kappa-opioid receptor effects of butorphanol in rhesus monkeys

Butorphanol and nalbuphine have substantial affinity for mu and kappa-opioi d receptor sites, yet their behavioral effects in monkeys are largely consi stent with a mu receptor mechanism of action. Using ethylketocyclazocine (E KC) discrimination and diuresis assays in rhesus monkeys (Macaca mulatta), the purpose of the current investigation was to characterize the in vivo ka ppa-opioid activity of these compounds through the use of an insurmountable mu-opioid receptor antagonist, clocinnamox. Alone, butorphanol (0.001-0.03 2 mg/kg i.m.) failed to generalize to EKC, and pretreatment with the compet itive opioid receptor antagonist quadazocine (0.1 or 0.32 mg/kg i.m.) did n ot alter this generalization. At 24 h after clocinnamox (0.1 mg/kg i.m.) ad ministration, butorphanol fully generalized to EKC, and this generalization was maintained in two of three monkeys at 72 h. Parallel results were obse rved in diuresis: butorphanol alone and in the presence of quadazocine (1 m g/kg i.m.) did not alter urine output, and a marked diuretic effect was dem onstrated 24 hto 2 weeks after clocinnamox administration. Clocinnamox did not alter the discriminative stimulus or diuretic effects of nalbuphine or of the K-opioid receptor agonists EKC or U69593. These results are consiste nt with an in vivo agonist activity of butorphanol at K-opioid receptors th at can only be demonstrated when an insurmountable antagonist has substanti ally eliminated the dominant receptor population through which it exerts it s action.