Mechano- and thermosensitivity of regenerating cutaneous afferent nerve fibers

Crush lesion of a skin nerve is followed by sprouting of myelinated (A) and unmyelinated (C) afferent fibers into the distal nerve stump. Here, we investigate quantitatively both ongoing activity and activity evoked by mechanical or thermal stimulation of the nerve in 43 A- and 135 C-fibers after crush lesion of the sural nerve using neurophysiological recordings in anesthetized rats. The discharge patterns in the injured afferent nerve fibers and in intact (control) afferent nerve fibers were compared. (1) Almost all (98%) A-fibers were mechanosensitive, some of them exhibited additionally weak cold/heat sensitivity; 7% had ongoing activity. (2) Three patterns of physiologically evoked activity were present in the lesioned C-fibers: (a) C-fibers with type 1 cold sensitivity (low cold threshold, inhibition on heating, high level of ongoing and cold-evoked activity; 23%): almost all of them were mechanoinsensitive and 40% of them were additionally heat-sensitive; (b) C-fibers with type 2 cold sensitivity (high cold threshold, low level of ongoing and cold-evoked activity; 23%). All of them were excited by mechanical and/or heat stimuli; (c) cold-insensitive C-fibers (54%), which were heat- and/or mechanosensitive. (3) The proportions of C-fibers exhibiting these three patterns of discharge to physiological stimuli were almost identical in the population of injured C-fibers and in a population of 91 intact cutaneous C-fibers. 4. Ongoing activity was present in 56% of the lesioned C-fibers. Incidence and rate of ongoing activity were the same in the populations of lesioned and intact type 1 cold-sensitive C-fibers. The incidence (but not rate) of ongoing activity was significantly higher in lesioned type 2 cold-sensitive and cold insensitive C-fibers than in the corresponding populations of intact C-fibers (42/93 fibers vs. 11/72 fibers).

[1]  J. Ochoa,et al.  Sensations evoked by intraneural microstimulation of single mechanoreceptor units innervating the human hand. , 1983, The Journal of physiology.

[2]  Clifford J. Woolf,et al.  TRPA1 Contributes to Cold, Mechanical, and Chemical Nociception but Is Not Essential for Hair-Cell Transduction , 2006, Neuron.

[3]  D. Buck-Gramcko,et al.  The Hoffmann-Tinel Sign , 1993 .

[4]  J. Ochoa,et al.  Sensations evoked by intraneural microstimulation of C nociceptor fibres in human skin nerves. , 1989, The Journal of physiology.

[5]  P. Anand,et al.  TRPV3 is a temperature-sensitive vanilloid receptor-like protein , 2002, Nature.

[6]  P. Heppenstall,et al.  Direct activation of the ion channel TRPA1 by Ca2+ , 2007, Nature Neuroscience.

[7]  Carolina Roza,et al.  Cold sensitivity in axotomized fibers of experimental neuromas in mice , 2006, Pain.

[8]  C. Belmonte,et al.  Specificity of cold thermotransduction is determined by differential ionic channel expression , 2002, Nature Neuroscience.

[9]  C. Belmonte,et al.  The contribution of TRPM8 channels to cold sensing in mammalian neurones , 2005, The Journal of physiology.

[10]  Yi Dai,et al.  TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. , 2005, The Journal of clinical investigation.

[11]  David Julius,et al.  TRPA1 Mediates the Inflammatory Actions of Environmental Irritants and Proalgesic Agents , 2006, Cell.

[12]  David Julius,et al.  The menthol receptor TRPM8 is the principal detector of environmental cold , 2007, Nature.

[13]  D. Kenshalo,et al.  Response characteristics of cutaneous cold receptors in the monkey. , 1977, Journal of neurophysiology.

[14]  W. Kessler,et al.  Excitation of cutaneous afferent nerve endings in vitro by a combination of inflammatory mediators and conditioning effect of substance P , 2004, Experimental Brain Research.

[15]  R. Coggeshall,et al.  Delayed loss of small dorsal root ganglion cells after transection of the rat sciatic nerve , 2000, The Journal of comparative neurology.

[16]  M. Caterina,et al.  TRPM8 mRNA is expressed in a subset of cold-responsive trigeminal neurons from rat. , 2003, Journal of neurophysiology.

[17]  S. Sunderland.  Nerves and nerve injuries , 1978 .

[18]  A. Patapoutian,et al.  TRPM8 Is Required for Cold Sensation in Mice , 2007, Neuron.

