title: Transient receptor potential melastatin 8 channel inhibition potentiates the hypothermic response to transient receptor potential vanilloid 1 activation in the conscious mouse.
abstract: OBJECTIVE
  Mild decrease in core temperature (therapeutic hypothermia) provides lasting neuroprotection following cardiac arrest or cerebral ischemia. However, current methods for producing therapeutic hypothermia trigger a cold-defense response that must be countered by sedatives, muscle paralytics, and mechanical ventilation. We aimed to determine methods for producing hypothermia in the conscious mouse by targeting two transient receptor potential channels involved in thermoregulation, two transient receptor potential (TRP) channels involved in thermoregulation, TRP vanilloid 1 (TRPV1) and TRP melastatin 8 (TRPM8).
  
  
  METHODS
  Controlled prospective animal study.
  
  
  METHODS
  Research laboratory at academic medical center.
  
  
  METHODS
  Conscious unrestrained young and aged male mice.
  
  
  METHODS
  Mice were treated with the TRPV1 agonist dihydrocapsaicin, a TRPM8 inhibitor ("compound 5"), or their combination and the effects on core temperature (Tcore) were measured by implanted thermocouples and wireless transponders.
  
  
  RESULTS
  TRPV1 agonist dihydrocapsaicin produced a dose-dependent (2-4 mg/kg s.c.) drop in Tcore. A loading dose followed by continuous infusion of dihydrocapsaicin produced a rapid and prolonged (> 6 hr) drop of Tcore within the therapeutic range (32-34°C). The hypothermic effect of dihydrocapsaicin was augmented in aged mice and was not desensitized with repeated administration. TRPM8 inhibitor "compound 5" (20 mg/kg s.c.) augmented the drop in core temperature during cold exposure (8°C). When "compound 5" (30 mg/kg) was combined with dihydrocapsaicin (1.25-2.5 mg/kg), the drop in Tcore was amplified and prolonged.
  
  
  CONCLUSIONS
  Activating warm receptors (TRPV1) produced rapid and lasting hypothermia in young and old mice. Furthermore, hypothermia induced by TRPV1 agonists was potentiated and prolonged by simultaneous inhibition of TRPM8.
authors.affiliation: 1Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX. 2Department of Anesthesiology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China. 3Department of Anesthesiology, Baylor College of Medicine, Houston, TX. 4Drug Discovery, Janssen Research & Development, LLC, Spring House, PA.
authors.forename: Viktor V
authors.initials: VV
authors.lastname: Feketa
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhijuan
authors.initials: Z
authors.lastname: Cao
authors.forename: Adithya
authors.initials: A
authors.lastname: Balasubramanian
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Flores
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
authors.forename: Sean P
authors.initials: SP
authors.lastname: Marrelli
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001833:Body Temperature Regulation / Q000502:physiology*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D007036:Hypothermia, Induced / Q000379:methods*; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050053:TRPM Cation Channels / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D050916:TRPV Cation Channels / Q000008:administration & dosage / Q000819:agonists*
chemical_list: C562242:3-(7-trifluoromethyl-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl)-1-oxa-2-azaspiro(4.5)dec-2-ene; D001562:Benzimidazoles; D007555:Isoxazoles; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D002211:Capsaicin; C012906:dihydrocapsaicin