TY - JOUR
T1 - 5-Iodoresiniferatoxin evokes hypothermia in mice and is a partial transient receptor potential vanilloid 1 agonist in vitro
AU - Shimizu, Isao
AU - Iida, Tohko
AU - Horiuchi, Nobuhiko
AU - Caterina, Michael J.
PY - 2005/9/1
Y1 - 2005/9/1
N2 - 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 Ca 2+ (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.
AB - 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 Ca 2+ (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.
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U2 - 10.1124/jpet.105.084277
DO - 10.1124/jpet.105.084277
M3 - Article
C2 - 15947039
AN - SCOPUS:23944483778
SN - 0022-3565
VL - 314
SP - 1378
EP - 1385
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -