Opioid–galanin receptor heteromers mediate the dopaminergic effects of opioids

Cai, Ning-Sheng; Quiroz, César; Bonaventura, Jordi; Bonifazi, Alessandro; Cole, Thomas O.; Purks, Julia; Billing, Amy; Massey, Ebonie; Wagner, Michael; Wish, Eric D.; Guitart, Xavier; Rea, William; Lam, Sherry; Moreno, Estefanía; Casadó-Anguera, Verònica; Greenblatt, Aaron D.; Jacobson, Arthur E.; Rice, Kenner C.; Casadó, Vicent; Newman, Amy Hauck; Winkelman, John W.; Michaelides, Michael; Weintraub, Eric; Volkow, Nora D.; Belcher, Annabelle M.; Ferré, Sergi

doi:10.1172/jci126912

Cited by 44 publications

(31 citation statements)

References 63 publications

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“…Thus, these pharmacodynamic differences between methadone and morphine may provide a way to dissociate the euphoric versus therapeutic effects of methadone-like compounds. Consistently, patients on methadone maintenance experienced fewer euphoria compared with those using other opioids (Cai et al, 2019). Thus, these data indicated MOR-GalR1 heterodimers mediate the dopaminergic effects of opioids and novel methadone-like compounds with reduced potency to activate MOR-GalR1 heterodimers may be safer than current opioids.…”

Section: Mor-galanin Receptor 1 (Gal1r) Heterodimersmentioning

confidence: 64%

“…MOR-Gal1R heterodimer plays a key role in the function of dopaminergic neurons and mediates the antagonistic interactions between MOR and Gal1R selective ligands ( Moreno et al., 2017 ). Cai et al. (2019) further found an agonist-dependent function of MOR-Gal1R heterodimers and elucidated the mechanisms underlying opioid-induced rewarding, suggesting the formation of opioid receptor heterodimers may alter the pharmacological properties of opioid receptor.…”

Section: Mor-galanin Receptor 1 (Gal1r) Heterodimersmentioning

confidence: 92%

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Mu Opioid Receptor Heterodimers Emerge as Novel Therapeutic Targets: Recent Progress and Future Perspective

Zhang

Hang

et al. 2020

Front. Pharmacol.

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Opioids are the most effective analgesics used in the clinical management of cancer pain or non-cancer pain. However, chronic opioids therapy can cause many side effects including respiratory depression, nausea, sedation, itch, constipation, analgesic tolerance, hyperalgesia, high addictive potential, and abuse liability. Opioids exert their effects through binding to the opioid receptors belonging to the G-protein coupled receptors (GPCRs) family, including mu opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR). Among them, MOR is essential for opioidinduced analgesia and also responsible for adverse effects of opioids. Importantly, MOR can form heterodimers with other opioid receptors and non-opioid receptors in vitro and in vivo, and has distinct pharmacological properties, different binding affinities for ligands, downstream signaling, and receptor trafficking. This mini review summarized recent progress on the function of Mu opioid receptor heterodimers, and we proposed that targeting mu opioid receptor heterodimers may represent an opportunity to develop new therapeutics, especially for chronic pain treatment.

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Section: Mor-galanin Receptor 1 (Gal1r) Heterodimersmentioning

confidence: 64%

Section: Mor-galanin Receptor 1 (Gal1r) Heterodimersmentioning

confidence: 92%

Mu Opioid Receptor Heterodimers Emerge as Novel Therapeutic Targets: Recent Progress and Future Perspective

Zhang

Hang

et al. 2020

Front. Pharmacol.

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“…The µ-opioid receptor can form heteromers with the galanin receptor 1 (GalR1) [ 61 ], which dramatically lowers the affinity of the µ-opioid receptor to methadone. At the heteromeric µ-opioid–Gal1-receptor complex, methadone stimulates dramatically lower dopaminergic effects in rat brains as compared to morphine (EC 50 : ~10 −4 M vs. ~10 −7 M) [ 62 ]. Beyond the µ-opioid receptor, methadone has been shown to directly modulate further target proteins, as summarized in Table 2 .…”

