PMID- 24595220
OWN - NLM
STAT- MEDLINE
DCOM- 20140611
LR  - 20211021
IS  - 1530-0293 (Electronic)
IS  - 0090-3493 (Print)
IS  - 0090-3493 (Linking)
VI  - 42
IP  - 5
DP  - 2014 May
TI  - Transient receptor potential melastatin 8 channel inhibition potentiates the 
      hypothermic response to transient receptor potential vanilloid 1 activation in 
      the conscious mouse.
PG  - e355-63
LID - 10.1097/CCM.0000000000000229 [doi]
AB  - OBJECTIVES: 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). DESIGN: 
      Controlled prospective animal study. SETTING: Research laboratory at academic 
      medical center. SUBJECTS: Conscious unrestrained young and aged male mice. 
      INTERVENTIONS: 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. MEASUREMENTS AND MAIN 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 degrees 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 degrees 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.
FAU - Feketa, Viktor V
AU  - Feketa VV
AD  - 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.
FAU - Zhang, Yi
AU  - Zhang Y
FAU - Cao, Zhijuan
AU  - Cao Z
FAU - Balasubramanian, Adithya
AU  - Balasubramanian A
FAU - Flores, Christopher M
AU  - Flores CM
FAU - Player, Mark R
AU  - Player MR
FAU - Marrelli, Sean P
AU  - Marrelli SP
LA  - eng
GR  - R01 HL088435/HL/NHLBI NIH HHS/United States
GR  - R21 NS077413/NS/NINDS NIH HHS/United States
GR  - HL088435/HL/NHLBI NIH HHS/United States
GR  - NS077413/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Crit Care Med
JT  - Critical care medicine
JID - 0355501
RN  - 0 
      (3-(7-trifluoromethyl-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl)-1-oxa-2-azaspiro(4.5)dec-2-ene)
RN  - 0 (Benzimidazoles)
RN  - 0 (Isoxazoles)
RN  - 0 (TRPM Cation Channels)
RN  - 0 (TRPM8 protein, mouse)
RN  - 0 (TRPV Cation Channels)
RN  - 0 (TRPV1 protein, mouse)
RN  - S07O44R1ZM (Capsaicin)
RN  - W9BV32M08A (dihydrocapsaicin)
SB  - IM
MH  - Age Factors
MH  - Analysis of Variance
MH  - Animals
MH  - Benzimidazoles/*pharmacology
MH  - Body Temperature Regulation/*physiology
MH  - Capsaicin/*analogs & derivatives/pharmacology
MH  - Disease Models, Animal
MH  - Hypothermia, Induced/*methods
MH  - Isoxazoles/*pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - TRPM Cation Channels/administration & dosage/*antagonists & inhibitors
MH  - TRPV Cation Channels/administration & dosage/*agonists
PMC - PMC4137592
MID - NIHMS606031
COIS- Copyright Form Disclosures: The remaining authors have disclosed that they do not 
      have any potential conflicts of interest.
EDAT- 2014/03/07 06:00
MHDA- 2014/06/12 06:00
PMCR- 2015/05/01
CRDT- 2014/03/06 06:00
PHST- 2014/03/06 06:00 [entrez]
PHST- 2014/03/07 06:00 [pubmed]
PHST- 2014/06/12 06:00 [medline]
PHST- 2015/05/01 00:00 [pmc-release]
AID - 10.1097/CCM.0000000000000229 [doi]
PST - ppublish
SO  - Crit Care Med. 2014 May;42(5):e355-63. doi: 10.1097/CCM.0000000000000229.