Therapeutic Potential of TRPM8 Modulators

The perception of temperature is a key tenet of sensory physiology and is critical in not only acute responses to changes in our environment, but also fundamental in regulating homeostatic mechanisms like core body temperature [1]. The somatosensory system is able to detect subtle changes in ambient temperature due to the coordinated efforts of thermosensory neurons which express temperature-sensitive members of the TRP channel family [2]. Remarkably, the range of temperatures that these channels respond to covers the entire perceived temperature spectrum, from warm to painfully hot, from pleasingly cool to excruciatingly cold. Moreover, many of these channels are receptors for ligands that elicit distinct psychophysical sensations, such as the heat associated with capsaicin and the cold felt with menthol [2]. The latter of these was influential in the discovery of the first TRP channel shown to be responsive to temperatures in the cold range (<30°C), TRPM8, a member of the melastatin TRP channel subfamily [3, 4]. In vitro, the channel is a receptor for a number of compounds which evoke the psychophysical sensation of cold (such as menthol and icilin), and is activated by temperatures that range from innocuous cool (26-15°C) to noxious cold (<15°C). Recent genetic evidence shows that TRPM8 is the predominant mammalian cold sensor and is involved in most, if not all, aspects of cold thermal transduction [5-8]. These studies demonstrated that TRPM8 mediates transduction of innocuous cool and noxious cold, hypersensitivity to cold caused by inflammation or nerve injury, and provides the analgesic effect produced by cold or chemical cooling compounds. This review highlights these findings and suggests some potential uses of both TRPM8 antagonists and agonists in the treatment of pain.