Oleoyl glycine: interference with the aversive effects of acute naloxone-precipitated MWD, but not morphine reward, in male Sprague–Dawley rats

Rationale: Oleoyl glycine (OlGly), a recently discovered fatty acid amide that is structurally similar to N- acylethanolamines, which include the endocannabinoid, anandamide (AEA), as well as endogenous peroxisome proliferator-activated receptor alpha (PPARα) agonists oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), has been shown to interfere with nicotine reward and dependence in mice. Objectives and methods: Behavioral and molecular techniques were used to investigate the ability of OlGly to interfere with the affective properties of morphine and morphine withdrawal (MWD) in male Sprague–Dawley rats. Results: Synthetic OlGly (1–30 mg/kg, intraperitoneal [ip]) produced neither a place preference nor aversion on its own; however, at doses of 1 and 5 mg/kg, ip, it blocked the aversive effects of MWD in a place aversion paradigm. This effect was reversed by the cannabinoid 1 (CB1) receptor antagonist, AM251 (1 mg/kg, ip), but not the PPARα antagonist, MK886 (1 mg/kg, ip). OlGly (5 or 30 mg/kg, ip) did not interfere with a morphine-induced place preference or reinstatement of a previously extinguished morphine-induced place preference. Ex vivo analysis of tissue (nucleus accumbens, amygdala, prefrontal cortex, and interoceptive insular cortex) collected from rats experiencing naloxone-precipitated MWD revealed that OlGly was selectively elevated in the nucleus accumbens. MWD did not modify levels of the endocannabinoids 2-AG and AEA, nor those of the PPARα ligands, OEA and PEA, in any region evaluated. Conclusion: Here, we show that OlGly interferes with the aversive properties of acute naloxone-precipitated morphine withdrawal in rats. These results suggest that OlGly may reduce the impact of MWD and may possess efficacy in treating opiate withdrawal.