unmyelinated nerve fibers


Summary: A class of nerve fibers as defined by their nerve sheath arrangement. The AXONS of the unmyelinated nerve fibers are small in diameter and usually several are surrounded by a single MYELIN SHEATH. They conduct low-velocity impulses, and represent the majority of peripheral sensory and autonomic fibers, but are also found in the BRAIN and SPINAL CORD.

Top Publications

  1. Leith J, Wilson A, Donaldson L, Lumb B. Cyclooxygenase-1-derived prostaglandins in the periaqueductal gray differentially control C- versus A-fiber-evoked spinal nociception. J Neurosci. 2007;27:11296-305 pubmed
    ..Thus, effects of centrally acting prostaglandins are pivotal, we suggest, to both the understanding of nociceptive processing and the development of new analgesic drugs. ..
  2. Liu Y, Zhou L, Hu N, Xu J, Wu C, Zhang T, et al. Tumor necrosis factor-alpha induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn in rats with nerve injury: the role of NF-kappa B, JNK and p38 MAPK. Neuropharmacology. 2007;52:708-15 pubmed
    ..These results suggest that TNF-alpha and its downstream molecules may have no acute effect on spinal synaptic transmission in intact animals and induce LTP in rats with neuropathic pain produced by nerve injury. ..
  3. George A, Serra J, Navarro X, Bostock H. Velocity recovery cycles of single C fibres innervating rat skin. J Physiol. 2007;578:213-32 pubmed
    ..These data indicate axonal membrane differences between different functional classes of C fibres, which resemble those previously described in human C fibres. ..
  4. Xin W, Gong Q, Xu J, Yang H, Zang Y, Zhang T, et al. Role of phosphorylation of ERK in induction and maintenance of LTP of the C-fiber evoked field potentials in spinal dorsal horn. J Neurosci Res. 2006;84:934-43 pubmed
    ..Our results suggested that activation of ERK/CREB pathway in spinal dorsal neurons is necessary for induction and maintenance of long-term potentiation of the C-fiber evoked field potentials. ..
  5. Hausdorf J, Lemmens M, Heck K, Grolms N, Korr H, Kertschanska S, et al. Selective loss of unmyelinated nerve fibers after extracorporeal shockwave application to the musculoskeletal system. Neuroscience. 2008;155:138-44 pubmed publisher
    ..Application of ESW resulted in a selective, substantial loss of unmyelinated nerve fibers within the femoral nerve of the treated hind limb, whereas the sciatic nerve of the treated hind limb ..
  6. Drdla R, Sandkühler J. Long-term potentiation at C-fibre synapses by low-level presynaptic activity in vivo. Mol Pain. 2008;4:18 pubmed publisher
    ..These pathways match those leading to hyperalgesia in behaving animals and humans. We thus propose that LTP induced by low-level activity in C-fibres may underlie some forms of hyperalgesia. ..
  7. De Col R, Messlinger K, Carr R. Conduction velocity is regulated by sodium channel inactivation in unmyelinated axons innervating the rat cranial meninges. J Physiol. 2008;586:1089-103 pubmed
    ..Since the process is primarily dependent upon sodium channel availability, tracking conduction velocity provides a means of accessing relative changes in the excitability of nociceptive neurons. ..
  8. McMullan S, Lumb B. Spinal dorsal horn neuronal responses to myelinated versus unmyelinated heat nociceptors and their modulation by activation of the periaqueductal grey in the rat. J Physiol. 2006;576:547-56 pubmed
    ..The data are discussed in relation to the role of the DL/L-PAG in mediating active coping strategies. ..
  9. Drdla R, Gassner M, Gingl E, Sandkühler J. Induction of synaptic long-term potentiation after opioid withdrawal. Science. 2009;325:207-10 pubmed publisher
    ..These findings provide a previously unrecognized target to selectively combat pro-nociceptive effects of opioids without compromising opioid analgesia. ..

