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 mu-delta OR heteromer represents a unique signaling complex with distinct properties compared with mu- and delta-OR homomers; however, its role in depression has not been characterized. As there are no ligands exclusively targeting the mu-delta heteromer, we devised a strategy to selectively antagonize the function of the mu-delta OR complex using a specific interfering peptide derived from the delta OR distal carboxyl tail, a sequence implicated in mu-delta OR heteromerization. In vitro studies using a minigene expressing this peptide demonstrated a loss of the unique pharmacological and trafficking properties of delta-agonists at the mu-delta heteromer, with no effect on mu- or delta-OR homomers, and a dissociation of the mu-delta OR complex. Intra-accumbens administration of the TAT-conjugated interfering peptide abolished the antidepressant-like and anxiolytic-like actions of the delta-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 mu OR or delta OR antagonists. Overall, these findings demonstrate that the mu-delta heteromer may be a potential suitable therapeutic target for treatment-resistant depression and anxiety disorders.