[19]  J. Serra,et al.  C‐polymodal nociceptors activated by noxious low temperature in human skin. , 1996, The Journal of physiology.

[20]  M. D'Andrea,et al.  Attenuated Cold Sensitivity in TRPM8 Null Mice , 2007, Neuron.

[21]  R. Baron,et al.  Cutaneous afferent C‐fibers regenerating along the distal nerve stump after crush lesion show two types of cold sensitivity , 2009, European journal of pain.

[22]  F. Porreca,et al.  Neuropathic Pain: Basic Mechanisms (Animal) , 2008 .

[23]  D. Julius,et al.  Cellular and molecular properties of primary afferent neurons , 2006 .

[24]  A. Patapoutian,et al.  Noxious Cold Ion Channel TRPA1 Is Activated by Pungent Compounds and Bradykinin , 2004, Neuron.

[25]  D. Kenshalo,et al.  Response characteristics of cutaneous warm receptors in the monkey. , 1977, Journal of neurophysiology.

[26]  G. Reid,et al.  A cold‐ and menthol‐activated current in rat dorsal root ganglion neurones: properties and role in cold transduction , 2002, The Journal of physiology.

[27]  Stephen B. McMahon,et al.  Inflammatory mediators and modulators of pain , 2005 .

[28]  Gordon Reid,et al.  ThermoTRP channels and cold sensing: what are they really up to? , 2005, Pflügers Archiv.

[29]  H. Bostock,et al.  Slowly conducting afferents activated by innocuous low temperature in human skin , 2001, The Journal of physiology.

[30]  D. Buck-Gramcko,et al.  The Hoffmann-Tinel sign. 1915. , 1993, Journal of hand surgery.

[31]  J. Jakobsen,et al.  Effect of nerve crush on perikaryal number and volume of neurons in adult rat dorsal root ganglion , 1999, The Journal of comparative neurology.

[32]  David E. Clapham,et al.  TRPV3 is a calcium-permeable temperature-sensitive cation channel , 2002, Nature.

[33]  D. Julius,et al.  The capsaicin receptor: a heat-activated ion channel in the pain pathway , 1997, Nature.

[34]  Sensitivity of cutaneous cold fibers to noxious heat: paradoxical cold discharge. , 1977, Journal of neurophysiology.

[35]  E. Dodt,et al.  The discharge of specific cold fibres at high temperatures; the paradoxical cold. , 1952, Acta physiologica Scandinavica.

[36]  M. C. Acosta,et al.  Contribution of TRPM8 Channels to Cold Transduction in Primary Sensory Neurons and Peripheral Nerve Terminals , 2006, The Journal of Neuroscience.

[37]  Y. Zotterman,et al.  The effect of menthol on the thermoreceptors. , 1951, Acta physiologica Scandinavica.

[38]  E. Boring.  CUTANEOUS SENSATION AFTER NERVE‐DIVISION , 1916 .

[39]  D. Julius,et al.  A capsaicin-receptor homologue with a high threshold for noxious heat , 1999, Nature.

[40]  M. Caterina,et al.  TRP Channel Knockout Mice Lose Their Cool , 2007, Neuron.

[41]  G. Lewin,et al.  The high threshold mechanotransducer: A status report , 2006, Pain.

[42]  A. Moqrich,et al.  Impaired Thermosensation in Mice Lacking TRPV3, a Heat and Camphor Sensor in the Skin , 2005, Science.

[43]  W D Willis,et al.  Cutaneous sensory receptors in the rat foot. , 1993, Journal of neurophysiology.

[44]  W. Jänig,et al.  Axotomized and Intact Muscle Afferents But No Skin Afferents Develop Ongoing Discharges of Dorsal Root Ganglion Origin after Peripheral Nerve Lesion , 2000, The Journal of Neuroscience.

[45]  M. Devor.  Response of nerves to injury in relation to neuropathic pain , 2006 .

[46]  R. Baron.  5.57 – Neuropathic Pain: Clinical , 2008 .

[47]  D. McKemy,et al.  Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1 , 2004, Nature.

[48]  R. Meyer,et al.  Uninjured C-fiber nociceptors develop spontaneous activity and alpha-adrenergic sensitivity following L6 spinal nerve ligation in monkey. , 1999, Journal of neurophysiology.

[49]  Gary R Lewin,et al.  Mechanosensation and pain. , 2004, Journal of neurobiology.

[50]  G. J. Romanes,et al.  Current Problems of Lower Vertebrate Phylogeny. , 1969 .

