Abstract: OBJECTIVE To explore the effect and mechanism of phosphodiesterase 2 inhibitor Bay 60-7550 on persistent post-surgical pain in mice model of short-term sleep disturbance-induced depression. METHODS The experimental mice were divided into sham operation group, incision group, stress+sham operation group, stress+incision group, stress+sham operation+Bay 60-7750 group and stress+incision+Bay 60-7750 group. Determination of paw withdrawl threshold and paw withdrawl latency were performed on one day before surgery, and 1, 4, 7, and 9 d after surgery, respectively. Assessment of depression-like behavior in mice was evaluated by forced swimming and sucrose preference test. The serum corticosterone levels and the expression of phosphorylation cAMP-response element binding protein(pCREB)/CREB and brain-derived neurotrophic factor(BDNF) in the hippocampus of each group of mice were measured. RESULTS Short-term sleep disturbance caused paw withdrawl threshold decreased significantly from 4 d after the operation, the latency period of heat pain decreased significantly from 7 d after the operation. At least these effects could be reversed by Bay 60-7550 until the 9th day after operation. In the forced swimming experiment, short-term sleep disturbance caused the immobility time increased significantly, in the sugar and water consumption experiment, short-term sleep disturbance led to a decrease in sugar and water consumption on the 4th day after surgery, Bay 60-7550 could improve the above situation. Both operation and short-term sleep disturbance caused an increase in serum corticosterone in mice, and this effect was reversed by Bay 60-7550. Both pCREB/CREB and BDNF protein expression were reduced in both surgery and short-term sleep disturbance. Bay 60-7550 was given to improve hippocampal pCREB/CREB and BDNF expression in mice. CONCLUSION PDE2 inhibitor Bay 60-7550 can improve persistent post-surgical pain in mice with short-term sleep disturbance. The mechanism may be related to the expression of glucocorticoid-related neuroprotective proteins.