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

Psychopharmacology (Berl). 2019 Sep;236(9):2623-2633. doi: 10.1007/s00213-019-05237-9. Epub 2019 Apr 16.


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.

Keywords: 2-Arachidonyl glycerol (2-AG); Anandamide (AEA); Conditioned place aversion (CPA); Fatty acid amide hydrolase (FAAH); Morphine withdrawal (MWD); N-Arachidonoyl glycine (AraGly); Oleoyl glycine (OlGly); Oleoylethanolamide (OEA); Palmitoylethanolamide (PEA).

MeSH terms

  • Amygdala / drug effects
  • Amygdala / metabolism
  • Analgesics, Opioid / adverse effects*
  • Animals
  • Dose-Response Relationship, Drug
  • Glycine / administration & dosage
  • Glycine / analogs & derivatives*
  • Glycine / metabolism
  • Male
  • Mice
  • Morphine / adverse effects*
  • Naloxone / toxicity*
  • Narcotic Antagonists / toxicity
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Oleic Acids / administration & dosage*
  • Oleic Acids / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reward*
  • Substance Withdrawal Syndrome / drug therapy*
  • Substance Withdrawal Syndrome / metabolism
  • Substance Withdrawal Syndrome / psychology


  • Analgesics, Opioid
  • Narcotic Antagonists
  • Oleic Acids
  • oleoylglycine
  • Naloxone
  • Morphine
  • Glycine