Abstract
Glycyl-glutamine (Gly-Gln; β-endorphin30-31) is an endogenous dipeptide synthesized from β-endorphin1-31. Previous investigations have shown that Gly-Gln inhibits the cardiovascular and respiratory depression caused by morphine and β-endorphin1-31, but it does not interfere with opioid analgesia. In this study, we tested whether Gly-Gln administration would influence morphine-induced conditioned place preference, tolerance, dependence, or withdrawal. For place preference experiments, rats were conditioned with morphine sulfate (2.5 mg/kg i.p.) or saline on alternate days for 6 days and tested on day 7. Glycyl-glutamine (1-100 nmol i.c.v.) pretreatment inhibited acquisition of a conditioned place preference to morphine significantly. Glycyl-glutamine (100 nmol i.c.v.) also blocked expression of a pre-established morphine place preference, but it did not interfere with acquisition of a conditioned place preference to palatable food, and it did not produce place preference or aversion when given alone to morphine-naive animals. To induce antinociceptive tolerance, rats were treated with morphine (10 mg/kg i.p.) twice daily for 7 days, and morphine antinociception was evaluated with the tail-flick test. Glycyl-glutamine (100 nmol i.c.v.) pretreatment delayed the onset of morphine tolerance significantly and partially reversed pre-established tolerance. Morphine dependence and withdrawal were assessed by measuring naloxone-precipitated withdrawal symptoms. Glycyl-glutamine inhibited the development of morphine dependence when given to rats twice daily immediately before they received morphine (10 mg/kg i.p.) and suppressed withdrawal symptoms of rats with subcutaneously implanted morphine pellets when administered 5 min before withdrawal was induced with naloxone. Glycyl-glutamine thus attenuates morphine-induced conditioned place preference, tolerance, dependence, and withdrawal without compromising morphine analgesia.
Footnotes
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This study was supported by Grant DA018029 from the National Institute on Drug Abuse.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.091553.
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ABBREVIATIONS: POMC, proopiomelanocortin; Gly-Gln, glycyl-glutamine; Gly-d-Gln, glycyl-d-glutamine; %MPE, maximal possible effect; ANOVA, analysis of variance; NMDA, N-methyl-d-aspartate.
- Received June 23, 2005.
- Accepted July 28, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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