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

Abstract

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. Glycylglutamine (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.

High specific activity tritium labelling of biologically active small peptides and a related analogue

“…Glycyl-L-glutamine (2) is an endogenous dipeptide that is biosynthesized from beta-endorphin . Interest in this small peptide has emerged in part because of its potential use for inhibiting addiction to a number of substances including alcohol [12] morphine [13] and nicotine [14]. It has also been investigated for its role as a cardioprotective agent [15].…”

Effects of glycyl-glutamine on the growth performance and lipid deposition in Yue-Huang broilers

“…Recently, Gly-Gln, which is also called β-endorphin (30-31), was identified as a neuron dipeptide generated from the two amino acids at the carboxyl terminal of β-endorphin 1-31 and belongs to the proopiomelanocortin (POMC) system (Krude and Gruters, 2000). Several lines of evidences suggested a wide range of biological activities of Gly-Gln, which can not only participate in immunological regulation, stimulate lymphocytosis, improve activities of natural killer cells (Ghanta et al, 1991), but also inhibit the dependence on opioid drugs (Cavun et al, 2005). Now that the physiological function of thermogenesis and energy equilibrium of POMC system has been well established (Low, 2004), whether the effects of Gly-Gln on the avian lipid metabolism act through the single Gln or the neuropeptide remains to be investigated.…”

Methamphetamine Reward in Mice as Assessed by Conditioned Place Preference Test with Supermex® Sensors: Effect of Subchronic Clorgyline Pretreatment

“…The compartments had different visual and texture cues (one was black with a smooth floor and the other was white with ca. 5 g of fresh wood-chips on a smooth floor) [26]. All compartments were cleaned and wiped dry between the sessions for each animal.…”