Glycyl-glutamine, an endogenous beta-endorphin-derived peptide, inhibits morphine-induced conditioned place preference, tolerance, dependence, and withdrawal

• Published in: The Journal of pharmacology and experimental therapeutics 2005-11, Vol.315 (2), p.949-958
• Main Authors: Cavun, Sinan, Göktalay, Gökhan, Millington, William R
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - antagonists & inhibitors; Analgesics, Opioid - pharmacology; Animals; Behavior, Animal - drug effects; beta-Endorphin - chemistry; beta-Endorphin - pharmacology; Conditioning, Operant - drug effects; Dipeptides - administration & dosage; Dipeptides - chemistry; Dipeptides - pharmacology; Dose-Response Relationship, Drug; Drug Tolerance; Food; Injections, Intraventricular; Male; Morphine - antagonists & inhibitors; Morphine - pharmacology; Morphine Dependence - prevention & control; Naloxone - pharmacology; Narcotic Antagonists - pharmacology; Rats; Rats, Sprague-Dawley; Reinforcement (Psychology); Substance Withdrawal Syndrome - prevention & control
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.105.091553

Glycyl-glutamine (Gly-Gln; beta-endorphin(30-31)) is an endogenous dipeptide synthesized from beta-endorphin(1-31). Previous investigations have shown that Gly-Gln inhibits the cardiovascular and respiratory depression caused by morphine and beta-endorphin(1-31), 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.