title: Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain.
abstract: BACKGROUND
  Chronic established pain, especially that following nerve injury, is difficult to treat and represents a largely unmet therapeutic need. New insights are urgently required, and we reasoned that endogenous processes such as cooling-induced analgesia may point the way to novel strategies for intervention. Molecular receptors for cooling have been identified in sensory nerves, and we demonstrate here how activation of one of these, TRPM8, produces profound, mechanistically novel analgesia in chronic pain states.
  
  
  RESULTS
  We show that activation of TRPM8 in a subpopulation of sensory afferents (by either cutaneous or intrathecal application of specific pharmacological agents or by modest cooling) elicits analgesia in neuropathic and other chronic pain models in rats, thereby inhibiting the characteristic sensitization of dorsal-horn neurons and behavioral-reflex facilitation. TRPM8 expression was increased in a subset of sensory neurons after nerve injury. The essential role of TRPM8 in suppression of sensitized pain responses was corroborated by specific knockdown of its expression after intrathecal application of an antisense oligonucleotide. We further show that the analgesic effect of TRPM8 activation is centrally mediated and relies on Group II/III metabotropic glutamate receptors (mGluRs), but not opioid receptors. We propose a scheme in which Group II/III mGluRs would respond to glutamate released from TRPM8-containing afferents to exert an inhibitory gate control over nociceptive inputs.
  
  
  CONCLUSIONS
  TRPM8 and its central downstream mediators, as elements of endogenous-cooling-induced analgesia, represent a novel analgesic axis that can be exploited in chronic sensitized pain states.
authors.affiliation: Centre for Neuroscience Research, Division of Veterinary Biomedical Sciences, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, United Kingdom.
authors.forename: Clare J
authors.initials: CJ
authors.lastname: Proudfoot
authors.forename: Emer M
authors.initials: EM
authors.lastname: Garry
authors.forename: David F
authors.initials: DF
authors.lastname: Cottrell
authors.forename: Roberta
authors.initials: R
authors.lastname: Rosie
authors.forename: Heather
authors.initials: H
authors.lastname: Anderson
authors.forename: Darren C
authors.initials: DC
authors.lastname: Robertson
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fleetwood-Walker
authors.forename: Rory
authors.initials: R
authors.lastname: Mitchell
mesh_terms: D000171:Acrolein / Q000031:analogs & derivatives / Q000494:pharmacology; D000596:Amino Acids / Q000494:pharmacology; D000698:Analgesia / Q000379:methods*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003080:Cold Temperature; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D007150:Immunohistochemistry; D008297:Male; D008610:Menthol / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism* / Q000628:therapy*; D016376:Oligonucleotides, Antisense; D011744:Pyrimidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000378:metabolism; D012018:Reflex / Q000187:drug effects; D050053:TRPM Cation Channels / Q000378:metabolism*; D014966:Xanthenes / Q000494:pharmacology
chemical_list: D000596:Amino Acids; C114624:LY 341495; D016376:Oligonucleotides, Antisense; D011744:Pyrimidinones; D017470:Receptors, Glutamate; D050053:TRPM Cation Channels; C498947:Trpm8 protein, rat; D014966:Xanthenes; D008610:Menthol; D000171:Acrolein; C490483:icilin; C012843:cinnamaldehyde