Transient receptor potential melastatin 8 (TRPM8) is a non-selective cation channel activated by coldtemperature and cooling agents. TRPM8 is expressed in peripheral cold thermoreceptors and plays a fundamental role insensing mild, cool temperatures. In addition, cumulative evidence obtained in humans and different animals models,combined with pharmacological and gene silencing techniques, suggest that TRPM8 may also play a role in colddiscomfort and the pathophysiology of cold pain. This article reviews the available evidence in a critical fashion. Inaddition, the article reviews the possible role of TRPM8 in basal tearing, cold urticaria and airway irritation. Collectively,these results suggest that pharmacological modulators of TRPM8 could have potential indications in a variety ofconditions, including dry eye disease, airway irritation, teeth hypersensitivity, migraine and neuropathic pain. However,additional studies, especially in humans, are needed to verify these preliminary observations. The paucity of potent,specific pharmacological TRPM8 antagonists available is a current limitation for further progress in this field.
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