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-mu-g, 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-mu-g phentolamine, 5-mu-g yohimbine, or 10-mu-g methysergide. I.t. administration of naloxone, at a dose (0.5-mu-g) 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.