The
opioid agonists
morphine,
etorphine,
buprenorphine and U50,488 were examined alone and in combination with the insurmountable
opioid antagonist clocinnamox (C-CAM) in squirrel monkeys responding under a schedule 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, each of these agonists increased the median intensity at which the monkeys maintained
shock [median
shock level (MSL)]. At the highest dose examined alone, each agonist produced maximal increases in MSL and, except
buprenorphine, decreased response rates. C-CAM dose-dependently antagonized the effects of
morphine,
etorphine and
buprenorphine on MSL. In the presence of the higher C-CAM doses,
etorphine,
morphine and
buprenorphine did not produce maximal effects on MSL. The effects of U50,488 were not systematically altered when tested in combination with the highest C-CAM dose. In general, C-CAM was more potent and the duration of antagonism was slightly longer against
buprenorphine than against
morphine and
etorphine. Quantitative analysis of these data according to an extended model of yielded the following apparent affinity and efficacy estimates, respectively:
etorphine (0. 085 mg/kg, 117);
morphine (49 mg/kg, 24) and
buprenorphine (0.62 mg/kg, 7.1). Determination of the individual q values over time indicated that the receptor population recovers more quickly after C-CAM antagonism of
etorphine than from C-CAM antagonism of either
morphine or
buprenorphine. These data suggest that C-CAM functions as a long-lasting antagonist of mu
opioid agonist actions in a
shock titration procedure and yields estimates of relative intrinsic efficacy with the rank order of
etorphine >
morphine >
buprenorphine.