Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors.
An involvement of the transient receptor potential vanilloid (TRPV) 1 channel in the regulation of body temperature (T(b)) has not been established decisively. To provide decisive evidence for such an involvement and determine its mechanisms were the aims of the present study. We synthesized a new TRPV1 antagonist, AMG0347 [(E)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(2-(piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylamide], and characterized it in vitro. We then found that this drug is the most potent TRPV1 antagonist known to increase T(b) of rats and mice and showed (by using knock-out mice) that the entire hyperthermic effect of AMG0347 is TRPV1 dependent. AMG0347-induced hyperthermia was brought about by one or both of the two major autonomic cold-defense effector mechanisms (tail-skin vasoconstriction and/or thermogenesis), but it did not involve warmth-seeking behavior. The magnitude of the hyperthermic response depended on neither T(b) nor tail-skin temperature at the time of AMG0347 administration, thus indicating that AMG0347-induced hyperthermia results from blockade of tonic TRPV1 activation by nonthermal factors. AMG0347 was no more effective in causing hyperthermia when administered into the brain (intracerebroventricularly) or spinal cord (intrathecally) than when given systemically (intravenously), which indicates a peripheral site of action. We then established that localized intra-abdominal desensitization of TRPV1 channels with intraperitoneal resiniferatoxin blocks the T(b) response to systemic AMG0347; the extent of desensitization was determined by using a comprehensive battery of functional tests. We conclude that tonic activation of TRPV1 channels in the abdominal viscera by yet unidentified nonthermal factors inhibits skin vasoconstriction and thermogenesis, thus having a suppressive effect on T(b).
Steiner
Alexandre A
AA
Systemic Inflammation Laboratory, Trauma Research, St. Joseph's Hospital, Phoenix, Arizona 85013, USA.
Turek
Victoria F
VF
Almeida
Maria C
MC
Burmeister
Jeffrey J
JJ
Oliveira
Daniela L
DL
Roberts
Jennifer L
JL
Bannon
Anthony W
AW
Norman
Mark H
MH
Louis
Jean-Claude
JC
Treanor
James J S
JJ
Gavva
Narender R
NR
Romanovsky
Andrej A
AA
D034841:Abdominal Cavity; D000178:Acrylamides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001341:Autonomic Nervous System / Q000502:physiology*; D001831:Body Temperature / Q000187:drug effects; D001833:Body Temperature Regulation / Q000502:physiology*; D016466:CHO Cells; D003080:Cold Temperature; D006224:Cricetinae; D003412:Cricetulus; D004224:Diterpenes / Q000494:pharmacology; D005334:Fever / Q000139:chemically induced / Q000503:physiopathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D012867:Skin / Q000098:blood supply; D012881:Skin Temperature; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D022722:Thermogenesis / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology; D014781:Viscera / Q000187:drug effects / Q000378:metabolism*
D000178:Acrylamides; D004224:Diterpenes; C521703:N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(2-(piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylamide; D011725:Pyridines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat; C024353:resiniferatoxin