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NEUROPHARMACOLOGY

Glycyl-Glutamine, an Endogenous -Endorphin-Derived Peptide, Inhibits Morphine-Induced Conditioned Place Preference, Tolerance, Dependence, and Withdrawal

Department of Basic and Pharmaceutical Sciences, Albany College of Pharmacy, Union University, Albany, New York (S.C., G.G., W.R.M.); Ion Technologies, Inc., Winston-Salem, North Carolina (G.G.); and Department of Pharmacology and Clinical Pharmacology, Uludag University School of Medicine, Bursa, Turkey (S.C., G.G.)

Glycyl-glutamine (Gly-Gln; -endorphin_30-31) is an endogenous dipeptide synthesized from -endorphin_1-31. Previous investigations have shown that Gly-Gln inhibits the cardiovascular and respiratory depression caused by morphine and -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.

Address correspondence to: Dr. William R. Millington, Department of Basic and Pharmaceutical Sciences, Albany College of Pharmacy, Union University, 106 New Scotland Ave., Albany, NY 12208. E-mail: millingw{at}acp.edu

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