Objective To observe the protective role of sulfentanyl pretreatment on acute gastric mucosal lesion induced by water immersion restraint stress(WIRS) in diabetic rats and investigate its’ possible mechanism. Methods Eighty adult SD rats were randomly divided into eight groups(n=8, each), including normal rats (Group A), normal rats suffering WIRS(group B1), diabetic rats suffering WIRSs(Group B2), normal rats suffering WIRS pretreated with sufentanil(Group C1), diabetic rats suffering WIRS pretreated with sufentanil(Group C2), normal rats suffering WIRS were pretreated with sufentanil plus specificity. Group B2, C2 are all diabetic rats. The acute gastric mucosal lesion models were copied by the classic WIRS,. All the experimental rates will killed at 6 hours after WIRS for stomach samples including the namoral rats in group A. Gastric mucosal injury index(GI) was assessed thought 10x dissecting microscope and pathologic histology were observed under optical microscope of each group. MDA, SOD and MPO of gastric tissue homogenate were measured with chromatometry. Results All rats who suffer WIRS can be found acute gastric mucosal lesion, GI is significantly higher in Group B2 vs Group B1 and C1 (p<0.05); GI is significantly higher in Group D2 and D3 vs Group C2(p<0.05), while there is no obviously differ between Group D1 and Group C2 (p>0.05). It can be found diversity degree of engorgement hydropsia and inflammatory cell infiltrate in those rats’ gastric mucosa at 6h after WIRS, those symptom is wost in group B2 and better in groups which were pretreatment with sufentanil. Conclusions It seams that diabetic rats will get severer injure of stomach mucous membrane than normal rats. Pretreatment with sufentanil can effectively protect stomach mucous membrane from WIRS-induced injury, the depression of lipid peroxidation, released oxygen radicals and increased neutrophils.