Topical menthol--a human model for cold pain by activation and sensitization of C nociceptors.

Although cold hyperalgesia is a frequent symptom in patients with neuropathic pain, it is poorly understood. We investigated the mechanisms of cold pain by studying the effect of menthol on pain, temperature perception, touch sensation and skin perfusion. In 10 subjects, 40% l-menthol, and ethanol, serving as control, were topically applied to the forearm in a double-blinded two-way crossover study. Menthol induced significant pain and cold sensations, punctate and cold hyperalgesia and an increase in cutaneous perfusion. Other mechano-sensory and thermal tests were unchanged (touch, cold and warm detection thresholds, heat pain threshold; no dynamic and static hyperalgesia, no wind-up). To investigate the underlying mechanisms, the effects of menthol versus ethanol on the dorsum of the hand were tested during A fibre conduction blockade of the superficial radial nerve in another 10 subjects. The block itself led to hypoaesthesia for mechanical stimuli and anaesthesia for cold perception, but induced an increase in cold-mediated pain. This was due to lack of inhibition of C nociceptors normally exerted by concomitant activation of A fibres. Under these conditions, menthol-induced cold sensation and punctate hyperalgesia were abolished. However, menthol induced spontaneous pain with a trend to higher values than without block. Furthermore, the hyperalgesia to cold stimuli, that was already present during A fibre block, was further increased significantly by menthol. We suggested that menthol acts to sensitize cold-sensitive peripheral vasoactive C nociceptors and activates cold-specific A delta fibres. Punctate hyperalgesia is due to central sensitization based on the ongoing activity in the sensitized cold-sensitive peripheral C nociceptors. In conclusion, topical menthol is a human model for cold pain by exposing for the first time the mechanism of sensitized peripheral cold C nociceptors that may also be involved in neuropathic pain.

[1]  R. LaMotte,et al.  Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms. , 1991, Journal of neurophysiology.

[2]  P. Mantyh,et al.  Enhanced responses of spinal dorsal horn neurons to heat and cold stimuli following mild freeze injury to the skin. , 2001, Journal of neurophysiology.

[3]  E. Carstens,et al.  Psychophysical study of stinging pain evoked by brief freezing of superficial skin and ensuing short-lasting changes in sensations of cool and cold pain , 1998, Pain.

[4]  R. Meyer,et al.  Secondary hyperalgesia to punctate mechanical stimuli. Central sensitization to A-fibre nociceptor input. , 1999, Brain : a journal of neurology.

[5]  M. Bushnell,et al.  Disruption of Thermal Perception in a Multiple Sclerosis Patient With Central Pain , 2002, The Clinical journal of pain.

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

[7]  D. Clapham.  Signal transduction. Hot and cold TRP ion channels. , 2002, Science.

[8]  P. McIntyre,et al.  A TRP Channel that Senses Cold Stimuli and Menthol , 2002, Cell.

[9]  H. E. Torebjörk,et al.  Afferent C units responding to mechanical, thermal and chemical stimuli in human non-glabrous skin. , 1974, Acta physiologica Scandinavica.

[10]  E. Perl,et al.  Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli. , 1969, Journal of neurophysiology.

[11]  J. Ochoa,et al.  Quantitative somatosensory thermotest. A key method for functional evaluation of small calibre afferent channels. , 1992, Brain : a journal of neurology.

[12]  E. Reiman,et al.  Thermosensory activation of insular cortex , 2000, Nature Neuroscience.

[13]  H. E. Torebjörk,et al.  Which nerve fibers mediate the axon reflex flare in human skin? , 2000, Neuroreport.

[14]  D Yarnitsky,et al.  Paradoxical heat sensation in healthy subjects: peripherally conducted by A delta or C fibres? , 1999, Brain : a journal of neurology.

[15]  Christoph Stein,et al.  The German counterpart to McGill Pain Questionnaire , 1988, Pain.

[16]  D Smart,et al.  Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1 , 2002, Nature Neuroscience.

[17]  R. Duclaux,et al.  Response of cat skin mechanothermal nociceptors to cold stimulation , 1985, Brain Research Bulletin.

[18]  J. Massagué.  TGF-beta signal transduction. , 1998, Annual review of biochemistry.