[51]  C. Belmonte,et al.  Molecular and cellular limits to somatosensory specificity , 2008, Molecular pain.

[52]  R. Baron,et al.  Enhancement of ectopic discharge in regenerating A- and C-fibers by inflammatory mediators. , 2009, Journal of neurophysiology.

[53]  J. Gu,et al.  Chemical and cold sensitivity of two distinct populations of TRPM8-expressing somatosensory neurons. , 2006, Journal of neurophysiology.

[54]  M. Caterina,et al.  Nociceptors Lacking TRPV1 and TRPV2 Have Normal Heat Responses , 2004, The Journal of Neuroscience.

[55]  W. Jänig,et al.  On the fate of sympathetic and sensory neurons projecting into a neuroma of the superficial peroneal nerve in the cat , 1984, The Journal of comparative neurology.

[56]  S. Yale,et al.  Jules Tinel (1879-1952) and Paul Hoffman (1884-1962). , 2006, Clinical medicine & research.

[57]  M. Tominaga,et al.  Thermosensation and pain. , 2004, Journal of neurobiology.

[58]  W. Jänig.  Pathophysiology of nerve following mechanical and ischemic injury , 1987, PAIN.

[59]  L. Mendell.  5.22 – Neurotrophins and Pain , 2008 .

[60]  W. Jänig,et al.  Discharge pattern of afferent fibers from a neuroma , 1984, Pain.

[61]  D. McKemy,et al.  Identification of a cold receptor reveals a general role for TRP channels in thermosensation , 2002, Nature.

[62]  S. Lawson.  Chapter 8 – The Peripheral Sensory Nervous System: Dorsal Root Ganglion Neurons , 2005 .

[63]  M. Gold,et al.  Cold transduction in rat trigeminal ganglia neurons in vitro , 2003, Neuroscience.

[64]  L. Djouhri,et al.  Spontaneous Pain, Both Neuropathic and Inflammatory, Is Related to Frequency of Spontaneous Firing in Intact C-Fiber Nociceptors , 2006, The Journal of Neuroscience.

[65]  F. J. Clark,et al.  Microstimulation of single tactile afferents from the human hand. Sensory attributes related to unit type and properties of receptive fields. , 1984, Brain : a journal of neurology.

[66]  H. M. Davies,et al.  Experimental studies in the innervation of the skin , 1909, The Journal of physiology.

[67]  E. Perl,et al.  Regeneration of cutaneous afferent unmyelinated (C) fibers after transection. , 1985, Journal of neurophysiology.

[68]  R. Coggeshall,et al.  Loss of dorsal root ganglion cells concomitant with dorsal root axon sprouting following segmental nerve lesions , 1997, Neuroscience.

[69]  W. Jänig,et al.  Ectopic activity in cutaneous regenerating afferent nerve fibers following nerve lesion in the rat , 2003, The European journal of neuroscience.

[70]  J. Gu,et al.  TRPM8 Mechanism of Cold Allodynia after Chronic Nerve Injury , 2007, The Journal of Neuroscience.

[71]  S. Lisney,et al.  Regeneration of unmyelinated axons after injury of mammalian peripheral nerve. , 1989, Quarterly journal of experimental physiology.

[72]  T. Hökfelt,et al.  Central consequences of peripheral nerve damage , 2006 .

[73]  H O Handwerker,et al.  Responsiveness and functional attributes of electrically localized terminals of cutaneous C-fibers in vivo and in vitro. , 1992, Journal of neurophysiology.

[74]  C. Woolf,et al.  The neuropathic pain triad: neurons, immune cells and glia , 2007, Nature Neuroscience.

[75]  Makoto Tominaga,et al.  Heat-Evoked Activation of the Ion Channel, TRPV4 , 2002, The Journal of Neuroscience.

[76]  J. Tinel.  “Tingling” Signs with Peripheral Nerve Injuries , 2005 .

[77]  Peter McIntyre,et al.  ANKTM1, a TRP-like Channel Expressed in Nociceptive Neurons, Is Activated by Cold Temperatures , 2003, Cell.

[78]  James N. Campbell,et al.  Early Onset of Spontaneous Activity in Uninjured C-Fiber Nociceptors after Injury to Neighboring Nerve Fibers , 2001, The Journal of Neuroscience.

[79]  E. McLachlan,et al.  Selective Reactions of Cutaneous and Muscle Afferent Neurons to Peripheral Nerve Transection in Rats , 2003, The Journal of Neuroscience.