More Information


  1. Dunham J, Kelly S, Donaldson L. Inflammation reduces mechanical thresholds in a population of transient receptor potential channel A1-expressing nociceptors in the rat. Eur J Neurosci. 2008;27:3151-60 pubmed publisher
    ..Our data show that a subset of afferents is sensitized to mechanical stimulation by inflammation and that these afferents are defined by expression of TRPA1. ..
  2. Namer B, Kleggetveit I, Handwerker H, Schmelz M, Jorum E. Role of TRPM8 and TRPA1 for cold allodynia in patients with cold injury. Pain. 2008;139:63-72 pubmed publisher
    ..We conclude from these data that the mechanisms for the induction of cold allodynia in the patients with cold injury are independent of TRPM8 or TRPA1 and differ therefore from neuropathic pain patients. ..
  3. Inoue M, Yamaguchi A, Kawakami M, Chun J, Ueda H. Loss of spinal substance P pain transmission under the condition of LPA1 receptor-mediated neuropathic pain. Mol Pain. 2006;2:25 pubmed
    ..All these results suggest that the loss of pain transmission through polymodal C-fiber neurons is also mediated by the LPA1 activation following nerve injury. ..
  4. Ikeda H, Stark J, Fischer H, Wagner M, Drdla R, Jäger T, et al. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science. 2006;312:1659-62 pubmed
    ..This model integrates known signal transduction pathways of hyperalgesia without contradiction. ..
  5. Schlegel T, Sauer S, Handwerker H, Reeh P. Responsiveness of C-fiber nociceptors to punctate force-controlled stimuli in isolated rat skin: lack of modulation by inflammatory mediators and flurbiprofen. Neurosci Lett. 2004;361:163-7 pubmed
    ..In conclusion, even refined mechanostimulation was unable to demonstrate sensitization of the predominant nociceptor classes in the rat skin. ..
  6. McMullan S, Lumb B. Midbrain control of spinal nociception discriminates between responses evoked by myelinated and unmyelinated heat nociceptors in the rat. Pain. 2006;124:59-68 pubmed
  7. Kobayashi K, Fukuoka T, Obata K, Yamanaka H, Dai Y, Tokunaga A, et al. Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with adelta/c-fibers and colocalization with trk receptors. J Comp Neurol. 2005;493:596-606 pubmed
  8. Zhang H, Zhou L, Hu X, Hu N, Zhang T, Liu X. Acute nerve injury induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn of intact rat. Sheng Li Xue Bao. 2004;56:591-6 pubmed
    ..The results further support the notion that LTP of C-fiber evoked field potentials may underlie neuropathic pain. ..
  9. Zhang X, Zhang Y, Zhao Z. Involvement of nitric oxide in long-term potentiation of spinal nociceptive responses in rats. Neuroreport. 2005;16:1197-201 pubmed
    ..These results suggest the involvement of nitric oxide in the spinal long-term potentiation of C-fiber-evoked field potentials and related behavior changes. ..
  10. McMullan S, Simpson D, Lumb B. A reliable method for the preferential activation of C- or A-fibre heat nociceptors. J Neurosci Methods. 2004;138:133-9 pubmed
    ..In contrast thresholds of responses to fast rates of skin heating were unchanged, indicating that nociceptors activated by this stimulus were capsaicin-insensitive A-fibre heat nociceptors. ..
  11. Seagrove L, Suzuki R, Dickenson A. Electrophysiological characterisations of rat lamina I dorsal horn neurones and the involvement of excitatory amino acid receptors. Pain. 2004;108:76-87 pubmed
    ..Overall, this study describes a high threshold, AMPA receptor possessing population of lamina I neurones, which seem to lack functional NMDA receptors, and are partially controlled by GABA(A) receptor activity. ..
  12. Campero M, Serra J, Bostock H, Ochoa J. Partial reversal of conduction slowing during repetitive stimulation of single sympathetic efferents in human skin. Acta Physiol Scand. 2004;182:305-11 pubmed
    ..The distinctive activity-dependent slowing profiles of these type-4 sympathetic C units may help identification in vitro, and suggest that hyperpolarization-activated channels have a particularly prominent role in the axonal membrane. ..
