Transient receptor potential melastatin 8 TRPM8 channels are involved in body temperature regulationReport as inadecuate




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Molecular Pain

, 8:36

First Online: 09 May 2012Received: 11 January 2012Accepted: 08 April 2012

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.

KeywordsTRPM8 antagonist AMG0635 AMG2850 AMG8788 AMG9678 Compound 496 Body temperature regulation AbbreviationsTbDeep body temperature

PIP2Phosphatidylinositol 4,5-bisphosphate

AMG0635R-N-pyridin-3-yl-1-4-trifluoromethylphenyl-3,4-dihydroisoquinoline-21 H-carboxamide

AMG2850R-8-4-trifluoromethylphenyl-N-S-1,1,1-trifluoropropan-2-yl-5,6-dihydro-1,7-naphthyridine-78 H-carboxamide

AMG8788R-N-4-fluorophenyl-1-4-trifluoromethylphenyl-3,4-dihydroisoquinoline-21 H-carboxamide

AMG9678R-1-4-trifluoromethylphenyl-N-S-1,1,1-trifluoropropan-2-yl-3,4-dihydroisoquinoline-21 H-carboxamide

Compound 4964-N-3-methylbenzobthiophen-2-yl-N-4-trifluoromethoxybenzylsulfamoylbenzoic acid.

Electronic supplementary materialThe online version of this article doi:10.1186-1744-8069-8-36 contains supplementary material, which is available to authorized users.

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Author: Narender R Gavva - Carl Davis - Sonya G Lehto - Sara Rao - Weiya Wang - Dawn XD Zhu

Source: https://link.springer.com/







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