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

摘要

Glycyl-glutamine (Gly-GIn;beta-endorphin_(30-31)) is an endogenous dipeptide synthesized from beta-endorphin_(1-31),.Previous investigations have shown that Gly-GIn inhibits the cardiovascular and respiratory depression caused by morphine and beta-endor-phin_(1-31),but it does not interfere with opioid analgesia.In this study,we tested whether Gly-GIn 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.