Antidepressant-like and anxiolytic-like effects following activation of the μ-δ opioid receptor heteromer in the nucleus accumbens.
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.
1] Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, ON, Canada [2] Departments of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
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Kabli
Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, ON, Canada.
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Nguyen
Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
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Balboni
1] Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, ON, Canada [2] Departments of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
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O'Dowd
1] Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, ON, Canada [2] Departments of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada [3] Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
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George
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000928:Antidepressive Agents; D001007:Anxiety / Q000188:drug therapy* / Q000503:physiopathology; D001562:Benzimidazoles / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000503:physiopathology; D009842:Oligopeptides / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D013315:Stress, Psychological
C526539:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1H-benzimidazol-2-yl)(carboxymethyl)methylamide; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D001562:Benzimidazoles; D009292:Narcotic Antagonists; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu