TRPM8 ion channel ligands for new therapeutic applications and as probes to study menthol pharmacology

Since the discovery of the TRPM8 gene in 2001, the TRPM8 ion channel, better known as the ‘cold receptor’ has been the target of a significant effort from the pharmaceutical industry to produce small-molecule agonists and antagonists of this receptor for various therapeutic applications ranging from cancer and urological disorders to the treatment of cold hypersensitivity and pain. Recently, a number of clinical studies have implicated menthol, the natural ligand of TRPM8, in facilitating and maintaining cigarette smoking behavior, possibly through its counter-irritant effects. However, a pharmacological link between menthol's action via TRPM8 and nicotine addiction has not been yet been investigated. This review gives an overview of reported small-molecule TRPM8 agonists and antagonists and discusses their efficacy in models of various disease states. These compounds may be useful pharmacological tools to investigate the effect of menthol on nicotine addiction.