Abstract
Acute mu opioid agonist pretreatment (4 hr) dose-dependently sensitizes rats responding for food reinforcement to the rate-decreasing effects of naltrexone (NTX). In the present study, adult rats were trained to respond in an intracranial self-stimulation autotitration procedure in which responding resulted in electrical stimulation of the medial forebrain bundle that decreased in frequency until reset to the initial value. In an acute sensitization experiment, pretreatment (4 hr) doses of 3.0 and 10 mg/kg morphine reduced the ED25 value for the intracranial self-stimulation rate-decreasing effect of NTX from 28.2 mg/kg to 0.29 and 0.02 mg/kg, respectively. All mu-selective opioid agonists tested, fentanyl > levorphanol > methadone > morphine > meperidine (listed in order of decreasing potency), produced similar large increases in sensitivity to NTX. Acute sensitization was not induced by the kappa-selective opioid agonist spiradoline, the dextrorotary enantiomer of levorphanol, dextrorphan, or the nonopioid drugs d-amphetamine and pentobarbital. Pretreatment with morphine for 10 days by continuous subcutaneous infusion (15 mg/kg/day) reduced the ED25 value of NTX from 28.2 to 0.002 ± 1.48 mg/kg. The correlation of decreases in ED25 values for the rate-decreasing effect of NTX after both acute and chronic morphine administration is consistent with the theory that acute agonist-induced sensitization reflects receptor-mediated changes occurring early in the development of physical dependence.
Footnotes
-
Send reprint requests to: Dr. Keith W. Easterling, Emory University School of Medicine, Department of Pharmacology, Atlanta, GA 30322.
-
↵1 This investigation was supported by National Institutes of Health Grant DA00541 and by Research Scientist Award K05/DA00008 to S.G.H.
-
↵2 Portions of this work were presented at the at the 57th annual meeting of the College on Problems of Drug Dependence (1995, Scottsdale, AR) and the 25th annual meeting of the Society for Neuroscience (1995, San Diego, CA).
- Abbreviations:
- ANOVA
- analysis of variance
- CRF
- continuous reinforcement
- ICSS
- intracranial self-stimulation
- NTX
- naltrexone hydrochloride
- Received May 8, 1996.
- Accepted December 24, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|