TRPV1 as a Polymodal Sensor: Potential to Discover TRPV1 Antagonists Selective for Specific Activating Modalities

The transient receptor potential V1, or TRPV1, channel has a complex polymodal activation profile that integrates information from membrane potential changes, heat, and protons in addition to channel gating following ligand binding. TRPV1 is expressed along the peripheral pain pathway from the distal endings of nociceptor neurons to dorsal root ganglia; but has limited expression in the central nervous system and is detected in arteriolar smooth muscle cells and various epithelia. Several TRPV1 antagonist candidate drugs have been tested in clinical trials over the past 5 years with varying results. The reported side-effect profile of these oral drug formulations includes hyperthermia and impaired detection of painful heat. These adverse events have tentatively been linked to characteristic in vitro profiles of the candidate drugs, specifically the ability of these molecules to differentially block one or several opening modalities. Thus the selection of lead candidates that are selective for specific modalities could be key to the development of a successful TRPV1 antagonist drug. This minireview updates the details of TRPV1 activation modes, existing in vitro assays available for screening of novel molecules and the clinical and preclinical profiles of next-generation TRPV1 candidate drugs developed by pharmaceutical companies.