociceptors that do not receive enough NGF will not survive. [45]

Nociceptor Survival


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

Increases in axon length, width and branching are all controlled by neurotrophins such as NGF. [38] These processes begin at embryonic day 11 to 13 in mice. [38] [39] By embryonic day 14, small c fibres such as nociceptors have reached the periphery target tissue such as the hindlimb of mice. [40] After activation of the Trk receptors by NGF, downstream signalling molecules cause these changes in axon. [39] These molecules include:

  • Molecules in the Ras-Raf-ERK cascade – results in Elongation of the Axons
  • PIK3 and Akt – increase the Diameter of the Axons
  • Akt – can also increase the branching of the axon [39]

During embryonic days 18-20 in mice, axons of centrally directed nociceptors extend into the grey matter (dorsal horn) of the spinal cord. [40] The axons project into the dorsal horn while maintaining in a somatotopic pattern. [52] 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. [53] This gives rise to the dermatomes. [53]

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. [54] This issue is overcome by factor Semaphorin 3A which inhibits aberrant nociceptor axon growth. [54] By embryonic day 18.5 in rat, neurons reach their peripheral target tissues. [41]

Axon Growth


4. Determination of the Physiological Phenotype of Nociceptors

A lot of this functional development occurs postnatally. For example, TRPV1, a receptor that detects noxious temperature and chemical stimuli, are expressed by postnatal day 2 nociceptors . [43] These receptors play a role in detecting mechanical and thermal stimuli during inflammation. On the other hand, tetrodotoxin (TTX) resistant voltage-gated sodium channel Nav1.8 is expressed as early as embryonic day 17 (E17) in rat. [42] These channels play an important role in generating chronic pain because they control the hyperexcitability of the neurons including nociceptors. However, adult levels of these sodium channels are not reached until postnatal day 7 (P7) in rat. [42]


5. Development of the Chemical Phenotype of Nociceptors

In nociceptors, as well as other small diameter neurons, neuropeptides such as substance P (SP) and calcitonin gene-related peptide CGRP, are expressed. [41] Expression of these neuropeptides that characterize nociceptors, are controlled by both intrinsic and extrinsic cues. These neuropeptides SP and CGRP rise as early as embryonic day 14.5 in mouse – at this stage nociceptors have not made contact with their target tissues. [41] 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. [55] Thus extrinsic cues, through the contact with target tissues, enhance the development of the chemical phenotype of nociceptors.


File:Chemical physiological phenotype of nociceptors.JPG



6. Increase in the Nociceptor Innervation Density

Sensory neurons, including the TrkA+ nociceptors, increases their innervation density due to access to local growth factors such as NGF and brain derived growth factor. [56] 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. [56]

File:Nociceptor Innervation Increases.JPG


7. Increase in Nociceptor Sensitivity

Nociceptor sensitisation to noxious stimuli such as heat and capsaicin occurs postnatally. [44] 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. [57] It has been shown that NGF is able to sensitise nociceptors during postnatal day 4-10 in rat. [44] NGF is unable to increase the sensitivity of nociceptors before this stage. Bradykinin, however, can increase the nociceptor sensitivity in neonatal neurons. [44]

Hot/Cold

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

The sensation of temperature is made through free nerve endings in the epidermis of the skin. These free nerve endings contain specialised ion channels called temperature activated transient receptor potential ion channels[58]. 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[58].

Warm

There are four main ThermoTRP receptors responsible for the perception of warm stimuli, both innocuous and noxious[59]. They are called TRPV1, TRPV2, TRPV3, and TRPV4. Each receptor is unresponsive to mechanical stimuli, but can be excited by some chemicals such as capsaicin in the chili plant. The firing of each receptor is inhibited by falling temperatures.

  • TRPV1. This receptor is responsible by the sensation of mild heat. The receptor is activated by temperatures over 30 ˚C. As temperature rises the rate of nerve impulses also increases, reaching a maximum rate at 42 ˚C[59]. Either side of 42 ˚C, the firing rate of the nerve decreases, forming a bell shaped curve. This means that the firing rate of the receptor conveys information relating to the environments temperature back to the central nervous system. It can be appreciated that thermosensation becomes ambiguous when using the bell shaped curve representing action potential rate plotted against temperature. Two temperatures will have the same action potential firing rate. This is overcome by the presence of the cold receptors. The firing rates of both the cold and warm receptors are "read" by the body to determine the environmental temperature.
  • TRPV2. This receptor only fires an action potential when in contact with temperatures sufficient to cause harm .This is generally temperatures over 52 ˚C [58] [59].
  • TRPV3. Activated strongly by temperatures in the 34-38 ˚C range.
  • TRPV4. Activated at 27 – 34 ˚C.

Cold

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

  • TRPM8. This receptor is responsible for the perception of innocuous cold temperatures, that is, temperatures that will not cause the body harm. They are activated when the temperature of the environment surrounding the nerve ending falls to between 25 and 28 ˚C. As seen with the TRPV1 receptor, the stimulation of TRPM8 by a range of temperatures produces a bell shaped curve with a maximum firing rate seen around 25-26 ˚C. [58] [59].
  • 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[58].

Embryology and Development

Diagram of thermosensation development


The development of thermosensation, like all senses, is intimately tied to the dorsal root ganglion (DRG). The neurons that project into the skin to house the thermoTRP channels also pass through the DRG where they synapse and the information is carried into the central nervous system[48]. 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 [60]. This corresponds to a stage 23 human embryo in the 58th day of gestation; this is also the last stage of embryonic development. There are many genes and proteins that control the development of the dorsal root ganglion and sensory peripheral nerves; the following is a summary of the most important. Please be advised that all research into these genes have been done of either rats or mice and may not correlate exactly to the human embryo.

