title: Effects of mu-opioid agonists on cocaine- and food-maintained responding and cocaine discrimination in rhesus monkeys: role of mu-agonist efficacy.
abstract: Mu-opioid agonists decrease cocaine self-administration in laboratory studies and cocaine use by many cocaine- and opioid-dependent polydrug abusers. To assess the role of mu-agonist efficacy as a determinant of these effects, this study evaluated cocaine- and food-maintained responding by rhesus monkeys (Macaca mulatta) during chronic treatment with saline or the high-efficacy mu-agonist fentanyl (0.001-0.01 mg/kg/h), the intermediate-efficacy mu-agonist morphine (0.032-0.32 mg/kg/h), or the low-efficacy mu-agonists nalbuphine (0.1-1.0 mg/kg/h) and butorphanol (0.0032-0.032 mg/kg/h). Responding was maintained by cocaine and food under a second order schedule of reinforcement during multiple daily sessions of cocaine and food availability. Saline and each opioid dose were administered continuously for 7 consecutive days during availability of each cocaine dose. All four mu-agonists produced dose-dependent and sustained decreases in cocaine self-administration across a range of cocaine doses (0.0032-0.1 mg/kg/injection). Nalbuphine and butorphanol produced the greatest decreases in cocaine self-administration and the smallest effects on food-maintained responding. Morphine and fentanyl produced smaller decreases in cocaine self-administration, and undesirable effects precluded evaluation of higher fentanyl and morphine doses. Decreases in cocaine self-administration produced by nalbuphine and butorphanol probably did not reflect a general blockade of cocaine's abuse-related effects, because nalbuphine and butorphanol did not block the discriminative stimulus effects of cocaine in monkeys trained to discriminate 0.4 mg/kg cocaine from saline in a food-reinforced drug discrimination procedure. These results suggest that low-efficacy mu-agonists may decrease cocaine self-administration to a greater degree and with fewer undesirable effects than high-efficacy mu-agonists.
authors.affiliation: Alcohol and Drug Abuse Research Center of McLean Hospital at Harvard Medical School, Belmont, Massachusetts 02178-9106, USA. negus@mclean.harvard.edu
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
authors.forename: Nancy K
authors.initials: NK
authors.lastname: Mello
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002077:Butorphanol / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D004192:Discrimination, Psychological / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005502:Food; D008253:Macaca mulatta; D009266:Nalbuphine / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D000701:Analgesics, Opioid; D018765:Dopamine Uptake Inhibitors; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D003042:Cocaine; D009266:Nalbuphine; D002077:Butorphanol