Glycyl-glutamine, an endogenous beta-endorphin-derived peptide, inhibits morphine-induced conditioned place preference, tolerance, dependence, and withdrawal.
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.
Cavun
Sinan
S
Department of Basic and Pharmaceutical Sciences, Albany College of Pharmacy, Union University, NY 12208, USA.
Göktalay
Gökhan
G
Millington
William R
WR
D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects*; D004151:Dipeptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005502:Food; D007276:Injections, Intraventricular; D008297:Male; D009020:Morphine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009021:Morphine Dependence / Q000517:prevention & control*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control*; D001615:beta-Endorphin / Q000737:chemistry / Q000494:pharmacology*
D000701:Analgesics, Opioid; D004151:Dipeptides; D009292:Narcotic Antagonists; C039788:glycylglutamine; D009270:Naloxone; D001615:beta-Endorphin; D009020:Morphine