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. 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.
Footnotes
-
This work was supported by grants (to M.J.C.) from The W.M. Keck Foundation, The Searle Scholars Program, The Arnold and Mabel Beckman Foundation, and Dainippon Pharmaceuticals.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.105.084277.
-
ABBREVIATIONS: TRPV1, transient receptor potential vanilloid 1; RTX, resiniferatoxin, 6,7-deepoxy-6,7-didehydro-5-deoxy-21-dephenyl-21-(phenylmethyl)-daphnetoxin,20-(4-hydroxy-3-ethoxybenzeneacetate); I-RTX, 5-iodoresiniferatoxin, 6,7-deepoxy-6,7-didehydro-5-deoxy-21-dephenyl-21-(phenylmethyl)-daphnetoxin,20-(4-hydroxy-5-iodo-3-ethoxybenzeneacetate); DMSO, dimethylsulfoxide; HEK, human embryonic kidney; HPLC, high-performance liquid chromatography; JYL1511, N-(4-tert-butylbenzyl)-N′-[3-methoxy-4-(methylsulfonylamino)benzyl]thiourea; JYL827, N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-[4-(methylsulfonylamino)benzyl]thiourea; CGRP, calcitonin gene-related peptide.
-
↵1 Both authors contributed equally to this work.
- Received January 28, 2005.
- Accepted June 6, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|