TRPM8 for Treating Chronic Pain

TRPM8, a member of the transient receptor potential family of nonselective cation channels, is activated by cold or by ligands that trigger the sensation of cold, such as menthol or icillin. Proudfoot et al. used a rat model of chronic pain to show that activation of TRPM8 produced analgesia. Topical application or intrathecal injection of icillin decreased the pain response of rats subjected to chronic constriction injury of the sciatic nerve. The frequency of firing of small afferent neurons was increased in response to icillin. TRPM8 was detected in the dorsal root ganglia, mostly in small unmyelinated neurons, and the abundance was increased in the small unmyelinated and the myelinated neurons following nerve injury. Antisense treatment to knock down TRPM8 confirmed that the behavior and nerve firing frequency changes in response to icillin were mediated by TRPM8. In the brain, TRPM8 positive afferents are believed to be glutamate-releasing neurons. Consistent with this, agonists of group II or group III metabotropic glutamate receptors (mGluRs) also decreased the pain response of the rats with chronic constriction injury. Antagonists of these mGluRs prevented icillin from mediating analgesia. In vivo recordings of spinal cord neurons that integrate nociceptive and nonnociceptive inputs showed that icillin inhibited the elevated neuronal responses in the rats with chronic constriction injury. Thus, TRPM8 appears to be an attractive target for pharmacological intervention of chronic pain. C. J. Proudfoot, E. M. Garry, D. F. Cottrell, R. Rosie, H. Anderson, D. C. Robertson, S. M. Fleetwood-Walker, R. Mitchell, Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. Curr. Biol. 16 , 1591-1605 (2006). [PubMed]