The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation.
The vanilloid receptor TRPV1 (transient receptor potential vanilloid 1) is a cation channel that serves as a polymodal detector of pain-producing stimuli such as capsaicin, protons (pH <5.7), and heat. TRPV1 antagonists block pain behaviors in rodent models of inflammatory, neuropathic, and cancer pain, suggesting their utility as analgesics. Here, we report that TRPV1 antagonists representing various chemotypes cause an increase in body temperature (hyperthermia), identifying a potential issue for their clinical development. Peripheral restriction of antagonists did not eliminate hyperthermia, suggesting that the site of action is predominantly outside of the blood-brain barrier. Antagonists that are ineffective against proton activation also caused hyperthermia, indicating that blocking capsaicin and heat activation of TRPV1 is sufficient to produce hyperthermia. All TRPV1 antagonists evaluated here caused hyperthermia, suggesting that TRPV1 is tonically activated in vivo and that TRPV1 antagonism and hyperthermia are not separable. TRPV1 antagonists caused hyperthermia in multiple species (rats, dogs, and monkeys), demonstrating that TRPV1 function in thermoregulation is conserved from rodents to primates. Together, these results indicate that tonic TRPV1 activation regulates body temperature.
Gavva
Narender R
NR
Department of Neuroscience, Amgen, Thousand Oaks, California 91320-1799, USA. ngavva@amgen.com
Bannon
Anthony W
AW
Surapaneni
Sekhar
S
Hovland
David N
DN
Lehto
Sonya G
SG
Gore
Anu
A
Juan
Todd
T
Deng
Hong
H
Han
Bora
B
Klionsky
Lana
L
Kuang
Rongzhen
R
Le
April
A
Tamir
Rami
R
Wang
Jue
J
Youngblood
Brad
B
Zhu
Dawn
D
Norman
Mark H
MH
Magal
Ella
E
Treanor
James J S
JJ
Louis
Jean-Claude
JC
D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D001833:Body Temperature Regulation / Q000502:physiology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D016466:CHO Cells; D002211:Capsaicin; D002478:Cells, Cultured; D017124:Conserved Sequence; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D005260:Female; D005334:Fever / Q000139:chemically induced / Q000503:physiopathology; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced / Q000503:physiopathology; D008252:Macaca fascicularis; D008297:Male; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013449:Sulfonamides / Q000494:pharmacology*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
C500530:3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)acrylamide; C519015:3-amino-5-((2-((2-methoxyethyl)amino)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)oxy)quinoxalin-2(1H)-one; D000178:Acrylamides; D052160:Benzothiazoles; D019086:Bridged Bicyclo Compounds, Heterocyclic; C466314:JYL 1421; C519016:N-((4-(((3-(6-((2-amino-1,3-benzothiazol-4-yl)oxy)pyrimidin-4-yl)) -6-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2-fluorophenyl)methanesulfonamide; D011810:Quinoxalines; D013449:Sulfonamides; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C519014:tert-butyl-2-(6-((2-(acetylamino)-1,3-benzothiazol-4-yl)oxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenylcarbamate; D013890:Thiourea; D002211:Capsaicin