  13. Dahlhaus A, Ruscheweyh R, Sandkühler J. Synaptic input of rat spinal lamina I projection and unidentified neurones in vitro. J Physiol. 2005;566:355-68 pubmed
  14. Matsumoto M, Inoue M, Hald A, Yamaguchi A, Ueda H. Characterization of three different sensory fibers by use of neonatal capsaicin treatment, spinal antagonism and a novel electrical stimulation-induced paw flexion test. Mol Pain. 2006;2:16 pubmed
    ..These results also suggest that the EPF analysis is useful for the evaluation of plasticity in sensory functions in animal disease models. ..
  15. Kawasaki Y, Kohno T, Zhuang Z, Brenner G, Wang H, Van Der Meer C, et al. Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. J Neurosci. 2004;24:8310-21 pubmed
  16. Djouhri L, Koutsikou S, Fang X, McMullan S, Lawson S. Spontaneous pain, both neuropathic and inflammatory, is related to frequency of spontaneous firing in intact C-fiber nociceptors. J Neurosci. 2006;26:1281-92 pubmed
    ..Overall, SFL was related to SA rate in intact C-nociceptors. Both L5 degeneration and chromic gut cause inflammation. Therefore, both SA and SFL/spontaneous pain after nerve injury (mSNA) may result from cumulative neuroinflammation. ..
  17. Coste J, Voisin D, Miraucourt L, Dallel R, Luccarini P. Dorsal horn NK1-expressing neurons control windup of downstream trigeminal nociceptive neurons. Pain. 2008;137:340-51 pubmed
    ..We conclude that, in contrast to central sensitization that is controlled by a spino-bulbo-spinal loop, Sp5O WDR neuron windup is regulated through a local circuit activated by MDH lamina III NK1Rs. ..
  18. Kim Y, Kim Y, Paik S, Cho Y, Kwon T, Ahn D, et al. Expression of metabotropic glutamate receptor mGluR5 in human dental pulp. J Endod. 2009;35:690-4 pubmed publisher
  19. Salat D, Tuch D, van der Kouwe A, Greve D, Pappu V, Lee S, et al. White matter pathology isolates the hippocampal formation in Alzheimer's disease. Neurobiol Aging. 2010;31:244-56 pubmed publisher
    ..These results demonstrate that deterioration of neocortical connections to the hippocampal formation results in part from the degeneration of critical MTL and associated fiber pathways. ..
  20. Blakely P, Kleinschmidt Demasters B, Tyler K, Irani D. Disrupted glutamate transporter expression in the spinal cord with acute flaccid paralysis caused by West Nile virus infection. J Neuropathol Exp Neurol. 2009;68:1061-72 pubmed publisher
    ..The pathogenesis of this increasingly common disorder likely involves immune response and excitotoxicity mechanisms that are potential therapeutic targets. ..
  21. Rivero Fernández M, Moreira Vicente V, Riesco López J, Rodríguez Gandía M, Garrido Gómez E, Milicua Salamero J. [Pain originating from the abdominal wall: a forgotten diagnostic option]. Gastroenterol Hepatol. 2007;30:244-50 pubmed
    ..Carnett's sign is a simple maneuver that discriminates between parietal and visceral pain. Management with topical anesthesia is effective in a majority of patients and can help to confirm the diagnosis. ..
  22. Velumian A, Wan Y, Samoilova M, Fehlings M. Modular double sucrose gap apparatus for improved recording of compound action potentials from rat and mouse spinal cord white matter preparations. J Neurosci Methods. 2010;187:33-40 pubmed publisher
  23. Meotti F, Coelho I, Santos A. The nociception induced by glutamate in mice is potentiated by protons released into the solution. J Pain. 2010;11:570-8 pubmed publisher
    ..Our findings showed that the protons released from glutamic acid have to be removed from the solution to avoid misinterpretation of results in the search for new analgesic drugs. ..