[19]  R T Verrillo,et al.  Sensory functions in chronic neuralgia. , 1979, Journal of neurology, neurosurgery, and psychiatry.

[20]  M. Bushnell,et al.  The thermal grill illusion: unmasking the burn of cold pain. , 1994, Science.

[21]  H. Lux,et al.  Effect of menthol on two types of Ca currents in cultured sensory neurons of vertebrates , 1987, Pflügers Archiv.

[22]  I. Hendry,et al.  Noxious heating of the skin releases immunoreactive substance P in the substantia gelatinosa of the cat: A study with antibody microprobes , 1987, Brain Research.

[23]  K. Davis.  Cold-induced pain and prickle in the glabrous and hairy skin , 1998, Pain.

[24]  A. Basbaum,et al.  Molecular mechanisms of nociception , 2001, Nature.

[25]  H. Fruhstorfer.  Thermal sensibility changes during ischemie nerve block , 1984, Pain.

[26]  Robert H. LaMotte,et al.  Response properties of high-threshold cutaneous cold receptors in the primate , 1982, Brain Research.

[27]  R. Baron.  Peripheral Neuropathic Pain: From Mechanisms to Symptoms , 2000, The Clinical journal of pain.

[28]  D. Clapham.  Hot and Cold TRP Ion Channels , 2002, Science.

[29]  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.

[30]  H O Handwerker,et al.  Different patterns of hyperalgesia induced by experimental inflammation in human skin. , 1994, Brain : a journal of neurology.

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

[32]  A I Basbaum,et al.  Impaired nociception and pain sensation in mice lacking the capsaicin receptor. , 2000, Science.

[33]  R. Dykes,et al.  "Cold" fiber population innervating palmar and digital skin of the monkey: responses to cooling pulses. , 1973, Journal of neurophysiology.

[34]  M. Rowbotham,et al.  Postherpetic Neuralgia: Irritable Nociceptors and Deafferentation , 1998, Neurobiology of Disease.

[35]  D. McKemy,et al.  Lessons from peppers and peppermint: the molecular logic of thermosensation , 2003, Current Opinion in Neurobiology.

[36]  M. Flonta,et al.  Ion channels activated by cold and menthol in cultured rat dorsal root ganglion neurones , 2002, Neuroscience Letters.

[37]  S. Simon,et al.  Selectivity of lingual nerve fibers to chemical stimuli , 1993, The Journal of general physiology.

[38]  B. Lynn,et al.  The vasodilator component of neurogenic inflammation is caused by a special subclass of heat‐sensitive nociceptors in the skin of the pig. , 1996, The Journal of physiology.

[39]  S. Ogawa,et al.  Effects of presurgical local infiltration of bupivacaine in the surgical field on postsurgical wound pain in laparoscopic gynecologic examinations: a possible preemptive analgesic effect. , 2000, The Clinical journal of pain.

[40]  P. Holzer.  Peptidergic sensory neurons in the control of vascular functions: mechanisms and significance in the cutaneous and splanchnic vascular beds. , 1992, Reviews of physiology, biochemistry and pharmacology.

[41]  J. Gybels,et al.  Response properties of thin myelinated (A-delta) fibers in human skin nerves. , 1983, Journal of neurophysiology.

[42]  D. Burke,et al.  Fibre function and perception during cutaneous nerve block. , 1975, Proceedings of the Australian Association of Neurologists.

[43]  R. Tuckett,et al.  Response of sensory units with unmyelinated fibres to mechanical, thermal and chemical stimulation of the cat's cornea. , 1993, The Journal of physiology.

[44]  Z. Ali,et al.  The conduction velocities of peripheral nerve fibres conveying sensations of warming and cooling. , 1988, Journal of neurology, neurosurgery, and psychiatry.

[45]  H. E. Torebjörk,et al.  Mechano-insensitive nociceptors encode pain evoked by tonic pressure to human skin , 2000, Neuroscience.

[46]  David Yarnitsky,et al.  Paradoxical heat sensation in healthy subjects: peripherally conducted by Aδ or C fibres? , 1999 .

