, Volume 236, Issue 9, pp 2623–2633 | Cite as

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

  • Gavin N. Petrie
  • Kiri L. Wills
  • Fabiana Piscitelli
  • Reem Smoum
  • Cheryl L. Limebeer
  • Erin M. Rock
  • Ashlyn E. Humphrey
  • Madeleine Sheppard-Perkins
  • Aron H. Lichtman
  • Raphael Mechoulam
  • Vincenzo Di Marzo
  • Linda A. ParkerEmail author
Original Investigation



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.


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.


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.


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


Author contributions

GP, KW, ER, MS, and AH performed behavioral experiments. FP and VD performed the molecular analyses. RS and RM synthesized OlGly. CL prepared all drugs and collected all tissues. GP, KW, AL, VD, RM, and LP designed the experiments and wrote the manuscript.


The research reported here was funded by research grants from the Natural Sciences and Engineering Research Council (NSERC 920157) and the Canadian Institutes for Health Research (CIHR 388239) to LAP, NIH grants R01DA039942, P30DA033934, and VCU School of Pharmacy start-up funds to AHL.

Compliance with ethical standards

All animal procedures were approved by the Animal Care Committee of the University of Guelph and adhere to the guidelines of the Canadian Council of Animal Care.

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Gavin N. Petrie
    • 1
  • Kiri L. Wills
    • 1
  • Fabiana Piscitelli
    • 2
  • Reem Smoum
    • 3
  • Cheryl L. Limebeer
    • 1
  • Erin M. Rock
    • 1
  • Ashlyn E. Humphrey
    • 1
  • Madeleine Sheppard-Perkins
    • 1
  • Aron H. Lichtman
    • 4
  • Raphael Mechoulam
    • 3
  • Vincenzo Di Marzo
    • 2
  • Linda A. Parker
    • 1
    Email author
  1. 1.Department of Psychology and CollaborativeUniversity of GuelphGuelphCanada
  2. 2.Institute of Biomolecular ChemistryEndocannabinoid Research Group, Consiglio Nazionale delle RicercheNaplesItaly
  3. 3.Institute for Drug Research, Medical FacultyHebrew UniversityJerusalemIsrael
  4. 4.Department of Pharmacology and Toxicology, Medical College of Virginia CampusVirginia Commonwealth UniversityRichmondUSA

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