  24. Sharp C, Reeve A, Collins S, Martindale J, Summerfield S, Sargent B, et al. Investigation into the role of P2X(3)/P2X(2/3) receptors in neuropathic pain following chronic constriction injury in the rat: an electrophysiological study. Br J Pharmacol. 2006;148:845-52 pubmed
    ..These data support a role for P2X(3)/P2X(2/3) antagonists in the modulation of neuropathic pain. ..
  25. Fazan V, Rodrigues Filho O, Jordão C, Moore K. Phrenic nerve diabetic neuropathy in rats: unmyelinated fibers morphometry. J Peripher Nerv Syst. 2009;14:137-45 pubmed publisher
    ..The present study adds useful information for further investigations on the ultrastructural basis of nerve function in diabetes. ..
  26. Liao M, Lee M, Hsieh M, Cheng M, Lee J, Weng H, et al. Evaluation of the pathophysiology of classical trigeminal neuralgia by blink reflex study and current perception threshold testing. J Headache Pain. 2010;11:241-6 pubmed publisher
    ..The findings suggest that classical TN is not a simple large-myelinated nerve fiber dysfunction but a more complex process with a main dysfunction of unmyelinated nerve fibers.
  27. Smith F, Lindsay R. Enhancement of bupivacaine local anesthesia with the potassium channel blocker ibutilide. Eur J Pain. 2007;11:551-6 pubmed
    ..Epinephrine augmented the enhancement by ibutilide of bupivacaine's potency by 6.8-fold. In summary, ibutilide may enhance the effects of bupivacaine by blocking K(+) channels on sensory nociceptive nerves. ..
  28. Boettger M, Hensellek S, Richter F, Gajda M, Stöckigt R, von Banchet G, et al. Antinociceptive effects of tumor necrosis factor alpha neutralization in a rat model of antigen-induced arthritis: evidence of a neuronal target. Arthritis Rheum. 2008;58:2368-78 pubmed publisher
    ..Overall, these data show the pronounced antinociceptive effects of TNFalpha neutralization, thus suggesting that reduction of the effects of TNFalpha on pain fibers themselves significantly contributes to pain relief. ..
  29. Katanosaka K, Banik R, Giron R, Higashi T, Tominaga M, Mizumura K. Contribution of TRPV1 to the bradykinin-evoked nociceptive behavior and excitation of cutaneous sensory neurons. Neurosci Res. 2008;62:168-75 pubmed publisher
    ..These results suggest that BK-evoked nociception/nociceptor response would not be simply explained by activation of TRPV1 and A1, and that BK-evoked nociceptor excitation would be mediated by several ionic mechanisms. ..
  30. Truini A, Galeotti F, Haanpaa M, Zucchi R, Albanesi A, Biasiotta A, et al. Pathophysiology of pain in postherpetic neuralgia: a clinical and neurophysiological study. Pain. 2008;140:405-10 pubmed publisher
    ..These findings might be useful for a better understanding of pain mechanisms in postherpetic neuralgia. ..
  31. Mechsner S, Kaiser A, Kopf A, Gericke C, Ebert A, Bartley J. A pilot study to evaluate the clinical relevance of endometriosis-associated nerve fibers in peritoneal endometriotic lesions. Fertil Steril. 2009;92:1856-61 pubmed publisher
    ..6% vs. 33.3%). The present study suggests that the presence of endometriosis-associated nerve fibers in the peritoneum is important for the development of endometriosis-associated pelvic pain and dysmenorrhea. ..
  32. Paik S, Lee D, Kim J, Bae J, Cho Y, Ahn D, et al. Quantitative ultrastructural analysis of the neurofilament 200-positive axons in the rat dental pulp. J Endod. 2010;36:1638-42 pubmed publisher
    ..These results suggest that pulpal innervation originates predominantly from myelinated axons, and the myelinated axons undergo extensive morphologic changes during their course from the radicular to the peripheral pulp. ..
