Abstract

The present studies characterized the agonist and antagonist effects of methoclocinnamox, a novel codeinone, in the warm-water (50 degrees C and 55 degrees C) tail-withdrawal assay of thermal antinociception in rhesus monkeys. Methoclocinnamox (0.1-1.0 mg/ kg) was fully effective in the warm-water tail-withdrawal assay in 50 degrees C but not 55 degrees C water, similar to previously studied mu-opioid partial agonists. Consistent with this, methoclocinnamox (0.32 mg/kg), at a time when it acted as an agonist in 50 degrees C water, was an antagonist of the higher efficacy mu-agonist fentanyl in 55 degrees C water. The agonist effects of methoclocinnamox were antagonized by quadazocine (1.0 mg/kg), but to a lesser degree than would be expected for competitive antagonism at mu-receptors. However, the nonequilibrium mu-selective antagonist clocinnamox (0.32 mg/kg) completely blocked the antinociceptive effect of methoclocinnamox. After its agonist effects had waned (typically < 24 hr), methoclocinnamox (0.1-1.0 mg/ kg) caused long-lasting and nonparallel shifts in the dose-effect curves of the mu-agonist morphine, whereas even at the highest dose (1.0 mg/kg) methoclocinnamox did not antagonize the kappa-agonist U50,488. It is concluded that methoclocinnamox exhibits initial opioid agonist effects, followed by prolonged, insurmountable, mu-antagonist effects.