Oleoyl alanine (HU595): a stable monomethylated oleoyl glycine interferes with acute naloxone precipitated morphine withdrawal in male rats

Samantha M. Ayoub, Reem Smoum, Mathew Farag, Harkirat Atwal, Stephen A. Collins, Erin M. Rock, Cheryl L. Limebeer, Fabiana Piscitelli, Fabio Arturo Iannotti, Aron H. Lichtman, Francesco Leri, Vincenzo Di Marzo, Raphael Mechoulam, Linda A. Parker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Rationale: Oleoyl glycine, a little studied fatty acid amide similar in structure to anandamide, interferes with nicotine addiction in mice and acute naloxone-precipitated morphine withdrawal (MWD) in rats. Because endogenous oleoyl glycine is subject to rapid enzymatic deactivation, we evaluated the potential of more stable analogs to interfere with opiate withdrawal. Objectives: The potential of monomethylated oleoyl glycine (oleoyl alanine, HU595) to interfere with somatic and aversive effects of acute naloxone-precipitated MWD, its duration, and mechanism of action was assessed in male Sprague Dawley rats. The potential of dimethylated oleoyl glycine (HU596) to interfere with the aversive effects of naloxone-precipitated MWD was also investigated. Results: Oleoyl alanine (HU595) interfered with somatic and aversive effects produced by naloxone-precipitated MWD at equivalent doses (1 and 5 mg/kg, i.p.) as we have reported for oleoyl glycine; however, oleoyl alanine produced a longer lasting (60 min) interference, yet did not produce rewarding or aversive effects on its own and did not modify locomotor activity. HU596 was not effective. The interference with aversive effects of naloxone-precipitated MWD by oleoyl alanine was prevented by both a PPARα antagonist and a CB1 receptor antagonist. Accordingly, the compound was found to inhibit FAAH and activate PPARα in vitro. Finally, oleoyl alanine also reduced acute naloxone-precipitated MWD anhedonia, as measured by decreased saccharin preference. Conclusions: Oleoyl alanine (also an endogenous fatty acid) may be a more stable and effective treatment for opiate withdrawal than oleoyl glycine.

Original languageAmerican English
Pages (from-to)2753-2765
Number of pages13
Issue number9
StatePublished - 1 Sep 2020

Bibliographical note

Funding Information:
The research was supported by grants from the Natural Sciences and Engineering Research Council of Canada (03629) and PlantExt to LAP and from PlantExt to RM.

Publisher Copyright:
© 2020, Springer-Verlag GmbH Germany, part of Springer Nature.


  • Anhedonia
  • CB
  • Conditioned place aversion
  • Naloxone-precipitated morphine withdrawal
  • Nausea
  • Oleoyl alanine
  • Oleoyl glycine
  • PPARα
  • Rat
  • Saccharin preference
  • Somatic withdrawal


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