No abstract

An involvement of the transient receptor potential vanilloid (TRPV) 1 channel in the regulation of body temperature (T b ) has not been established decisively. To provide decisive evidence for such an involvement and determine its mechanisms were the aims of the present study. We synthesized a new TRPV1 antagonist, AMG0347 [(E)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(2-(piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylamide], and characterized it in vitro. We then found that this drug is the most potent TRPV1 antagonist known to increase T b of rats and mice and showed (by using knock-out mice) that the entire hyperthermic effect of AMG0347 is TRPV1 dependent. AMG0347-induced hyperthermia was brought about by one or both of the two major autonomic cold-defense effector mechanisms (tail-skin vasoconstriction and/or thermogenesis), but it did not involve warmth-seeking behavior. The magnitude of the hyperthermic response depended on neither T b nor tail-skin temperature at the time of AMG0347 administration, thus indicating that AMG0347-induced hyperthermia results from blockade of tonic TRPV1 activation by nonthermal factors. AMG0347 was no more effective in causing hyperthermia when administered into the brain (intracerebroventricularly) or spinal cord (intrathecally) than when given systemically (intravenously), which indicates a peripheral site of action. We then established that localized intra-abdominal desensitization of TRPV1 channels with intraperitoneal resiniferatoxin blocks the T b response to systemic AMG0347; the extent of desensitization was determined by using a comprehensive battery of functional tests. We conclude that tonic activation of TRPV1 channels in the abdominal viscera by yet unidentified nonthermal factors inhibits skin vasoconstriction and thermogenesis, thus having a suppressive effect on T b .

The 5-HT indirect agonist, d-fenfluramine, attenuates cue reinstatement of extinguished cocaine-seeking behavior. To investigate the role of 5-HT receptor subtypes in this effect, we examined whether the attenuation is reversed by either a 5-HT 1A , 5-HT 2A/C , or 5-HT 2C receptor antagonist. We also examined the effects of the antagonists alone on both cue and cocaine-primed reinstatement. Rats that had been trained to press a lever for cocaine (0.75 mg/kg/0.1 ml, i.v.) paired with light and tone cues underwent daily extinction sessions during which responding had no consequences. We then examined the effects of WAY 100635 (0-1.0 mg/kg, s.c.), ketanserin (0-10.0 mg/kg, i.p.), or SB 242,084 (0-1.0 mg/kg, i.p.) with and without d-fenfluramine (1.0 mg/kg, i.p.) pretreatment on cue reinstatement. Subsequently, we examined the effects of the antagonists on cocaine-primed (7.5 or 15.0 mg/kg, i.p.) reinstatement. The 5-HT 1A antagonist, WAY 100635, failed to alter cue reinstatement, but attenuated cocaine reinstatement. Conversely, the 5-HT 2A/C antagonist, ketanserin, attenuated cue reinstatement, but failed to alter cocaine reinstatement. The 5-HT 2C -selective antagonist, SB 242,084, did not alter cue or cocaine reinstatement, but was the only drug that reversed the d-fenfluramine-induced attenuation of cue reinstatement. The findings suggest that stimulation of 5-HT 1A receptors plays a critical role in cocaine-primed, but not cue, reinstatement. Furthermore, 5-HT 2A and 5-HT 2C receptors may play oppositional roles in cue reinstatement. The SB 242,084 reversal of the d-fenfluramine attenuation suggests that stimulation of 5-HT 2C receptors inhibits cue reinstatement, whereas the ketanserin-induced attenuation of cue reinstatement suggests that decreased stimulation of 5-HT 2A receptors inhibits this behavior.

These findings suggest that 5-HT indirect agonists effectively attenuate cocaine-seeking behavior elicited by cocaine-associated stimuli, but are much less effective in attenuating cocaine-seeking behavior elicited by cocaine priming.

There is a paucity of available information on the QT interval for most analgesics. Of those for which there is a lot of data, only methadone, oxycodone, and LAAM (levo--acetylmethadol) appear to have a known and accepted level of effect on the QT interval.