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Antidepressant-like and anxiolytic-like effects following activation of the μ-δ opioid receptor heteromer in the nucleus accumbens

Molecular Psychiatry volume 19, pages 986–994 (2014)Cite this article

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Abstract

Treatment-resistant major depressive disorder remains inadequately treated with currently available antidepressants. Opioid receptors (ORs) are involved in the pathophysiology of depression yet remain an untapped therapeutic intervention. The μ-δ OR heteromer represents a unique signaling complex with distinct properties compared with μ- and δ-OR homomers; however, its role in depression has not been characterized. As there are no ligands exclusively targeting the μ-δ heteromer, we devised a strategy to selectively antagonize the function of the μ-δOR complex using a specific interfering peptide derived from the δOR distal carboxyl tail, a sequence implicated in μ-δOR heteromerization. In vitro studies using a minigene expressing this peptide demonstrated a loss of the unique pharmacological and trafficking properties of δ-agonists at the μ-δ heteromer, with no effect on μ- or δ-OR homomers, and a dissociation of the μ-δOR complex. Intra-accumbens administration of the TAT-conjugated interfering peptide abolished the antidepressant-like and anxiolytic-like actions of the δ-agonist UFP-512 (H-Dmt-Tic-NH-CH(CH2-COOH)-Bid) measured in the forced swim test, novelty-induced hypophagia and elevated plus maze paradigms in rats. UFP-512’s antidepressant-like and anxiolytic-like actions were abolished by pretreatment with either μOR or δOR antagonists. Overall, these findings demonstrate that the μ-δ heteromer may be a potential suitable therapeutic target for treatment-resistant depression and anxiety disorders.

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Acknowledgements

This work was funded by a grant from the Canadian Institutes of Health Research and an Ontario Mental Health Foundation Research Studentship (NK). Dr Susan R George holds a Tier I Canada Research Chair in Molecular Neuroscience.

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Authors and Affiliations

  1. Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, ON, Canada

    N Kabli, T Nguyen, B F O'Dowd & S R George

  2. Departments of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    N Kabli, B F O'Dowd & S R George

  3. Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy

    G Balboni

  4. Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    S R George

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Correspondence to S R George.

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NK and SRG designed the study and wrote the manuscript. NK performed radioligand binding, whole-cell binding, protein expression and coimmunoprecipitation, stereotaxic surgery and behavioral experiments. TN made the peptide minigene constructs. GB synthesized UFP-512. SRG and BFO supervised the project.

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Kabli, N., Nguyen, T., Balboni, G. et al. Antidepressant-like and anxiolytic-like effects following activation of the μ-δ opioid receptor heteromer in the nucleus accumbens. Mol Psychiatry 19, 986–994 (2014). https://doi.org/10.1038/mp.2013.115

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