RT Journal Article
SR Electronic
T1 Nonthermal Activation of Transient Receptor Potential Vanilloid-1 Channels in Abdominal Viscera Tonically Inhibits Autonomic Cold-Defense Effectors
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 7459
OP 7468
DO 10.1523/JNEUROSCI.1483-07.2007
VO 27
IS 28
A1 Alexandre A. Steiner
A1 Victoria F. Turek
A1 Maria C. Almeida
A1 Jeffrey J. Burmeister
A1 Daniela L. Oliveira
A1 Jennifer L. Roberts
A1 Anthony W. Bannon
A1 Mark H. Norman
A1 Jean-Claude Louis
A1 James J. S. Treanor
A1 Narender R. Gavva
A1 Andrej A. Romanovsky
YR 2007
UL http://www.jneurosci.org/content/27/28/7459.abstract
AB An involvement of the transient receptor potential vanilloid (TRPV) 1 channel in the regulation of body temperature (Tb) 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 Tb 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 Tb 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 Tb 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 Tb.