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.


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


  • Receptor, Metabotropic Glutamate 5
  • Receptors, Opioid, mu
  • Morphine