METHOCLOCINNAMOX - AGONIST AND ANTAGONIST EFFECTS OF A NOVEL LONG-LASTING OPIOID IN RHESUS-MONKEYS

The present studies characterized the agonist and antagonist effects o f 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 deg rees 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 agonis t effects of methoclocinnamox were antagonized by quadazocine (1.0 mg/ kg), but to a lesser degree than would be expected for competitive ant agonism at mu-receptors. However, the nonequilibrium mu-selective anta gonist clocinnamox (0.32 mg/kg) completely blocked the antinociceptive effect of methoclocinnamox. After its agonist effects had waned (typi cally <24 hr), methoclocinnamox (0.1-1.0 mg/kg) caused long-lasting an d nonparallel shifts in the dose-effect curves oi the mu-agonist morph ine, whereas even at the highest dose (1.0 mg/kg) methoclocinnamox did not antagonize the kappa-agonist U50,488. It is concluded that methoc locinnamox exhibits initial opioid agonist effects, followed by prolon ged, insurmountable, mu-antagonist effects.