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Mei-Xiang Zhan,1,2,* Li Tang,3,* Yun-Fei Lu,4,* Huang-Hui Wu,1,* Zhi-Bin Guo,1 Zhong-Mou Shi,1 Chen-Long Yang,1 Yi-Qing Zou,1,2 Fei Yang,1,2,5 Guo-Zhong Chen1,2 1Department of Anesthesiology and Perioperative Medicine, Clinical Medical College, (900 Hospital of the Joint Logistic Support Force), Fujian Medical University, Fuzhou, Fujian, 350025, People’s Republic of China; 2Department of Anesthesiology and Perioperative Medicine, Dongfang Hospital, Xiamen University, Fuzhou, Fujian, 350025, People’s Republic of China; 3Department of Stomatology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China; 4Department of Anesthesiology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, People’s Republic of China; 5Laboratory of Pain Research, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guo-Zhong Chen; Fei YangDepartment of Anesthesiology and Perioperative Medicine, 900 Hospital of the Joint Logistic Support Force, Fujian Medical University, #156 West 2 nd Ring Road North, Gulou District, Fuzhou, 350025, People’s Republic of ChinaEmail cgzssq2000@sina.com; yangfeimedbrain@outlook.comIntroduction: Ulinastatin, a broad-spectrum serine protease inhibitor, has been widely used to treat various diseases clinically. However, so far, the antinociceptive effect of ulinastatin remains less studied experimentally and the underlying mechanisms of ulinastatin for pain relief remain unclear. This study aimed to find evidence of the analgesic effect of ulinastatin on acute somatic and visceral pain.Methods: The analgesic effect of ulinastatin on acute somatic and visceral pain was evaluated by using formalin and acetic acid-induced writhing test. The analgesic mechanism of ulinastatin was verified by detecting the peripheral inflammatory cell infiltration and spinal glial activation with hematoxylin-eosin (H&E) and immunohistochemistry staining.Results: We found that both of intraperitoneal (i.p.) pre-administration and post-administration of ulinastatin could reduce the total number of flinching and the licking duration following intraplantar formalin injection in a dose-related manner. However, the inhibitory effect of ulinastatin existed only in the second phase (Phase 2) of formalin-induced spontaneous pain response, with no effect in the first phase (Phase 1). The formalin-induced edema and ulcer were also improved by i.p. administration of ulinastatin. Moreover, i.p. administration of ulinastatin was also able to delay the occurrence of acetic acid-induced writhing and reduced the total number of writhes dose-dependently. We further demonstrated that ulinastatin significantly decreased the local inflammatory cell infiltration in injured paw and peritoneum tissue under formalin and acetic acid test separately. The microglial and astrocytic activation in the spinal dorsal horn induced by intraplantar formalin and i.p. acetic acid injection were also dramatically inhibited by i.p. administration of ulinastatin.Conclusion: Our results for the first time provided a new line of evidence showing that ulinastatin could attenuate acute somatic and visceral pain by inhibiting the peripheral and spinal inflammatory reaction.Keywords: Ulinastatin, formalin, somatic pain, visceral pain, inflammation, antinociception