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Abstract

Pharmacologic characterization of the sensitization to the rate-decreasing effects of naltrexone induced by acute opioid pretreatment in rats.

J U Adams and S G Holtzman
Journal of Pharmacology and Experimental Therapeutics May 1990, 253 (2) 483-489;
J U Adams
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S G Holtzman
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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.

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Journal of Pharmacology and Experimental Therapeutics
Vol. 253, Issue 2
1 May 1990
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Abstract

Pharmacologic characterization of the sensitization to the rate-decreasing effects of naltrexone induced by acute opioid pretreatment in rats.

J U Adams and S G Holtzman
Journal of Pharmacology and Experimental Therapeutics May 1, 1990, 253 (2) 483-489;

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Abstract

Pharmacologic characterization of the sensitization to the rate-decreasing effects of naltrexone induced by acute opioid pretreatment in rats.

J U Adams and S G Holtzman
Journal of Pharmacology and Experimental Therapeutics May 1, 1990, 253 (2) 483-489;
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