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
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Research Article Neuroscience

Opioid–galanin receptor heteromers mediate the dopaminergic effects of opioids

Abstract

Identifying nonaddictive opioid medications is a high priority in medical science, but μ-opioid receptors (MORs) 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 MORs with galanin Gal1 receptors (Gal1Rs), rendering a profound decrease in the potency of methadone. This finding was explained by the weaker proficiency of methadone in activating the dopaminergic system as compared with morphine and predicted a dissociation of the therapeutic and euphoric effects of methadone, which was corroborated by a significantly lower incidence of self-reports of feeling “high” in methadone-medicated patients. These results suggest that μ-opioid–Gal1R heteromers mediate the dopaminergic effects of opioids. The results further suggest a lower addictive liability of some opioids, such as methadone, due to their selective low potency for the μ-opioid–Gal1R heteromer.

Authors

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

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Figure 1

Gal1R-dependent allosteric modulation of MOR agonists.

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Gal1R-dependent allosteric modulation of MOR agonists. (A and B) Effect ...
(A and B) Effect of the MOR antagonist CTOP and the Gal1R/Gal2R antagonist M40 on DMR induced by the MOR agonists EM1 (A) and morphine (B) in MU and MU-Gal1R cells. Values are shown as dots and the mean ± SEM (n = 5–6 triplicates/group). ###P < 0.001 versus EM1; 1-way ANOVA with Tukey’s multiple comparisons test. (C) Effect of CTOP and M40 on MAPK activation induced by EM1 in MU-GAL cells. Values are shown as dots and the mean ± SEM n = 6–15 triplicates/group). ***P < 0.001 versus control; ###P < 0.001 versus EM1; 1-way ANOVA with Tukey’s multiple comparisons test. (D) Effect of CTOP and M40 on internalization of MOR induced by the MOR agonist DAMGO and lack of MOR-induced internalization by the Gal1R agonist M617 in MU-GAL cells. Values are shown as dots and the mean ± SEM (n = 6 triplicates/group). ***P < 0.001 versus control; ###P < 0.001 versus control DAMGO; 1-way ANOVA with Tukey’s multiple comparisons test. (E and F), Representative competitive inhibition experiments of [3H]DAMGO versus DAMGO in membrane preparations from MU (E) and MU-GAL (F) cells with or without M617 or M40. Values are expressed as the mean ± SEM of triplicates. See Results and Supplemental Figure 2 for the total number of experiments and statistical comparisons. Concentrations of agonists and antagonists were always 0.1 μM and 1 μM, respectively.