Centrally-mediated antinociceptive action of RWJ-22757 (formerly McN-5195): involvement of spinal descending inhibitory pathways (an hypothesis).
The present studies were an attempt to examine the mechanism of action of the novel antinociceptive compound RWJ-22757, (+/-)-trans-3-(2-bromophenyl)-octahydroindolizine (McN-5195). Intracerebroventricular (i.c.v.) administration of RWJ-22757 produced dose-related antinociception in the mouse tail-flick (48 degrees C) and rat hot-plate (51 degrees C) tests (ED50 = 243.3 and 261.3 micrograms, respectively). In contrast, intrathecal (i.t.) administration was without effect. The antinociception produced by peripherally (i.p.) or centrally (i.c.v.) administered RWJ-22757 was attenuated by i.t. administration of 2 micrograms phentolamine, 5 micrograms yohimbine, or 10 micrograms methysergide. I.t. administration of naloxone, at a dose (0.5 micrograms) that significantly attenuated the antinociceptive effects of peripherally or centrally administered morphine, had no effect on RWJ-22757-induced antinociception. We conclude from these results, coupled with the overall pharmacological and neurochemical profile of RWJ-22757, that the data are consistent with the hypothesis that RWJ-22757 produces antinociception predominantly at a site or sites located supraspinally with little or no activity at the spinal level and that RWJ-22757 activates adrenergic and serotonergic descending inhibitory pathways, increasing the tonic activity of endogenous antinociceptive systems.
Vaught
J L
JL
Drug Discovery Research, R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477-0776.
Raffa
R B
RB
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007212:Indolizines / Q000494:pharmacology*; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D008784:Methysergide / Q000494:pharmacology; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D010646:Phentolamine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013116:Spinal Cord / Q000187:drug effects*; D015016:Yohimbine / Q000494:pharmacology
D000700:Analgesics; D007212:Indolizines; C058653:3-(2-bromophenyl)octahydroindolizine; D015016:Yohimbine; D009270:Naloxone; D009020:Morphine; D008784:Methysergide; D010646:Phentolamine