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 4

Differential ability of morphine and methadone to influence metabolic activity in the basal forebrain.

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Differential ability of morphine and methadone to influence metabolic ac...
Metabolic mapping using [18F]FDG PET scanning in rats. (A) Timeline of the experiment. (B) [18F]FDG uptake after administration of saline (baseline, n = 14), morphine (1 mg/kg, n = 7), or methadone (1 mg/kg, n = 7). Coronal and sagittal images (1.5 mm anterior to bregma and 1.4 mm lateral from the midline, respectively) show the average SUVR calculated using the whole brain as a reference region. (C) Voxel-based parametric mapping analyses revealed significantly decreased metabolic activity from baseline values in a basal forebrain region that included the NAc and its projecting areas after morphine, but not methadone, treatment. Statistical parametric maps of significant decreases of [18F]FDG uptake (P < 0.05, paired t test). (D and E) VOI analyses of the frontal cortex (FCx), dorsal striatum (DS), and basal forebrain (BF) region, showing a significant differential pattern of [18F]FDG uptake after administration of morphine (D) or methadone (E). Values are shown as dots and as the median with interquartile ranges. *P < 0.05 versus the corresponding baseline value; 2-tailed Wilcoxon matched-pairs test (n = 7 animals/group).