TRPM8 Channels as Potential Therapeutic Targets for Pain, Analgesia, and Thermoregulation

The perception of temperature is critical in not only acute responses to changes in the environment but also fundamental in regulating homeostatic mechanisms like core body temperature. The somatosensory system detects changes in ambient temperature via the coordinated efforts of thermosensory nerves expressing temperature-sensitive members of the TRP family of ion channels. These channels respond over a wide range of temperatures that covers the entire perceived spectrum from comfortably warm to painfully hot and from pleasingly cool to excruciatingly cold. Many of these channels are receptors for natural products that elicit distinct psychophysical sensations, such as the heat associated with capsaicin and the cold felt with menthol, the latter influential in the discovery of TRPM8, the first TRP channel shown to be responsive to cold temperatures. TRPM8, a member of the melastatin TRP channel subfamily, is a receptor for a number of cold mimetics such as menthol and icilin, and is activated by temperatures that range from innocuous cool (26–15�C) to noxious cold (<15�C). In vivo, TRPM8 is the predominant mammalian cold sensor and is involved in most, if not all, aspects of cold thermal transduction, including the transduction of innocuous cool and noxious cold, hypersensitivity to cold caused by inflammation, nerve injury or chemotherapeutic toxicity, regulation of core body temperature, and provides the analgesic effect produced by cold or chemical cooling compounds. This chapter describes the physiological roles attributed to TRPM8 and highlights some potential uses of both TRPM8 antagonists and agonists in the treatment of pain and metabolic homeostasis.