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 degrees C). Since thermoregulation is a homeostatic process that maintains T-b about 37 degrees 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.