Glycyl-glutamine (β-endorphin30-31) inhibits morphine-induced dopamine efflux in the nucleus accumbens

Abstract

Glycyl-glutamine (Gly-Gln) is an endogenous dipeptide that is synthesized from beta-endorphin post-translationally. Previously, we showed that Gly-Gln prevents acquisition of morphine-conditioned place preference, a behavioral test of morphine reward, but does not interfere with morphine analgesia. In this study, we tested the hypothesis that Gly-Gln inhibits morphine reward by blocking morphine-induced dopamine efflux in the nucleus accumbens (NAc). Extracellular dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) were sampled by microdialysis and analyzed by high-performance liquid chromatography with electrochemical detection. Guide cannulas were implanted in the right NAc and left lateral ventricle of male Sprague-Dawley rats stereotaxically. Approximately 24 h later, a microdialysis probe was inserted into the NAc and perfused at 1 microl/min. Gly-Gln (1, 3, 30, or 100 nmol/5 microl) or saline was administered intracerebroventricularly, morphine (2.5 mg/kg) was injected intraperitoneally (i.p.) 2 min later, and extracellular dopamine and DOPAC were sampled at 20-min intervals. Morphine administration increased extracellular dopamine concentrations by approximately 600% within 40 min. Gly-Gln pretreatment inhibited the rise in extracellular dopamine in a dose-related manner; the lowest significantly inhibitory dose was 1 nmol. Gly-Gln also inhibited the morphine-induced rise in extracellular DOPAC concentrations but did not affect extracellular dopamine or DOPAC in control animals. Gly-Gln (100 nmol/5 microl) prevented morphine-induced dopamine efflux in rats treated with morphine chronically (10 mg/kg, i.p. twice daily for 6 days), although it did not affect DOPAC concentrations significantly. These data support the hypothesis that Gly-Gln abolishes the rewarding effect of morphine by inhibiting the ability of morphine to stimulate dopamine release in the NAc.

A liquid chromatography–tandem mass spectrometry assay for detection and quantitation of the dipeptide Gly-Gln in rat brain

“…It apparently acts by a unique and as yet undefined mechanism [5]. Along with inhibition of voluntary alcohol consumption activity, Gly-Gln has also been shown to inhibit the reward benefiting effects of morphine and nicotine [8; 9; 10]. All these findings corroborate the fact that Gly-Gln has an interesting and potentially useful pharmacological activity.…”

Averting Opioid-induced Respiratory Depression without Affecting Analgesia

“…79 More recently it was shown that glycyl-glutamine abolishes the rewarding effect of morphine by inhibition of morphine-induced dopamine release in the nucleus accumbens. 80 The receptor target of glycyl-glutamine remains still unknown, but the inability to antagonize its effects with opioid antagonists precludes an opioid receptor target. 77 Currently no human data are available on the effect of glycyl-glutamine on depressed breathing.…”

“…The tripeptide thyrotropin-releasing hormone (Glu-His-Pro-NH 2 ) is a potent but short-lived respiratory stimulant in animals and humans. [80][81][82][83][84] It induces rhythmic bursting in respiratory neurons of the nucleus tractus solitarius through modulation of membrane excitability. 81 In rabbit and monkey, thyrotropin-releasing hormone produces a rapid arousal from penthobarbital anesthesia.…”

“…Reversal of fentanyl-induced respiratory depression 75,76 Glycyl-L-glutamine Glycyl-glutamine Inhibits cardiorespiratory depression by β-endorphin and morphine [77][78][79] ; Abolishes the rewarding effects of morphine 80…”

Methodological Approach in Perception Management

“…Dopamine release decreases, when an expectation ends. Increasing effect of morphine on dopamine release from the nucleus accumbens is suppressed by Gly-Gln, which is one of the degradation products of β-endorphin, and thus rewarding effect of morphine is eliminated [27] [28]. People who intend to manage the perceptions get the population to come along by deliberately shifting the population from one expectation to another.…”