Objective To investigate the effects of clopidogrel on behavioral,content of inflamma-tory cytokines,and microglial in mice with comorbidity of pain and depression.Methods Twenty-four male pathogen-free C57BL/6J mice,aged 8 weeks,weighing 23-27 g,were selected.The mice were randomly divided into three groups:sham group(group C),spared nerve injury(SNI)group(group S),and SNI+clopidogrel group(group L),8 mice in each group.The surgical procedure in group C was consistent with the SNI model,but the nerve and maintained nerve integrity were not damaged.Group S was prepared with the SNI model,and group L was given clopidogrel 10 mg/kg since 21 days after the SNI model was prepared for 14 days continuously.Mechanical withdrawal threshold(MWT)was detected 1 day before surgery,7,14,21,28,and 35 days after surgery.The tail suspension test(TST)and forced swim test(FST)were performed 35 and 37 days after surgery,and the motionless time was calculated.Then the mice were killed,and the right hippocampal tissue was harvested to detect the concentration of IL-1β,IL-6,and TNF-α by enzyme-linked immunosorbent assay(ELISA),the expression of IL-1β,IL-6,and TNF-α mRNA by reverse transcription-polymerase chain reaction(RT-PCR),and the number of microglia by immunofluores-cence staining.Results Compared with group C,MWT were significantly decreased 7,14,21,28,and 35 days after operation,the immobility time of TST and FST were significantly prolonged,the concentrations and mRNA expressions of IL-1β,IL-6,and TNF-α were significantly increased,and the number of micro-glia were significantly increased in groups S and L(P＜0.05).Compared with group S,MWT were signifi-cantly increased 28 and 35 days after operation,the immobility time of TST and FST were significantly short-ened,the concentrations and mRNA expressions of IL-1β,IL-6,and TNF-α were significantly decreased,and the number of microglia was significantly reduced in group L(P＜0.05).Conclusion Clopidogrel can reduce the concentrations and mRNA expressions of IL-1β,IL-6,and TNF-α,inhibit the inflammatory reaction,reduce the number of activated microglia,and improve the and chronic neuropathic pain and de-pression in mice with comorbidity of pain and depression.