title: Pharmacologic characterization of the sensitization to the rate-decreasing effects of naltrexone induced by acute opioid pretreatment in rats.
abstract: The pharmacologic specificity of the sensitization to naltrexone induced by acute opioid pretreatment was studied in rats trained to lever-press on a multiple-trial, fixed-interval 3-min schedule of food reinforcement. Cumulative doses of naltrexone were given until responding was suppressed; control naltrexone ED50 values for decreasing response rates ranged from 5.0 to 22 mg/kg. Agonists were administered 4 hr before naltrexone challenge. Pretreatment with morphine (10 mg/kg) initially produced a 4-fold shift to the left of the naltrexone dose-effect curve, but after repeated weekly testing with various agonists, produced a 1700-fold shift. Pretreatment with other millimicrons agonists (i.e., 0.3 mg/kg of levorphanol, 0.06 mg/kg of fentanyl and 3.0 mg/kg of methadone) produced similarly large (100- to 250-fold) increases in sensitivity to the rate-decreasing effects of naltrexone. On the other hand, pretreatment with agonists selective for kappa (1.0 mg/kg of ethylketocyclazocine and 3.0 mg/kg of U-50,488) or sigma (10 mg/kg of [+]-N-allylnormetazocine) receptors, produced smaller (10-fold) changes in sensitization to naltrexone. Neither dextrorphan (3.0 mg/kg) nor pentobarbital (18 mg/kg) pretreatment altered sensitivity to naltrexone. Thus, the sensitization to naltrexone induced by acute opioid pretreatment was a stereoselective, opioid-specific effect, and appeared to be mediated primarily by a mu-opioid mechanism. With repeated testing, the effect of acute morphine pretreatment was comparable to that reported after chronic administration, thus supporting the hypothesis that this phenomenon reflects receptor-mediated changes that underlie the state of opioid physical dependence.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: J U
authors.initials: JU
authors.lastname: Adams
authors.forename: S G
authors.initials: SG
authors.lastname: Holtzman
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity; D004347:Drug Interactions; D008297:Male; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D011292:Premedication; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time / Q000187:drug effects
chemical_list: D009292:Narcotic Antagonists; D009294:Narcotics; D009271:Naltrexone