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J Clin Invest. 2019 Mar 26;129(7):2730-2744. doi: 10.1172/JCI126912.

Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids.

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Integrative Neurobiology Section.
Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, and.
Medicinal Chemistry Section, National Institute on Drug Abuse (NIDA), Intramural Research Program (IRP), NIH, Baltimore, Maryland, USA.
Division of Alcohol and Drug Abuse, Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
Massachusetts General Hospital, Departments of Psychiatry and Neurology, Harvard Medical School, Boston, Massachusetts, USA.
Center for Substance Abuse Research, University of Maryland, College Park, Maryland, USA.
Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Barcelona, Spain.
Drug Design and Synthesis Section, NIDA, IRP, and.
NIDA, NIH, Baltimore, Maryland, USA.


Identifying non-addictive opioid medications is a high priority in medical sciences, but μ-opioid receptors mediate both the analgesic and addictive effects of opioids. We found a significant pharmacodynamic difference between morphine and methadone that is determined entirely by heteromerization of μ-opioid receptors with galanin Gal1 receptors, rendering a profound decrease in the potency of methadone. This was explained by methadone's weaker proficiency to activate the dopaminergic system as compared to morphine and predicted a dissociation of therapeutic versus euphoric effects of methadone, which was corroborated by a significantly lower incidence of self-report of "high" in methadone-maintained patients. These results suggest that μ-opioid-Gal1 receptor heteromers mediate the dopaminergic effects of opioids that may lead to a lower addictive liability of opioids with selective low potency for the μ-opioid-Gal1 receptor heteromer, exemplified by methadone.


Addiction; G-protein coupled receptors; Neuroscience; Therapeutics

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