Methoclocinnamox: Agonist and antagonist effects of a novel long-lasting opioid in rhesus monkeys

The present studies characterized the agonist and antagonist effects of methoclocinnamox, a novel codeinone, in the warm-water (50°C and 55°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°C but not 55°C water, similar to previously studied μ-opioid partial agonists. Consistent with this, methoclocinnamox (0.32 mg/kg), at a time when it acted as an agonist in 50°C water, was an antagonist of the higher efficacy μ-agonist fentanyl in 55°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 μ-receptors. However, the nonequilibrium μ-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 μ-agonist morphine, whereas even at the highest dose (1.0 mg/kg) methoclocinnamox did not antagonize the κ-agonist U50,488. It is concluded that methoclocinnamox exhibits initial opioid agonist effects, followed by prolonged, insurmountable, μ-antagonist effects.