C tactile afferent

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Low-threshold C mechanoreceptors[edit]

C tactile (CT) neurons are a class of low-threshold C neurons that innervate the human skin. In animals, these neurons are referred to as C low-threshold mechanoreceptors (C-LTMRs). CT neurons belong to a group C nerve fibers; these are unmyelinated, and have slow conduction velocities. CT afferents were discovered by Åke Vallbo using the technique of microneurography.[1]

Structure and location[edit]

In humans, using microneurography, CT neurons have been found in the hairy skin.[2] In animals, these neurons have been genetically labelled and visualized with their relative patterns of axonal endings in hairy skin and in the spinal cord.[3] In the rodent hairy skin, out of the three, two hair follicle sub-types (awl/auchene, and zigzag) have been found to be innervated by C-LTMRs in combination with other LTMRs.[3]

In humans, new psychophysical data suggests that CT neurons may also be present in the glabrous skin, but it might be that they have different biochemical and structural characteristics to the ones found in the hairy skin.[4] In animals, they have been found electrophysiologically in the glabrous skin of the rat hindpaw,[5] supporting the evidence of their existence in glabrous skin.

Molecular markers[edit]

Since these CTs or C-LTMRs are non-peptidergic, immuno-labelling was a challenge. However, in combination with RNA-seq data and genetically modified mouse models, several labeling markers, i.e. VGLUT3,[6] TAFA4,[7] CaV3.2,[8] CaV3.3[9] and GINIP[10] have been discovered to visualize C-LTMRs using double staining methods in combination with tyrosine hydroxylase (TH).

Role in pain[edit]

While these neurons are non-nociceptive and likely mediate low threshold innocuous mechanical sensations, in the context of background muscle pain using hypertonic saline they have been shown to mediate allodynia[11] - pain due to a non-painful stimulus. Later, the role of CTs was also found in mediating allodynia in the model of a delayed onset muscle soreness, i.e. pain following eccentric exercise.[12]

Recently, several animal studies have shown the role of C-LTMRs in neuropathic pain behaviors, which suggests that both mechanical and cold allodynia, but not heat hyperalgesia, is mediated by them.[8][6]

Pain modulation[edit]

In humans, their role in pain increase has been contested as, in some instances, they have been shown to reduce pain, depending on the context of the stimulus.[13] This dual role is also confirmed by the markers found for C-LTMRs in animal models, i.e. some markers are glutaminergic and some are GABAergic in nature.[6][10]

Role in pleasantness[edit]

In humans, these CTs have always been linked to pleasant touch behavior and are most responsive during slow gentle stroking of a brush with the velocity of 3 cm/s.[14] CT neurons project to the insular cortex in the brain,[15][16] and the firing frequency of CT neurons correlate with perceived pleasantness of skin stroking.[14]