One of the earliest markers of the thermosensory neurons is their expression of TrkA, a nerve growth factor receptor [61]. The actual expression of TrKA is dependent on two other proteins, Neurog 1 and Neurog 2 [62]. 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[48]. These RET+ neurons are important as it is from them that the thermosensory nerves are derived [48]. This switching is not complete at birth, only finishing at postnatal day 30 [60].

RET is an important receptor for glial-cell-derived neurotrophic factor [63]. 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 [60]. 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 [60].

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 [64]. 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 [64]. This means that Brn3a is important for the migration of thermosensory neurons into their destination in the skin.

Abnormalities of the Somatosensory Development

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


Disease Description of Disease Cause of Disease and Link to Embryology
Minamata disease (Methylmercury poisoning) related Somatosensory Disorders MeHg is a highly toxic compound that can easily pass through the placenta and damage fetal brain development. MeHg can be ingested through consuming mercury contaminated fish. These somatosensory disorders are caused by pregnant mothers ingesting large amounts of these MeHg contaminated fish. [65] Methymercury (MeHg) interferes with the fetal development of the somatosensory cortex. Patients with Minnamata disease or MeHg poisoning had higher touch thresholds in their extremities and their trunks. [66] This even disturbance of touch sensations indicates it is the central somatosensory cortex that is damaged and not just the peripheral nerves. [67] Patients also had astereognosis and apraxia limb kinetics which are other indicators of somatosensory cortical defects. [67]
Fragile X Mental Retardation Syndrome related Barrel Dendritic abnormalities of the Somatosensory Cortex Fragile X mental retardation syndrome (FXS) is the second most prevalent inherited mental retardation (Down’s syndrome is first). FXS affects more males than females; it affects 1 in 1210 boys and 1 in 2418 females in Finland. [68] Similar results were found in a swedish study. [69] As part of normal brain development, immature dendritic spines of neurons must be pruned so that adult neurons have a lower density in dendritic spines. In people with FXS, this pruning was found to be abnormal in the somatosensory cortex. In rodents with FXS, the layer IV of the somatosensory cortex had stellate cells displaying abnormal developmental pruning of the cell dendrites. This could be due to the lack an abnormal of Fragile X mental retardation protein (FMRP) in humans or animals with FXS. It was found FMRP play a role in regulating the dendritic pruning of these stellate cells of the somatosensory cortex. [70]
Abnormal Homuncular Organisation of Somatosensory cortex in patients with Dystonia In a normal somatosensory cortex, the homunculus of the hand has the area of the somatosensory cortex controlling digit 1 (D1) positioned lateral and inferior to the area controlling the digit 5 (D5). In people suffering from hand dystonia, their homuncular organisation of the somatosensory cortex for the hand is reversed. This means D1 is positioned medial to D5. The distancebetween D1 and D5 are also shorter in these patients. [71] Causes of the abnormal homuncular organisation is theorized to be congenital; however, afferent sensory inputs into the primary somatosensory cortex can alter its organisation postnatally as well. [71]

Current Research

Somatosensory Activation by Corneal Pain:

Somatotopic Activation by corneal pain and eye blink

Investigation is currently done on to localize somatotopic representation of pain from the cornea. [72] This type of research gives insight into the mechanism of chronic pain development in various eye conditions. [72] This study shows processing of corneal pain information occur in localized regions of the primary somatosensory cortex. [72] When the cornea pain receptors are stimulated, these localized regions o the somatosensory cortex are activated. [72] 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).[72] See figure


Sleep can Remodel the Somatosensory Cortex

In the mice somatosensory cortex, the synaptic connections can be remodelled during sleep. In a recent study, turnover of filopodia and dendritic spines of layer 5 neurons in the somatosensory cortex was examined using 2-photon microscopy. [73] These neurons were fluorescently tagged and the amount of filopodia formation and elimination were measured in both sleep and wakefulness. [73] It was found that elimination of these filopodia occurred at a higher rate during sleep. [73]

Glossary

Apraxia
a disorder of the nervous system, characterized by an inability to perform purposeful movements, but not accompanied by a loss of sensory function or paralysis. [1]
Astereognosis
the inability to determine the shape of an object by touching or feeling it [2]
Cutaneous
Used for describing if a nerve, receptor or cell is affecting or associating with skin.
Dermis
Layer of skin between the epidermis and subcutaneous tissue
Dermal Papillae
Most superficial layer of the dermis
Epidermis
Most exterior/outer layer of skin
Innocuous
A stimulus that poses no threat of harming the tissues and structures of the body.
Neutrophins
Neurotrphic growth factors – proteins supporting the growth and survival of neurons
Noxious
A stimulus that me be toxic to the tissues of the human body. An example of this would be the extremely hot temperatures of a fire, which are perceived as noxious by thermorecepters in the skin.
Receptive Field
an area of the body surface over which a single sensory receptor, or its afferent nerve fiber, is capable of sensing stimuli.
Schwann cells
Primary glia, non-neuronal cells. Supporting homeostasis in the body, neuron growth and formation of myelin.

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External Links

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Additional Pacinian Corpuscle Image 1

Additional Pacinian Corpuscle Image 2

Additional Meissner Corpuscel Image 1

Additional Meissner Corpuscle Image 2

Comparative study between encapsulated and capsulated nerve/receptor cells


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


2012 Projects: Vision | Somatosensory | Taste | Olfaction | Abnormal Vision | Hearing