  33. Kiasalari Z, Salehi I, Zhong Y, McMahon S, Michael Titus A, Michael G. Identification of perineal sensory neurons activated by innocuous heat. J Comp Neurol. 2010;518:137-62 pubmed publisher
    ..We hypothesize that apart from participating in normal thermal sensation relevant to thermoregulation and reproductive functions, HE TRPV1 cells may mediate burning pain in chronic pain syndromes with perineal localization. ..
  34. Xu Y, Zhang J, Zheng J, Zhang S, Kang D, Fan D. Fully intact contact heat evoked potentials in patients with amyotrophic lateral sclerosis. Muscle Nerve. 2009;39:735-8 pubmed publisher
    ..05). Our results suggest that the nociceptive pathway is intact and support the idea that small fibers and their sensory pathway are spared in ALS. ..
  35. Rojas Piloni G, Dickenson A, Condés Lara M. Superficial dorsal horn neurons with double spike activity in the rat. Neurosci Lett. 2007;419:147-52 pubmed
    ..The present work shows evidence that double spikes in superficial spinal cord neurones are related to the nociceptive stimulation, and they are possibly part of an acute pain-control mechanism. ..
  36. Kong S, Liu J, Ramage A, Wang Y. Cardiac vagal preganglionic neurones in the intermediate zone of the brainstem in anaesthetized cats. Exp Physiol. 2007;92:1023-8 pubmed
    ..Right atrial injections of phenylbiguanide excited all four CVPNs tested. In conclusion, CVPNs located in the intermediate zone have similar properties to those in the dorsal vagal nucleus but not the nucleus ambiguus...
  37. Zhang Q, Zhao Y, Guo Y, Cao D, Tang X, Tian Y, et al. Activation and sensitization of C and Adelta afferent fibers mediated by P2X receptors in rat dorsal skin. Brain Res. 2006;1102:78-85 pubmed
    ..These results suggest that peripheral P2X receptors are involved in mediating peripheral excitation of C and Adelta fibers. ..
  38. Zhou Y, Sun L, Liu Z, Bu G, Pang X, Sun S, et al. Functional impact of the hyperpolarization-activated current on the excitability of myelinated A-type vagal afferent neurons in the rat. Clin Exp Pharmacol Physiol. 2010;37:852-61 pubmed publisher
  39. Stoffers D, Sheldon S, Kuperman J, Goldstein J, Corey Bloom J, Aron A. Contrasting gray and white matter changes in preclinical Huntington disease: an MRI study. Neurology. 2010;74:1208-16 pubmed publisher
    ..The empirically derived group difference images from this study are provided as regions-of-interest masks for improved sensitivity in future longitudinal studies. ..
  40. De Ridder D, Hans G, Pals P, Menovsky T. A C-fiber-mediated neuropathic brachioradial pruritus. J Neurosurg. 2010;113:118-21 pubmed publisher
    ..Treatment consisted of 2 cervical epidural steroid applications that resulted in clinical disappearance of the itch and improvement in C-fiber function on quantitative sensory testing...
  41. Banik R, Brennan T. Trpv1 mediates spontaneous firing and heat sensitization of cutaneous primary afferents after plantar incision. Pain. 2009;141:41-51 pubmed publisher
    ..KO of TrpV1 influences SA in these unclassified afferents in incised skin. SA in these afferents is perhaps a manifestation of heat sensitization. ..
  42. Zhu Z, Tang X, Wang W, Ren W, Xing J, Zhang J, et al. Conduction failures in rabbit saphenous nerve unmyelinated fibers. Neurosignals. 2009;17:181-95 pubmed publisher
  43. Gorodetskaya N, Grossmann L, Constantin C, Jänig W. Functional properties of cutaneous A- and C-fibers 1-15 months after a nerve lesion. J Neurophysiol. 2009;102:3129-41 pubmed publisher
    ..The reinnervation of skin by afferent C-fibers is extremely slow and may never recover to normal. ..
