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Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids.

ABSTRACT: Identifying non-addictive opioid medications is a high priority in medical sciences, but ?-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 ?-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 ?-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 ?-opioid-Gal1 receptor heteromer, exemplified by methadone.

SUBMITTER: Cai NS

PROVIDER: S-EPMC6597217 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids.

Cai Ning-Sheng NS Quiroz César C Bonaventura Jordi J Bonifazi Alessandro A Cole Thomas O TO Purks Julia J Billing Amy S AS Massey Ebonie E Wagner Michael M Wish Eric D ED Guitart Xavier X Rea William W Lam Sherry S Moreno Estefanía E Casadó-Anguera Verònica V Greenblatt Aaron D AD Jacobson Arthur E AE Rice Kenner C KC Casadó Vicent V Newman Amy H AH Winkelman John W JW Michaelides Michael M Weintraub Eric E Volkow Nora D ND Belcher Annabelle M AM Ferré Sergi S

The Journal of clinical investigation 20190326 7

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 ...[more]

PMID: 30913037

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Project description:The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of μ-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin-opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells, we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR-Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative cross talk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified in situ in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKT and CREB phosphorylation. Furthermore, in vivo microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders.The μ-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form functional heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R heteromer can explain previous results showing antagonistic galanin-opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder.

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Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids.

Publications

Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids.

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