Transient Receptor Potential Melastatin 8 (TRPM8) Channels are Involved in Body Temperature Regulation

Abstract

BackgroundTransient 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 (Tb), it is not known if TRPM8 plays a role in Tb regulation. Since TRPM8 has been considered as a potential target for chronic pain therapeutics, we have investigated the role of TRPM8 in Tb regulation.ResultsWe characterized five chemically distinct compounds (AMG0635, AMG2850, AMG8788, AMG9678, and Compound 496) as potent and selective antagonists of TRPM8 and tested their effects on Tb in rats and mice implanted with radiotelemetry probes. All five antagonists used in the study caused a transient decrease in Tb (maximum decrease of 0.98°C). Since thermoregulation is a homeostatic process that maintains Tb about 37°C, we further evaluated whether repeated administration of an antagonist attenuated the decrease in Tb. Indeed, repeated daily administration of AMG9678 for four consecutive days showed a reduction in the magnitude of the Tb decrease Day 2 onwards.ConclusionsThe data reported here demonstrate that TRPM8 channels play a role in Tb regulation. Further, a reduction of magnitude in Tb decrease after repeated dosing of an antagonist suggests that TRPM8’s role in Tb maintenance may not pose an issue for developing TRPM8 antagonists as therapeutics.

Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition

“…However, the existing data do not support this prediction. Several studies, which explored the effects of genetic deletion and pharmacological inhibition of TRPM8 on core temperature during mild and moderate cooling (ambient temperatures ranging from 10 to 22°C), consistently report ϳ1°C lower core temperatures after TRPM8 ablation compared with controls (1,11,17,33). In agreement, in the current study a ϳ1°C difference was observed in mice treated with TRPM8 inhibitor compound 5 and exposed to mild cooling at 18°C for 2 h, compared with vehicle-treated mice.…”

“…The drop in core temperature after 70 min at 18°C relative to the preinjection value was Ϫ1.1 Ϯ 0.1 vs. Ϫ1.7 Ϯ 0.2 in vehicle-and compound 5-treated mice, respectively (P ϭ 0.02). The hypothermic effect of compound 5 observed here is in agreement with the effects of other reported TRPM8 inhibitors (1,11,17), which is consistent with the inhibition of TRPM8 activity by compound 5.…”

“…Similar results obtained with pharmacological and genetic approaches increase the reliability of conclusions in the current study. Nevertheless, it would be important to confirm these findings by measuring the shivering response in mice treated with other developed TRPM8 inhibitors (1,11,17), as well as in conditional KO mice with acute genetic deletion of TRPM8 gene. Finally, because not all possible scenarios can be tested, we cannot completely rule out the possibility that TRPM8 still plays at least a minor role in shivering in some specific set of conditions (including specific species, ambient temperature, method of cooling, etc.)…”

“…In particular, inhibitors of the transient receptor potential (TRP) melastatin 8 (TRPM8) ion channel and activators of the TRP vanilloid 1 (TRPV1) ion channel were shown to decrease core temperature in conscious organisms of a number of species (1,10,11,14,17). TRPM8 is a molecular cold sensor of the primary coldsensitive neurons, while TRPV1 is a heat and pain receptor expressed within peripheral and central sensory nervous system (23,30).…”

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

“…Assessment of trpm8 2/2 mice and use of pharmacologic agents indicate that TRPM8 has diverse sensory roles and contributes to cold-induced allodynia and analgesia, pruritus, and inflammatory processes (Namer et al, 2008;Caspani et al, 2009;Su et al, 2011;Calvo et al, 2012;Lippoldt et al, 2013;Ramachandran et al, 2013;Shapovalov et al, 2013;Than et al, 2013). The use of selective antagonists have confirmed the involvement of TRPM8 in thermoregulation and augmented nerve excitability through voltagegated Na + channels (Gavva et al, 2012;Sarria et al, 2012). Furthermore, TRPM8 is an integrator of cell signaling pathways: it can bind G proteins and therefore play a role in initiating signaling pathways through mechanisms that are yet to be completely understood (Klasen et al, 2012).…”