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JCI - Opioid–galanin receptor heteromers mediate the dopaminergic effects of opioids

️The Journal of Clinical Investigation
️Mon Jul 01 2019

Opioid–galanin receptor heteromers mediate the dopaminergic effects of opioids

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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

Gal1R-dependent pharmacodynamic differences of MOR agonists.

(

–

) Representative concentration-response experiments of ligand-induced BRET changes in HEK-293T cells transfected with the MOR fused to Rluc and the α subunit of the Gi1 protein fused to YFP. Values represent the mean ± SEM of triplicates. The effect of increasing concentrations of the MOR agonists morphine (

), EM1 (

), DAMGO (

), fentanyl (

), and methadone (

) were evaluated without cotransfection with Gal1R, in the absence or presence of the Gal1R/Gal2R antagonist M40 (red and green curves, respectively), or with cotransfection with Gal1R, with or without M40 (blue and purple curves, respectively). (

and

) Comparison of the E_max and E₅₀ values obtained with and without cotransfection with the Gal1R. **

< 0.01 versus transfection with MOR alone; unpaired, 2-tailed

test (

); **

< 0.01 versus transfection with MOR alone; 2-tailed Mann-Whitney

test (

). E_max and EC₅₀ values are shown as dots, presented with the mean ± SEM (

) or median with interquartile ranges (

) (

= 5–10 triplicates/group).