Emotional Impairment and Persistent Upregulation of mGlu5 Receptor following Morphine Abstinence: Implications of an mGlu5-MOPr Interaction

Panos Zanos; Polymnia Georgiou; Loreto Rojo Gonzalez; Susanna Hourani; Ying Chen; Ian Kitchen; Brigitte L Kieffer; Raphaelle Winsky-Sommerer; Alexis Bailey

doi:10.1093/ijnp/pyw011

Emotional Impairment and Persistent Upregulation of mGlu5 Receptor following Morphine Abstinence: Implications of an mGlu5-MOPr Interaction

Int J Neuropsychopharmacol. 2016 Jul 5;19(7):pyw011. doi: 10.1093/ijnp/pyw011. Print 2016 Jul.

Authors

Panos Zanos¹, Polymnia Georgiou¹, Loreto Rojo Gonzalez¹, Susanna Hourani¹, Ying Chen¹, Ian Kitchen¹, Brigitte L Kieffer¹, Raphaelle Winsky-Sommerer¹, Alexis Bailey²

Affiliations

¹ School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (Dr Zanos, Dr Georgiou, Ms Rojo Gonzalez, Prof. Hourani, Prof. Kitchen, Dr Winsky-Sommerer, and Dr Bailey); Department of Psychiatry, University of Maryland, School of Medicine, Baltimore, MD (Dr Zanos and Dr Georgiou); Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK (Dr Chen); Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch, France (Prof. Kieffer); Douglas Hospital Research Center, Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada (Prof. Kieffer); Institute of Medical and Biomedical Education, St George's University of London, London (Dr Bailey).
² School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK (Dr Zanos, Dr Georgiou, Ms Rojo Gonzalez, Prof. Hourani, Prof. Kitchen, Dr Winsky-Sommerer, and Dr Bailey); Department of Psychiatry, University of Maryland, School of Medicine, Baltimore, MD (Dr Zanos and Dr Georgiou); Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK (Dr Chen); Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch, France (Prof. Kieffer); Douglas Hospital Research Center, Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada (Prof. Kieffer); Institute of Medical and Biomedical Education, St George's University of London, London (Dr Bailey). abailey@sgul.ac.uk.

Abstract

Background: A difficult problem in treating opioid addicts is the maintenance of a drug-free state because of the negative emotional symptoms associated with withdrawal, which may trigger relapse. Several lines of evidence suggest a role for the metabotropic glutamate receptor 5 in opioid addiction; however, its involvement during opioid withdrawal is not clear.

Methods: Mice were treated with a 7-day escalating-dose morphine administration paradigm. Following withdrawal, the development of affective behaviors was assessed using the 3-chambered box, open-field, elevated plus-maze and forced-swim tests. Metabotropic glutamate receptor 5 autoradiographic binding was performed in mouse brains undergoing chronic morphine treatment and 7 days withdrawal. Moreover, since there is evidence showing direct effects of opioid drugs on the metabotropic glutamate receptor 5 system, the presence of an metabotropic glutamate receptor 5/μ-opioid receptor interaction was assessed by performing metabotropic glutamate receptor 5 autoradiographic binding in brains of mice lacking the μ-opioid receptor gene.

Results: Withdrawal from chronic morphine administration induced anxiety-like, depressive-like, and impaired sociability behaviors concomitant with a marked upregulation of metabotropic glutamate receptor 5 binding. Administration of the metabotropic glutamate receptor 5 antagonist, 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine, reversed morphine abstinence-induced depressive-like behaviors. A brain region-specific increase in metabotropic glutamate receptor 5 binding was observed in the nucleus accumbens shell, thalamus, hypothalamus, and amygdala of μ-opioid receptor knockout mice compared with controls.

Conclusions: These results suggest an association between metabotropic glutamate receptor 5 alterations and the emergence of opioid withdrawal-related affective behaviors. This study supports metabotropic glutamate receptor 5 system as a target for the development of pharmacotherapies for the treatment of opioid addiction. Moreover, our data show direct effects of μ-opioid receptor system manipulation on metabotropic glutamate receptor 5 binding in the brain.

Keywords: Morphine; mGlu5R; opioids; withdrawal; μ-opioid receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Behavior, Animal / drug effects
Brain / metabolism
Emotions / drug effects*
Male
Mice
Mice, Knockout
Morphine / adverse effects*
Morphine / pharmacology
Receptor, Metabotropic Glutamate 5 / metabolism*
Receptors, Opioid, mu / genetics*
Substance Withdrawal Syndrome / metabolism*
Up-Regulation / drug effects

Substances

Receptor, Metabotropic Glutamate 5
Receptors, Opioid, mu
Morphine