title: Transient receptor potential melastatin 8 (TRPM8) channels are involved in body temperature regulation.
abstract: 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 (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.
  
  
  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 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Neuroscience, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320, USA. ngavva@amgen.com
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
authors.forename: Carl
authors.initials: C
authors.lastname: Davis
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Lehto
authors.forename: Sara
authors.initials: S
authors.lastname: Rao
authors.forename: Weiya
authors.initials: W
authors.lastname: Wang
authors.forename: Dawn X D
authors.initials: DX
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D049990:Membrane Transport Modulators / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009287:Naphthyridines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C000603942:AMG2850; D049990:Membrane Transport Modulators; D009287:Naphthyridines; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; C498947:Trpm8 protein, rat