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

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Received for publication January 31, 2005.
Revised June 3, 2005.
Accepted for publication June 6, 2005.

5-Iodoresiniferatoxin evokes hypothermia in mice and is a partial TRPV1 agonist in vitro

Isao Shimizu 1, Tohko Iida 2, Nobuhiko Horiuchi 3, Michael J. Caterina 2*

1 Johns Hopkins Sch. of Medicine and Dainippon Pharmaceutical Co. Ltd. 2 Dept. Biol. Chemistry and Neuroscience, Johns Hopkins School of Medicine 3 Dainippon Pharmaceutical Co., Ltd.

* Address correspondence to: E-mail: caterina{at}jhmi.edu

Abstract

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. We therefore examined the effects of a selective TRPV1 antagonist, 5-Iodoresiniferatoxin (I-RTX), on mouse body temperature. Surprisingly, subcutaneous administration of I-RTX (0.1 - 1 µmol/kg) evoked a hypothermic response similar to that evoked by capsaicin (9.8 µmol/kg) in naïve wild-type mice, but not in mice pretreated with resiniferatoxin, a potent TRPV1 agonist, or in naïve 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.


Key words: TRPV1, capsaicin, iodoresiniferatoxin, resiniferatoxin, thermoregulation, vanilloid


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