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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 9, 2005; DOI: 10.1124/jpet.105.084277

0022-3565/05/3143-1378-1385$20.00
JPET 314:1378-1385, 2005
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*Compound via MeSH
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Hazardous Substances DB
*CALCIUM COMPOUNDS
*CALCIUM, ELEMENTAL
*CAPSAICIN

NEUROPHARMACOLOGY

5-Iodoresiniferatoxin Evokes Hypothermia in Mice and Is a Partial Transient Receptor Potential Vanilloid 1 Agonist in Vitro

Isao Shimizu1, Tohko Iida1, Nobuhiko Horiuchi, and Michael J. Caterina

Departments of Biological Chemistry and Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland (I.S., T.I., M.J.C.); and Dainippon Pharmaceutical Company, Limited, Suita/Osaka, Japan (I.S., N.H.)

Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated ion channel required for normal in vivo responses to these painful stimuli. However, growing evidence suggests that TRPV1 also participates in thermoregulation. Therefore, we examined the effects of a selective TRPV1 antagonist, 5-iodoresiniferatoxin (I-RTX), on mouse body temperature. Surprisingly, s.c. administration of I-RTX (0.1–1 µmol/kg) evoked a hypothermic response similar to that evoked by capsaicin (9.8 µmol/kg) in naive wild-type mice, but not in mice pretreated with resiniferatoxin, a potent TRPV1 agonist, or in naive TRPV1-null mice. In response to I-RTX in vitro, HEK293 cells expressing rat TRPV1 exhibited increases in intracellular Ca2+ (biphasic, EC50 = 56.7 nM and 9.9 µM) that depended on Ca2+ influx and outwardly rectifying, capsazepine-sensitive currents that were smaller than those evoked by 1 µM capsaicin. Thus, I-RTX induces TRPV1-dependent hypothermia in vivo and is a partial TRPV1 agonist in vitro.

Received for publication January 28, 2005
Accepted June 6, 2005.

Address correspondence to: Dr. Michael J. Caterina, Department of Biological Chemistry, Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205. E-mail: caterina{at}jhmi.edu




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