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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.

Author information

1
Integrative Neurobiology Section.
2
Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, and.
3
Medicinal Chemistry Section, National Institute on Drug Abuse (NIDA), Intramural Research Program (IRP), NIH, Baltimore, Maryland, USA.
4
Division of Alcohol and Drug Abuse, Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
5
Massachusetts General Hospital, Departments of Psychiatry and Neurology, Harvard Medical School, Boston, Massachusetts, USA.
6
Center for Substance Abuse Research, University of Maryland, College Park, Maryland, USA.
7
Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Barcelona, Spain.
8
Drug Design and Synthesis Section, NIDA, IRP, and.
9
NIDA, NIH, Baltimore, Maryland, USA.

Abstract

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.

KEYWORDS:

Addiction; G-protein coupled receptors; Neuroscience; Therapeutics

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