CLOCINNAMOX ANTAGONISM OF THE ANTINOCICEPTIVE EFFECTS OF MU-OPIOIDS IN SQUIRREL-MONKEYS

The opioid agonists morphine, etorphine, buprenorphine and U50,488 wer e examined alone and in combination with the insurmountable opioid ant agonist clocinnamox (C-CAM) in squirrel monkeys responding under a sch edule of shock titration. In this procedure, shock intensity increased every 15 sec from 0.01 to 2.0 mA in 30 increments. Five lever presses during any given 15-sec shock period produced a 15-sec timeout, after which shock resumed at the next lower intensity, When given alone, ea ch of these agonists increased the median intensity at which the monke ys maintained shock [median shock level (MSL)]. At the highest dose ex amined alone, each agonist produced maximal increases in MSL and, exce pt buprenorphine, decreased response rates. C-CAM dose-dependently ant agonized the effects of morphine, etorphine and buprenorphine on MSL. In the presence of the higher C-CAM doses, etorphine, morphine and bup renorphine did not produce maximal effects on MSL. The effects of U50, 488 were not systematically altered when tested in combination with th e highest C-CAM dose. In general, C-CAM was more potent and the durati on of antagonism was slightly longer against buprenorphine than agains t morphine and etorphine. Quantitative analysis of these data accordin g to an extended model of Black and Leff [(1983) Proc R Soc Lend B Bio l 220:141-162] yielded the following apparent affinity and efficacy es timates, respectively: etorphine (0.085 mg/kg, 117); morphine (49 mg/k g, 24) and buprenorphine (0.62 mg/kg, 7.1), Determination of the indiv idual q values over time indicated that the receptor population recove rs more quickly after C-CAM antagonism of etorphine than from C-CAM an tagonism of either morphine or buprenorphine. These data suggest that C-CAM functions as a longlasting antagonist of mu opioid agonist actio ns in a shock titration procedure and yields estimates of relative int rinsic efficacy with the rank order of etorphine > morphine > buprenor phine.