Acute sensitization to opioid antagonists.
Acute morphine pretreatment sensitizes rats to the response rate-decreasing effects of opioid antagonists naloxone and naltrexone. The effect appears to be mu-opioid receptor specific, as pretreatment with non-mu-selective opioid agonists results in less pronounced sensitization. In the present study, food-deprived rats were trained to respond for food reinforcement on a FI 3-min schedule (9.5 min) with multiple trials. Doses of opioid antagonists were administered cumulatively before each trial of a session following 4-h pretreatment with either vehicle or morphine (3.0 mg/kg). Morphine pretreatment sensitized rats to naltrexone, lowering its ED50 from 20 to 0.03 mg/kg. It also sensitized rats to naloxone and to diprenorphine, another pure antagonist. Morphine-induced sensitization was stereoselective among the optical isomers of the benzomorphans, cyclazocine, pentazocine, and N-allylnormetzocine. In addition, acute morphine pretreatment resulted in sensitization to the mixed agonist/antagonist nalorphine, but not to buprenorphine or nalbuphine. The results extend previous findings concerning the importance of the mu-opioid receptor in the development of sensitization to opioid antagonists.
White-Gbadebo
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Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322.
Holtzman
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SG
D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects; D012055:Reinforcement Schedule; D013237:Stereoisomerism
D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009271:Naltrexone; D009020:Morphine