Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain.
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.
Proudfoot
Clare J
CJ
Centre for Neuroscience Research, Division of Veterinary Biomedical Sciences, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, United Kingdom.
Garry
Emer M
EM
Cottrell
David F
DF
Rosie
Roberta
R
Anderson
Heather
H
Robertson
Darren C
DC
Fleetwood-Walker
Susan M
SM
Mitchell
Rory
R
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
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