Proudfoot CJ et al. (2006) Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. Curr Biol 16: 1591–1605

Peripheral or central activation of the TRPM8 (transient receptor potential melastatine family member 8) cool-sensitive ion channel can produce an analgesic effect, reversing hypersensitivity and reducing chronic neuropathic pain resulting from peripheral nerve damage, reports a paper in Current Biology. These findings are important given the dearth of treatments currently available for this severe clinical problem.

The TRPM8 channel is expressed by subsets of sensory neurons in dorsal root and trigenimal ganglia and is activated by cold or ligands, such as menthol or icilin, that trigger cold sensation. In a rat model of neuropathic pain, mild cooling of the skin or peripheral or central application of icilin produced marked analgesic effects, inhibiting sensitization of dorsal-horn neurons and facilitation of behavioral reflexes. Following nerve injury, TRPM8 expression was increased in a subset of sensory neurons. Further experiments confirmed TRPM8's importance in pain response and showed its analgesic effect to be centrally mediated and to rely on Group II/III metabotropic glutamate receptors (inhibitors of nociceptive responses). By contrast, results were obtained indicating that the TRPA1 cool-sensitive ion channel is unlikely to have a role in analgesia.

The TRPM8 activators were needed at very low concentrations, produced few side effects, and also produced analgesic effects in sensitized pain states not induced by nerve injury. The authors, therefore, propose TRPM8 activators and downstream central mediators of TRPM8 action—such as Group II/III metabotropic glutamate receptors—as likely targets for the development of novel analgesics.