Analgesia mediated by the TRPM8 cold receptor in neuropathic pain

Chronic pain, particularly neuropathic pain, is a major clinical problem which currently represents a largely unmet therapeutic need.To identify novel analgesic strategies for chronic pain, we investigated the phenomenon of analgesia produced by cutaneous cooling. The recent identification of specific cold sensory receptors has allowed, for the first time, investigation of the molecular mechanism underlying cooling-induced analgesia.We have shown that the cold-and-menthol receptor, TRPM8, is critically involved in cooling-induced analgesia. Activation of TRPM8 in a subpopulation of sensory afferents (by either cutaneous or intrathecal application of pharmacological agents or by modest cooling) elicits analgesia in neuropathic and other chronic pain models in rats, and inhibits the characteristic sensitisation of dorsal horn neurons that occurs ipsilateral to nerve injury. This analgesia is abolished following antisense knockdown of the TRPM8 receptor.In contrast, activation of the related putative cold-receptor TRPA1 produces hyperalgesia in naive and neuropathic rats.TRPM8 expression was observed in small diameter sensory neurons in dorsal root ganglia and on afferent terminals in the spinal cord, with increases in specific subsets of sensory neurons following nerve injury.We further found that the central mechanism of TRPM8-mediated analgesia is mediated through inhibitory Group II/III metabotropic glutamate receptors, and is opioid-independent.These results identify TRPM8 as an essential molecular mediator of coolinginduced analgesia. We propose a novel analgesic axis in which activation of TRPM8- expressing afferents by innocuous cooling or chemical ligands leads to activation of inhibitory Group II/III metabotropic glutamate receptors in the spinal cord, which then exert inhibition over nociceptive inputs. These findings suggest that both TRPM8 and the inhibitory metabotropic glutamate receptors are promising targets for the development of novel analgesics for the treatment of neuropathic pain states