Vol. 290, Issue 1, 259-265, July 1999

-Opioid Receptor Effects of Butorphanol in Rhesus Monkeys¹

Jeffrey A. Vivian, Michael B. DeYoung, Tina L. Sumpter, John R. Traynor, John W. Lewis and James H. Woods

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (J.A.V., M.B.D., T.L.S., J.R.T., J.H.W.); Department of Psychology, University of Michigan, Ann Arbor, Michigan (J.H.W.); and Department of Chemistry, University of Bristol, Bristol, England (J.W.L.)

Butorphanol and nalbuphine have substantial affinity for µ and -opioid receptor sites, yet their behavioral effects in monkeys are largely consistent with a µ receptor mechanism of action. Using ethylketocyclazocine (EKC) discrimination and diuresis assays in rhesus monkeys (Macaca mulatta), the purpose of the current investigation was to characterize the in vivo -opioid activity of these compounds through the use of an insurmountable µ-opioid receptor antagonist, clocinnamox. Alone, butorphanol (0.001-0.032 mg/kg i.m.) failed to generalize to EKC, and pretreatment with the competitive opioid receptor antagonist quadazocine (0.1 or 0.32 mg/kg i.m.) did not alter this generalization. At 24 h after clocinnamox (0.1 mg/kg i.m.) administration, butorphanol fully generalized to EKC, and this generalization was maintained in two of three monkeys at 72 h. Parallel results were observed in diuresis: butorphanol alone and in the presence of quadazocine (1 mg/kg i.m.) did not alter urine output, and a marked diuretic effect was demonstrated 24 h to 2 weeks after clocinnamox administration. Clocinnamox did not alter the discriminative stimulus or diuretic effects of nalbuphine or of the -opioid receptor agonists EKC or U69593. These results are consistent with an in vivo agonist activity of butorphanol at -opioid receptors that can only be demonstrated when an insurmountable antagonist has substantially eliminated the dominant receptor population through which it exerts its action.