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Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids
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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.
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CAI, Ning-sheng, QUIROZ, César, BONAVENTURA, Jordi, BONIFAZI, Alessandro, COLE, Thomas o., PURKS, Julia, BILLING, Amy s., MASSEY, Ebonie, WAGNER, Michael, WISH, Eric d., GUITART, Xavier, REA, William, LAM, Sherry, MORENO GUILLÉN, Estefanía, CASADÓ ANGUERA, Verònica, GREENBLATT, Aaron d., JACOBSON, Arthur e., RICE, Kenner c., CASADÓ, Vicent, NEWMAN, Amy hauck, WINKELMAN, John w., MICHAELIDES, Michael, WEINTRAUB, Eric, VOLKOW, Nora d., BELCHER, Annabelle m., FERRÉ, Sergi. Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids. _Journal of Clinical Investigation_. 2019. Vol. 129, núm. 7, pàgs. 2730-2744. [consulta: 7 de febrer de 2026]. ISSN: 0021-9738. [Disponible a: https://hdl.handle.net/2445/150155]