Objective To observe the effects of ketamine on the behavior and indoleamine 2,3-dioxygenase (IDO ) signaling pathway in the rats with pain and depression comorbidity. Methods Twenty-four male adult SD rats,aged 2 months,weighing 200-250 g,were randomized into three groups:control group (group S),saline group (group N)and ketamine group (group K), eight in each group.CFA (50 μl)was injected into the right tibiotarsal joint cavity to establish the model of pain and depression comorbidity in the groups N and K,whereas saline (50 μl)was injected in the group S.The mechanical withdrawal threshold (MWT)and the immobility time were measured 1,7,and 14 days after the CFA injection.After the behavioral tests 14 days after the CFA injection, saline (1 ml)was intraperitoneal administrated in the group N and ketamine 20 mg/kg (1 ml)was in-traperitoneal administrated in the group K 14 days after CFA injection.The MWT and immobility time were measured 1 h after administration in the three groups to evaluate the behavioral changes. Then,the hippocampus,prefrontal cortex,cingulated gyrus and plasma were harvested to determine the levels of IL-6 and IDO using an enzyme-linked immunosorbent assay after the behavioral tests. Results Compared with the group S,the MWT was decreased and the immobility time was signifi-cantly increased in the group N and group K (P <0.05).Compared with the group N,the MWT was increased (P <0.05),the immobility time was decreased (P <0.05),and the levels of IL-6 and IDO in the hippocampus,prefrontal cortex and cingulated gyrus were significantly decreased in the group K (P < 0.05 ).Conclusion Ketamine can effectively treat pain and depression comorbidity,which may be attributed to the inhibition of IDO signaling pathway in different brain regions of rats.