Spontaneous and Naloxone-Precipitated Withdrawal Behaviors From Chronic Opiates are Accompanied by Changes in N-Oleoylglycine and N-Oleoylalanine Levels in the Brain and Ameliorated by Treatment With These Mediators

Frontiers in Pharmacology, Vol. 12 (2021)

Mots clés
Auteurs
  • Samantha M. Ayoub
  • Department of Psychology and Collaborative Neuroscience, University of Guelph, Guelph, ON, Canada
  • Fabiana Piscitelli
  • Institute of Biomolecular Chemistry, Endocannabinoid Research Group Consiglio Nazionale delle Richerche, Pozzuli, Italy
  • Cristoforo Silvestri
  • Centre de Recherche de l’Institut Universitaire de Cardiologie et Pneumologie de Québec, Faculty of Medicine, Centre NUTRISS, Université Laval, Québec City, QC, Canada
  • Cheryl L. Limebeer
  • Department of Psychology and Collaborative Neuroscience, University of Guelph, Guelph, ON, Canada
  • Erin M. Rock
  • Department of Psychology and Collaborative Neuroscience, University of Guelph, Guelph, ON, Canada
  • Reem Smoum
  • Institute of Drug Research, School of Pharmacy, Medical Faculty, Hebrew University of Jerusalem, Jerusalem, Israel
  • Mathew Farag
  • Department of Psychology and Collaborative Neuroscience, University of Guelph, Guelph, ON, Canada
  • Hannah de Almeida
  • Department of Psychology and Collaborative Neuroscience, University of Guelph, Guelph, ON, Canada
  • Megan T. Sullivan
  • Department of Psychology and Collaborative Neuroscience, University of Guelph, Guelph, ON, Canada
  • Sébastien Lacroix
  • Centre de Recherche de l’Institut Universitaire de Cardiologie et Pneumologie de Québec, Faculty of Medicine, Centre NUTRISS, Université Laval, Québec City, QC, Canada
  • Besma Boubertakh
  • Centre de Recherche de l’Institut Universitaire de Cardiologie et Pneumologie de Québec, Faculty of Medicine, Centre NUTRISS, Université Laval, Québec City, QC, Canada
  • Nayudu Nallabelli
  • Centre de Recherche de l’Institut Universitaire de Cardiologie et Pneumologie de Québec, Faculty of Medicine, Centre NUTRISS, Université Laval, Québec City, QC, Canada
  • Aron H Lichtman
  • Department of Pharmacology and Toxicology, Medical College of Virginia Campus Virginia Commonwealth University, Richmond, VA, United States
  • Francesco Leri
  • Department of Psychology and Collaborative Neuroscience, University of Guelph, Guelph, ON, Canada
  • Raphael Mechoulam
  • Institute of Drug Research, School of Pharmacy, Medical Faculty, Hebrew University of Jerusalem, Jerusalem, Israel
  • Vincenzo Di Marzo
  • Institute of Biomolecular Chemistry, Endocannabinoid Research Group Consiglio Nazionale delle Richerche, Pozzuli, Italy
  • Vincenzo Di Marzo
  • Centre de Recherche de l’Institut Universitaire de Cardiologie et Pneumologie de Québec, Faculty of Medicine, Centre NUTRISS, Université Laval, Québec City, QC, Canada
  • Vincenzo Di Marzo
  • Faculty of Agriculture and Food Science, INAF, Université Laval, Québec City, QC, Canada
  • Vincenzo Di Marzo
  • Canada Excellence Research Chair on the Microbiome/Endocannabinoidome Axis in Metabolic Health, Québec City, QC, Canada
  • Linda A. Parker
  • Department of Psychology and Collaborative Neuroscience, University of Guelph, Guelph, ON, Canada

Résumé

Rationale: The endocannabinoidome mediators, N-Oleoylglycine (OlGly) and N-Oleoylalanine (OlAla), have been shown to reduce acute naloxone-precipitated morphine withdrawal affective and somatic responses.Objectives: To determine the role and mechanism of action of OlGly and OlAla in withdrawal responses from chronic exposure to opiates in male Sprague-Dawley rats.Methods: Opiate withdrawal was produced: 1) spontaneously 24 h following chronic exposure to escalating doses of morphine over 14 days (Experiments 1 and 2) and steady-state exposure to heroin by minipumps for 12 days (Experiment 3), 2) by naloxone injection during steady-state heroin exposure (Experiment 4), 3) by naloxone injection during operant heroin self-administration (Experiment 5).Results: In Experiment 1, spontaneous morphine withdrawal produced somatic withdrawal reactions. The behavioral withdrawal reactions were accompanied by suppressed endogenous levels of OlGly in the nucleus accumbens, amygdala, and prefrontal cortex, N-Arachidonylglycerol and OlAla in the amygdala, 2-arachidonoylglycerol in the nucleus accumbens, amygdala and interoceptive insular cortex, and by changes in colonic microbiota composition. In Experiment 2, treatment with OlAla, but not OlGly, reduced spontaneous morphine withdrawal responses. In Experiment 3, OlAla attenuated spontaneous steady-state heroin withdrawal responses at both 5 and 20 mg/kg; OlGly only reduced withdrawal responses at the higher dose of 20 mg/kg. Experiment 4 demonstrated that naloxone-precipitated heroin withdrawal from steady-state exposure to heroin (7 mg/kg/day for 12 days) is accompanied by tissue-specific changes in brain or gut endocannabinoidome mediator, including OlGly and OlAla, levels and colonic microbiota composition, and that OlAla (5 mg/kg) attenuated behavioural withdrawal reactions, while also reversing some of the changes in brain and gut endocannabinoidome and gut microbiota induced by naloxone. Experiment 5 demonstrated that although OlAla (5 mg/kg) did not interfere with operant heroin self-administration on its own, it blocked naloxone-precipitated elevation of heroin self-administration behavior.Conclusion: These results suggest that OlAla and OlGly are two endogenous mediators whose brain concentrations respond to chronic opiate treatment and withdrawal concomitantly with changes in colon microbiota composition, and that OlAla may be more effective than OlGly in suppressing chronic opiate withdrawal responses.

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