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The Journal of Neuroscience, March 28, 2007, 27(13):3366-3374; doi:10.1523/JNEUROSCI.4833-06.2007
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Cellular/Molecular
The Vanilloid Receptor TRPV1 Is Tonically Activated In Vivo and Involved in Body Temperature Regulation
Narender R. Gavva,1 Anthony W. Bannon,1 Sekhar Surapaneni,2 David N. Hovland, Jr,3 Sonya G. Lehto,1 Anu Gore,4 Todd Juan,5 Hong Deng,1 Bora Han,3 Lana Klionsky,1 Rongzhen Kuang,1 April Le,1 Rami Tamir,1 Jue Wang,1 Brad Youngblood,1 Dawn Zhu,1 Mark H. Norman,6 Ella Magal,1 James J. S. Treanor,1 andJean-Claude Louis1 Departments of 1Neuroscience, 2Pharmacokinetics and Drug Metabolism, 3Toxicology, 4Pharmaceutics, 5Protein Sciences, and 6Chemistry Research and Discovery, Amgen, Thousand Oaks, California 91320-1799
Correspondence should be addressed to Dr. Narender R. Gavva, Department of Neuroscience, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320-1799. Email: ngavva{at}amgen.com
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.
Key words: antagonist; calcium channels; capsaicin; hyperthermia; pain; TRPV
Received Nov. 7, 2006; revised Jan. 16, 2007; accepted Feb. 7, 2007.
Correspondence should be addressed to Dr. Narender R. Gavva, Department of Neuroscience, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320-1799. Email: ngavva{at}amgen.com
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