Transient receptor potential melastatin 8 (TRPM8) channels are involved in body temperature regulation

BACKGROUND: Transient receptor potential cation channel subfamily M member 8 (TRPM8) is activated by cold temperature in vitro and has been demonstrated to act as a ‘cold temperature sensor’ in vivo. Although it is known that agonists of this ‘cold temperature sensor’, such as menthol and icilin, cause a transient increase in body temperature (T(b)), it is not known if TRPM8 plays a role in T(b) regulation. Since TRPM8 has been considered as a potential target for chronic pain therapeutics, we have investigated the role of TRPM8 in T(b) regulation. RESULTS: We characterized five chemically distinct compounds (AMG0635, AMG2850, AMG8788, AMG9678, and Compound 496) as potent and selective antagonists of TRPM8 and tested their effects on T(b) in rats and mice implanted with radiotelemetry probes. All five antagonists used in the study caused a transient decrease in T(b) (maximum decrease of 0.98°C). Since thermoregulation is a homeostatic process that maintains T(b) about 37°C, we further evaluated whether repeated administration of an antagonist attenuated the decrease in T(b). Indeed, repeated daily administration of AMG9678 for four consecutive days showed a reduction in the magnitude of the T(b) decrease Day 2 onwards. CONCLUSIONS: The data reported here demonstrate that TRPM8 channels play a role in T(b) regulation. Further, a reduction of magnitude in T(b) decrease after repeated dosing of an antagonist suggests that TRPM8’s role in T(b) maintenance may not pose an issue for developing TRPM8 antagonists as therapeutics.