Section: Methadone Target Moleculesmentioning

confidence: 99%

Against Repurposing Methadone for Glioblastoma Therapy

et al. 2020

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Methadone, which is used as maintenance medication for outpatient treatment of opioid dependence or as an analgesic drug, has been suggested by preclinical in vitro and mouse studies to induce cell death and sensitivity to chemo- or radiotherapy in leukemia, glioblastoma, and carcinoma cells. These data together with episodical public reports on long-term surviving cancer patients who use methadone led to a hype of methadone as an anti-cancer drug in social and public media. However, clinical evidence for a tumoricidal effect of methadone is missing and prospective clinical trials, except in colorectal cancer, are not envisaged because of the limited preclinical data available. The present article reviews the pharmacokinetics, potential molecular targets, as well as the evidence for a tumoricidal effect of methadone in view of the therapeutically achievable doses in the brain. Moreover, it provides original in vitro data showing that methadone at clinically relevant concentrations fails to impair clonogenicity or radioresistance of glioblastoma cells.

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“…The same mechanism has recently been reported for the selective significant decrease in potency of the μ-opioid receptor agonist methadone, compared with morphine and fentanyl, in the μ-opioid-galanin Gal 1 receptor heteromer. 34 Since these heteromers are selectively localized in the ventral tegmental area (localization of cell bodies of dopaminergic cells involved in the processing of natural rewards), this could explain a selective dissociation of the clinical therapeutic versus euphoric/rewarding effects of methadone compared with other opioids. 34 Therefore, changes in the pharmacological properties of ligands induced by receptor heteromerization should constitute a very important strategy in the search for new therapeutic agents with further selectivity for their therapeutic versus side, unwanted effects.…”

Section: Functional Role Of the Presynaptic Striatal A1r-a2ar Heterotmentioning

confidence: 99%

Functional and Neuroprotective Role of Striatal Adenosine A_2AReceptor Heterotetramers

Ferré

Ciruela

2019

Journal of Caffeine and Adenosine Research

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In the striatum, adenosine A 2A receptors (A 2A R) are mainly expressed within the soma and dendrites of the striatopallidal neuron. A predominant proportion of these striatal postsynaptic A 2A R form part of the macromolecular complexes that include A 2A R-dopamine D 2 receptor (D 2 R) heteromers, G olf and G i/o proteins, and the effector adenylyl cyclase (AC), subtype AC5. The A 2A R-D 2 R heteromers have a tetrameric structure, constituted by A 2A R and D 2 R homomers. By means of reciprocal antagonistic allosteric interactions and antagonistic interactions at the effector level between adenosine and dopamine, the A 2A R-D 2 R heterotetramer-AC5 complex acts an integrative molecular device, which determines a switch between the adenosine-facilitated activation and the dopamine-facilitated inhibition of the striatopallidal neuron. Striatal adenosine also plays an important presynaptic modulatory role, driving the function of corticostriatal terminals. This control is mediated by adenosine A 1 receptors (A 1 R) and A 2A R, which establish intermolecular interactions forming A 1 R-A 2A R heterotetramers. Here, we review the functional role of both presynaptic and postsynaptic striatal A 2A R heterotetramers as well as their possible neuroprotective role. We hypothesize that alterations in the homomer/heteromer stoichiometry (i.e., increase or decrease in the proportion of A 2A R forming homomers or heteromers) are pathogenetically involved in neurological disorders, specifically in Parkinson's disease and restless legs syndrome.

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Opioid–galanin receptor heteromers mediate the dopaminergic effects of opioids

Cited by 44 publications

References 63 publications

Mu Opioid Receptor Heterodimers Emerge as Novel Therapeutic Targets: Recent Progress and Future Perspective

Mu Opioid Receptor Heterodimers Emerge as Novel Therapeutic Targets: Recent Progress and Future Perspective

Against Repurposing Methadone for Glioblastoma Therapy

Functional and Neuroprotective Role of Striatal Adenosine A_2AReceptor Heterotetramers

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Opioid–galanin receptor heteromers mediate the dopaminergic effects of opioids

Cited by 44 publications

References 63 publications

Mu Opioid Receptor Heterodimers Emerge as Novel Therapeutic Targets: Recent Progress and Future Perspective

Mu Opioid Receptor Heterodimers Emerge as Novel Therapeutic Targets: Recent Progress and Future Perspective

Against Repurposing Methadone for Glioblastoma Therapy

Functional and Neuroprotective Role of Striatal Adenosine A2AReceptor Heterotetramers

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Functional and Neuroprotective Role of Striatal Adenosine A_2AReceptor Heterotetramers