Rapid‐Onset Therapeutic Effects of Delta Opioid Receptor Agonists on Depression‐Like Behaviors Induced by Chronic Social Defeat Stress

Depression is prevalent, yet conventional antidepressants often require time to produce therapeutic effects. Therefore, novel antidepressants with a more rapid onset of action are urgently needed. This study investigated the potential of δ opioid receptor (DOP) agonists as fast-acting antidepressants, comparing their efficacy with that of existing treatments. We utilized the chronic social defeat stress (CSDS) model, which closely mimics clinical depressive symptoms, to evaluate the therapeutic effects of DOP agonists (SNC80, KNT-127) and paroxetine, a selective serotonin reuptake inhibitor. Mice exposed to CSDS for 10 days showed social avoidance toward aggressor mice along with generalized depression and anxiety-like behaviors. Both DOP agonists demonstrated dose-dependent therapeutic effects at 1-10 mg/kg and showed improvements within 10-14 days of chronic administration. In contrast, paroxetine alleviated these symptoms after 28 days of treatment. These findings suggest that DOP agonists may offer a faster-acting alternative to current antidepressant therapies.