Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids
Ning-Sheng Cai, César Quiroz, Jordi Bonaventura, Alessandro Bonifazi, Thomas O Cole, Julia Purks, Amy S Billing, Ebonie Massey, Michael Wagner, Eric D Wish, Xavier Guitart, William Rea, Sherry Lam, Estefanía Moreno, Verònica Casadó-Anguera, Aaron D Greenblatt, Arthur E Jacobson, Kenner C Rice, Vicent Casadó, Amy H Newman, John W Winkelman, Michael Michaelides, Eric Weintraub, Nora D Volkow, Annabelle M Belcher, Sergi Ferré, Ning-Sheng Cai, César Quiroz, Jordi Bonaventura, Alessandro Bonifazi, Thomas O Cole, Julia Purks, Amy S Billing, Ebonie Massey, Michael Wagner, Eric D Wish, Xavier Guitart, William Rea, Sherry Lam, Estefanía Moreno, Verònica Casadó-Anguera, Aaron D Greenblatt, Arthur E Jacobson, Kenner C Rice, Vicent Casadó, Amy H Newman, John W Winkelman, Michael Michaelides, Eric Weintraub, Nora D Volkow, Annabelle M Belcher, Sergi Ferré
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.
Conflict of interest statement
Conflict of interest: The authors have declared that no conflict of interest exists.
Figures
![Figure 1. Gal1R-dependent allosteric modulation of MOR…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6597217/bin/jci-129-126912-g021.jpg)
![Figure 2. Gal1R-dependent pharmacodynamic differences of MOR…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6597217/bin/jci-129-126912-g022.jpg)
![Figure 3. Weaker ability of methadone to…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6597217/bin/jci-129-126912-g023.jpg)
![Figure 4. Differential ability of morphine and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6597217/bin/jci-129-126912-g024.jpg)
![Figure 5. Very low reporting of feeling…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6597217/bin/jci-129-126912-g025.jpg)
Source: PubMed