Rationale: Many patients respond inadequately to antidepressant drug treatment; the search for alternate pharmacological treatment mechanisms is ongoing. Until the 1950's, opium was sometimes used to treat depression, but eventually abandoned due to addiction risk. Recent insights into opioid biology have sparked a renewed interest in the potential antidepressant properties of opioids. Objective: We studied how mu (MOR), kappa (KOR) and delta (DOR) opioid receptor ligands affect the dysregulation of motivated behavior (progressive ratio responding; PR), stresscoping behavior (forced swim test; FST) and hippocampal neurogenesis in rats, all induced by the back-translational interferon-alpha (IFN-α)-induced depression model. Methods: Male Wistar rats (3-months old, 8/group) were treated with recombinant human IFNα (170,000 IU/kg, 3 times/week) or saline. Ligands of the MOR, KOR and DOR receptors were administered as follows: a single subcutaneous dose, 30min before PR and 1h before FST, of the MOR agonist morphine (full agonist; 5mg/kg), the partial agonist RDC 2944 (0.1mg/kg) and the antagonist, cyprodime (10mg/kg); of the KOR agonist, U50 488 (5mg/kg), the antagonist, DIPPA (10mg/kg); and the DOR agonist, SNC 80 (20mg/kg) and antagonist naltrindole (10mg/kg). After 4 days of treatment with the mitotic BrdU marker, hippocampi were harvested and analysed for neurogenesis. Fluoxetine (10 mg/kg/day for 4 weeks, orally) served as control for assay sensitivity in the FST. Results: The KOR antagonist, DIPPA, the DOR agonist SNC 80 and fluoxetine reversed the IFN-αinduced immobility increase in the FST. The MOR agonist, morphine, the KOR antagonist DIPPA, and the KOR agonist U50 488 reduced the IFN-α-induced increase in the breakpoint in the PR. The DOR agonist SNC 80 recovered the IFN-α-induced decrease in BrdU+ hippocampal cells. Conclusion: Opioid receptors mediate different aspects of the IFN-α-induced dysregulation of motivational and stress-coping behaviors and hippocampal neurogenesis in a backtranslational model of depression. KORs and DORs appear to play more prominent roles in 3 torpor-inertia-type behaviors, whereas DORs appear more involved in the regulation of neurogenesis.