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Current Topics in Opioid Research

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Psychiatry | doi: 10.3389/fpsyt.2018.00630

CB1 Agonism Alters Addiction-Related Behaviours in Mice Lacking Mu or Delta Opioid Receptors

  • 1LNCA CNRS Université de Strasbourg, UMR7364 Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), France
  • 2UPR3212 Institut des Neurosciences Cellulaires et Intégratives (INCI), France
  • 3Centre for Neuroscience Studies, Queen's University, Canada
  • 4Department of Psychology, Queens University, Canada

Opioids are powerful analgesics but the clinical utility of these compounds is reduced by aversive outcomes, including the development of affective and substance use disorders. Opioid systems do not function in isolation so understanding how these interact with other neuropharmacological systems could lead to novel therapeutics that minimize withdrawal, tolerance, and emotional dysregulation. The cannabinoid system is an obvious candidate as anatomical, pharmacological, and behavioural studies point to opioid-cannabinoid interactions in the mediation of these processes. The aim of our study is to uncover the role of specific cannabinoid and opioid receptors in addiction-related behaviours, specifically nociception, withdrawal, anxiety, and depression. To do so, we tested the effects of a selective CB1 agonist, arachidonyl-2-chloroethylamide (ACEA), on mouse behaviour in tail immersion, naloxone-precipitated withdrawal, light-dark, and splash tests. We examined cannabinoid-opioid interactions in these tests by comparing responses of wildtype (WT) mice to mutant lines lacking either Mu or Delta opioid receptors. ACEA, both acute or repeated injections, had no effect on nociceptive thresholds in WT or Mu knockout (KO) mice suggesting that analgesic properties of CB1 agonists may be restricted to chronic pain conditions. The opioid antagonist, naloxone, induced similar levels of withdrawal in all three genotypes following ACEA treatment, confirming an opioidergic contribution to cannabinoid withdrawal. Anxiety-like responses in the light-dark test were similar across WT and KO lines; neither acute nor repeated ACEA injections modified this behaviour. Similarly, administration of the Delta opioid receptor antagonist, naltrindole, alone or in combination with ACEA, did not alter responses of WT mice in the light-dark test. Thus, there may be a dissociation in the effect of pharmacological blockade versus genetic deletion of Delta opioid receptors on anxiety-like behaviour in mice. Finally, our study revealed a biphasic effect of ACEA on depressive-like behaviour in the splash test, with a prodepressive state induced by acute exposure, followed by a shift to an anti-depressive state with repeated injections. The initial pro-depressive effect of ACEA was absent in Mu KO mice. In sum, our findings confirm interactions between opioid and cannabinoid systems in withdrawal and reveal reduced depressive-like symptoms with repeated CB1 receptor activation.

Keywords: ACEA, Nociception, withdrawal, Depression, Anxiety, CB1, opioid

Received: 30 Jul 2018; Accepted: 06 Nov 2018.

Edited by:

Gary T. Hardiman, Medical University of South Carolina, United States

Reviewed by:

Kabirullah Lutfy, Western University of Health Sciences, United States
Elena Martín-García, Universidad Pompeu Fabra, Spain  

Copyright: © 2018 Roeckel, Massotte, Olmstead and Befort. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Katia Befort, UMR7364 Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), LNCA CNRS Université de Strasbourg, Strasbourg, 67000, Alsace, France,