  44. Kaidoh T, Inoue T. N-cadherin expression in palisade nerve endings of rat vellus hairs. J Comp Neurol. 2008;506:525-34 pubmed
    ..In contrast, sensory nerve fibers just proximal to the LNs formed common unmyelinated nerve fibers, in which N-cadherin was located mainly at the mesaxon of type I terminal Schwann cells (tSCIs)...
  45. Naka M, Kanamori A, Negi A, Nakamura M. Reduced expression of aquaporin-9 in rat optic nerve head and retina following elevated intraocular pressure. Invest Ophthalmol Vis Sci. 2010;51:4618-26 pubmed publisher
    ..Given that AQP9 presumably acts as a channel for metabolites to pass from astrocytes to neurons, the reduced expression of AQP9 at these specific sites may be implicated in the pathogenesis of glaucomatous optic neuropathy. ..
  46. Serra J, Solà R, Quiles C, Casanova Molla J, Pascual V, Bostock H, et al. C-nociceptors sensitized to cold in a patient with small-fiber neuropathy and cold allodynia. Pain. 2009;147:46-53 pubmed publisher
    ..The responsiveness of C-nociceptors to menthol suggests an abnormal expression or function of TRPM8 channels in this patient with a small-fiber polyneuropathy. ..
  47. Zhou L, Zhong Y, Ren W, Li Y, Zhang T, Liu X. BDNF induces late-phase LTP of C-fiber evoked field potentials in rat spinal dorsal horn. Exp Neurol. 2008;212:507-14 pubmed publisher
    ..The results suggest that BDNF play a crucial role in protein synthesis-dependent L-LTP in spinal dorsal horn via activation of ERK, p38 MAPK and NF-kappaB signal pathways. ..
  48. Ziskin J, Nishiyama A, Rubio M, Fukaya M, Bergles D. Vesicular release of glutamate from unmyelinated axons in white matter. Nat Neurosci. 2007;10:321-30 pubmed
    ..This activity-dependent secretion of glutamate was prevalent in the developing and mature mouse corpus callosum, indicating that axons within white matter both conduct action potentials and engage in rapid neuron-glia communication. ..
  49. Millqvist E. Rhinitis as a part of sensory hyperreactivity characterized by increased capsaicin cough sensitivity. Clin Allergy Immunol. 2007;19:401-10 pubmed
  50. Virnik A, Gaggl A, Likar R, Stettner H, Chiari F. [Comparison of the peripheral and central effects of opiates after iliac crest transplants. Reconstruction of severely atrophied maxilla]. Schmerz. 2009;23:259-62, 264-6 pubmed publisher
    ..In the early rehabilitation period the effect of intraoperatively local peripherally placed opiates is superior to intraoperatively centrally administered opiates. ..
  51. Adelson D, Lao L, Zhang G, Kim W, Marvizón J. Substance P release and neurokinin 1 receptor activation in the rat spinal cord increase with the firing frequency of C-fibers. Neuroscience. 2009;161:538-53 pubmed publisher
    ..In conclusion, the instantaneous firing frequency in C-fibers determines the amount of substance P released by noxious stimuli. ..
  52. Green A, Krishnan S, Finucane F, Rayman G. Altered C-fiber function as an indicator of early peripheral neuropathy in individuals with impaired glucose tolerance. Diabetes Care. 2010;33:174-6 pubmed publisher
    ..The absence of similar small-fiber neuropathy in those with longstanding type 1 diabetes suggests that glycemia may not be the major determinant of small-fiber neuropathy in IGT. ..
  53. Ruehle B, Handwerker H, Lennerz J, Ringler R, Forster C. Brain activation during input from mechanoinsensitive versus polymodal C-nociceptors. J Neurosci. 2006;26:5492-9 pubmed
    ..The posterior cingulate cortex was selectively activated by ICS and is apparently important for the processing of inflammatory pain. ..