[47]  R. Treede,et al.  Pain related cerebral potentials: late and ultralate components. , 1987, The International journal of neuroscience.

[48]  B. Green.  Menthol modulates oral sensations of warmth and cold , 1985, Physiology & Behavior.

[49]  A. Craig,et al.  Effects of systemic morphine on lamina I spinothalamic tract neurons in the cat , 1994, Brain Research.

[50]  R. Eccles.  Role of cold receptors and menthol in thirst, the drive to breathe and arousal , 2000, Appetite.

[51]  H. Fruhstorfer,et al.  Method for quantitative estimation of thermal thresholds in patients. , 1976, Journal of neurology, neurosurgery, and psychiatry.

[52]  J. Szolcsányi.  Antidromic vasodilatation and neurogenic inflammation , 1988, Agents and Actions.

[53]  J. Ochoa,et al.  Mechanical hyperalgesias in neuropathic pain patients: Dynamic and static subtypes , 1993, Annals of neurology.

[54]  Alan C. Evans,et al.  Functional imaging of an illusion of pain , 1996, Nature.

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

[56]  J. Ochoa,et al.  Release of cold-induced burning pain by block of cold-specific afferent input. , 1990, Brain : a journal of neurology.

[57]  B. Green.  The sensory effects of l-menthol on human skin. , 1992, Somatosensory & motor research.

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

[59]  Robert H. LaMotte,et al.  Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin , 1989, Pain.

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

[61]  T. Lewis.  The blood vessels of the human skin and their responses , 1927 .

[62]  R. Eccles.  Menthol and Related Cooling Compounds , 1994, The Journal of pharmacy and pharmacology.

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

[64]  R. Hallin,et al.  Identification of afferent C units in intact human skin nerves. , 1974 .

[65]  R. Melzack.  The McGill Pain Questionnaire: Major properties and scoring methods , 1975, PAIN.

[66]  E. Torebjörk,et al.  Central suppression of cold-induced C fibre pain by myelinated fibre input , 1989, Pain.

[67]  E. Torebjörk,et al.  Quantitative sensory tests in patients with neuralgia 11 to 25 years after injury , 1992, Pain.

[68]  J. Ochoa,et al.  Warm and cold specific somatosensory systems. Psychophysical thresholds, reaction times and peripheral conduction velocities. , 1991, Brain : a journal of neurology.

[69]  D. Julius,et al.  The vanilloid receptor: a molecular gateway to the pain pathway. , 2001, Annual review of neuroscience.

[70]  Martin Koltzenburg,et al.  Dynamic and static components of mechanical hyperalgesia in human hairy skin , 1992, Pain.

[71]  C. Woolf,et al.  Neuropathic pain: aetiology, symptoms, mechanisms, and management , 1999, The Lancet.

[72]  Walter Magerl,et al.  Neurogenic hyperalgesia versus painful hypoalgesia: two distinct mechanisms of neuropathic pain , 2002, Pain.

[73]  J. Ochoa,et al.  The triple cold syndrome. Cold hyperalgesia, cold hypoaesthesia and cold skin in peripheral nerve disease. , 1994, Brain : a journal of neurology.

[74]  S. Lindström,et al.  Cold‐ and menthol‐sensitive C afferents of cat urinary bladder , 2002, The Journal of physiology.

[75]  K. Kashihara,et al.  Cold-induced dysaesthesia in acute idiopathic polyneuritis , 1987, Journal of Neurology.

[76]  H. Maibach,et al.  Effect of topically applied menthol on thermal, pain and itch sensations and biophysical properties of the skin , 1996, Archives of Dermatological Research.

[77]  D. R. Kenshalo,et al.  Facilitation of the responses of primate spinothalamic cells to cold and to tactile stimuli by noxious heating of the skin , 1982, PAIN®.

[78]  M. Koltzenburg,et al.  Pain and hyperalgesia in acute inflammatory and chronic neuropathic conditions , 1995, The Lancet.

[79]  H. E. Torebjfrk.  Perceptual changes accompanying controlled preferential blocking of A and C fibre responses in intact human skin nerves H. E. Torebjörk and R. G. Hallin, Exp. Brain Res., 16 (1973) 311–332 , 1975, PAIN.