title: kappa-Opioid receptor effects of butorphanol in rhesus monkeys.
abstract: Butorphanol and nalbuphine have substantial affinity for mu and kappa-opioid receptor sites, yet their behavioral effects in monkeys are largely consistent with a mu 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 kappa-opioid activity of these compounds through the use of an insurmountable mu-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 kappa-opioid receptor agonists EKC or U69593. These results are consistent with an in vivo agonist activity of butorphanol at kappa-opioid receptors that can only be demonstrated when an insurmountable antagonist has substantially eliminated the dominant receptor population through which it exerts its action.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA. jivian@umich.edu
authors.forename: J A
authors.initials: JA
authors.lastname: Vivian
authors.forename: M B
authors.initials: MB
authors.lastname: DeYoung
authors.forename: T L
authors.initials: TL
authors.lastname: Sumpter
authors.forename: J R
authors.initials: JR
authors.lastname: Traynor
authors.forename: J W
authors.initials: JW
authors.lastname: Lewis
authors.forename: J H
authors.initials: JH
authors.lastname: Woods
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001392:Azocines / Q000494:pharmacology; D044482:Benzeneacetamides; D002077:Butorphanol / Q000494:pharmacology*; D002934:Cinnamates / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects; D004231:Diuresis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016314:Ethylketocyclazocine / Q000494:pharmacology; D005260:Female; D007273:Injections, Intramuscular; D008253:Macaca mulatta; D008297:Male; D009022:Morphine Derivatives / Q000494:pharmacology; D009266:Nalbuphine / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D001392:Azocines; D044482:Benzeneacetamides; D002934:Cinnamates; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C076806:clocinnamox; D016314:Ethylketocyclazocine; C045444:U 69593; D009266:Nalbuphine; D002077:Butorphanol; C035969:quadazocine