  1. ^ Vallbo, Åke; Olausson, Håkan; Wessberg, Johan; Norrsell, Ulf (1993). "A system of unmyelinated afferents for innocuous mechanoreception in the human skin". Brain Research. 628 (1–2): 301–4. doi:10.1016/0006-8993(93)90968-S. PMID 8313159.
  2. ^ McGlone, Francis; Wessberg, Johan; Olausson, Håkan (2014). "Discriminative and Affective Touch: Sensing and Feeling". Neuron. 82 (4): 737–55. doi:10.1016/j.neuron.2014.05.001. PMID 24853935.
  3. ^ a b Li, Lishi; Rutlin, Michael; Abraira, Victoria E.; Cassidy, Colleen; Kus, Laura; Gong, Shiaoching; Jankowski, Michael P.; Luo, Wenqin; Heintz, Nathaniel (December 2011). "The Functional Organization of Cutaneous Low-Threshold Mechanosensory Neurons". Cell. 147 (7): 1615–1627. doi:10.1016/j.cell.2011.11.027. ISSN 0092-8674. PMC 3262167. PMID 22196735.
  4. ^ Nagi, Saad S.; Mahns, David A. (2013-08-18). "Mechanical allodynia in human glabrous skin mediated by low-threshold cutaneous mechanoreceptors with unmyelinated fibres". Experimental Brain Research. 231 (2): 139–151. doi:10.1007/s00221-013-3677-z. ISSN 0014-4819. PMID 23955107.
  5. ^ Djouhri, Laiche (2016-02-02). "Electrophysiological evidence for the existence of a rare population of C-fiber low threshold mechanoreceptive (C-LTM) neurons in glabrous skin of the rat hindpaw". Neuroscience Letters. 613: 25–29. doi:10.1016/j.neulet.2015.12.040. ISSN 1872-7972. PMID 26752785.
  6. ^ a b c Seal, Rebecca P.; Wang, Xidao; Guan, Yun; Raja, Srinivasa N.; Woodbury, C. Jeffery; Basbaum, Allan I.; Edwards, Robert H. (2009-12-03). "Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors". Nature. 462 (7273): 651–655. doi:10.1038/nature08505. ISSN 1476-4687. PMC 2810205. PMID 19915548.
  7. ^ Delfini, Marie-Claire; Mantilleri, Annabelle; Gaillard, Stéphane; Hao, Jizhe; Reynders, Ana; Malapert, Pascale; Alonso, Serge; François, Amaury; Barrere, Christian (October 2013). "TAFA4, a Chemokine-like Protein, Modulates Injury-Induced Mechanical and Chemical Pain Hypersensitivity in Mice". Cell Reports. 5 (2): 378–388. doi:10.1016/j.celrep.2013.09.013. ISSN 2211-1247. PMID 24139797.
  8. ^ a b François, Amaury; Schüetter, Niklas; Laffray, Sophie; Sanguesa, Juan; Pizzoccaro, Anne; Dubel, Stefan; Mantilleri, Annabelle; Nargeot, Joel; Noël, Jacques (2015-01-14). "The Low-Threshold Calcium Channel Cav3.2 Determines Low-Threshold Mechanoreceptor Function" (PDF). Cell Reports. 10 (3): 370–382. doi:10.1016/j.celrep.2014.12.042. ISSN 2211-1247. PMID 25600872.
  9. ^ Reynders, Ana; Mantilleri, Annabelle; Malapert, Pascale; Rialle, Stéphanie; Nidelet, Sabine; Laffray, Sophie; Beurrier, Corinne; Bourinet, Emmanuel; Moqrich, Aziz (2015-02-12). "Transcriptional Profiling of Cutaneous MRGPRD Free Nerve Endings and C-LTMRs". Cell Reports. 10 (6): 1007–1019. doi:10.1016/j.celrep.2015.01.022. ISSN 2211-1247. PMC 4542317. PMID 25683706.
  10. ^ a b Gaillard, Stéphane; Lo Re, Laure; Mantilleri, Annabelle; Hepp, Régine; Urien, Louise; Malapert, Pascale; Alonso, Serge; Deage, Michael; Kambrun, Charline (October 2014). "GINIP, a G αi -Interacting Protein, Functions as a Key Modulator of Peripheral GABA B Receptor-Mediated Analgesia". Neuron. 84 (1): 123–136. doi:10.1016/j.neuron.2014.08.056. ISSN 0896-6273. PMID 25242222.
  11. ^ Nagi, Saad S.; Rubin, Troy K.; Chelvanayagam, David K.; Macefield, Vaughan G.; Mahns, David A. (2011-08-15). "Allodynia mediated by C-tactile afferents in human hairy skin". The Journal of Physiology. 589 (Pt 16): 4065–4075. doi:10.1113/jphysiol.2011.211326. ISSN 1469-7793. PMC 3180003. PMID 21727219.
  12. ^ Nagi, Saad S.; Mahns, David A. (May 2013). "C-tactile Fibers Contribute to Cutaneous Allodynia After Eccentric Exercise". The Journal of Pain. 14 (5): 538–548. doi:10.1016/j.jpain.2013.01.009. ISSN 1526-5900. PMID 23562300.
  13. ^ Shaikh, Sumaiya; Nagi, Saad S.; McGlone, Francis; Mahns, David A. (2015). "Psychophysical Investigations into the Role of Low-Threshold C Fibres in Non-Painful Affective Processing and Pain Modulation". PLOS ONE. 10 (9): e0138299. doi:10.1371/journal.pone.0138299. ISSN 1932-6203. PMC 4570804. PMID 26372601.
  14. ^ a b Löken, Line S.; Wessberg, Johan; Morrison, India; McGlone, Francis; Olausson, Håkan (May 2009). "Coding of pleasant touch by unmyelinated afferents in humans". Nature Neuroscience. 12 (5): 547–548. doi:10.1038/nn.2312. ISSN 1546-1726. PMID 19363489.
  15. ^ Olausson, H.; Lamarre, Y.; Backlund, H.; Morin, C.; Wallin, B.G.; Starck, G.; Ekholm, S.; Strigo, I.; Worsley, K.; Vallbo, Å.B.; Bushnell, M.C. (2002). "Unmyelinated tactile afferents signal touch and project to insular cortex". Nature Neuroscience. 5 (9): 900–4. doi:10.1038/nn896. PMID 12145636.
  16. ^ Bjornsdotter, M.; Loken, L.; Olausson, H.; Vallbo, A.; Wessberg, J. (2009). "Somatotopic Organization of Gentle Touch Processing in the Posterior Insular Cortex". Journal of Neuroscience. 29 (29): 9314–20. doi:10.1523/JNEUROSCI.0400-09.2009. PMID 19625521.