Zhan Mei-Xiang, Tang Li, Lu Yun-Fei, Wu Huang-Hui, Guo Zhi-Bin, Shi Zhong-Mou, Yang Chen-Long, Zou Yi-Qing, Yang Fei, Chen Guo-Zhong
Department 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.
Department of Anesthesiology and Perioperative Medicine, Dongfang Hospital, Xiamen University, Fuzhou, Fujian, 350025, People's Republic of China.
J Pain Res. 2021 May 4;14:1201-1214. doi: 10.2147/JPR.S303595. eCollection 2021.
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.
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.
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.
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.
乌司他丁是一种广谱丝氨酸蛋白酶抑制剂，已在临床上广泛用于治疗各种疾病。然而，迄今为止，乌司他丁的抗伤害感受作用在实验研究中仍较少，其缓解疼痛的潜在机制尚不清楚。本研究旨在寻找乌司他丁对急性躯体和内脏疼痛镇痛作用的证据。
采用福尔马林和醋酸诱导的扭体试验评估乌司他丁对急性躯体和内脏疼痛的镇痛作用。通过苏木精-伊红（H&E）染色和免疫组化染色检测外周炎症细胞浸润和脊髓胶质细胞活化，以验证乌司他丁的镇痛机制。
我们发现，腹腔内（i.p.）预先给药和给药后，乌司他丁均可剂量依赖性地减少足底注射福尔马林后缩足总数和舔足持续时间。然而，乌司他丁的抑制作用仅存在于福尔马林诱导的自发疼痛反应的第二阶段（第2期），对第一阶段（第1期）无影响。腹腔内注射乌司他丁也可改善福尔马林诱导的水肿和溃疡。此外，腹腔内注射乌司他丁还能够延迟醋酸诱导的扭体的发生，并剂量依赖性地减少扭体总数。我们进一步证明，乌司他丁分别显著减少了福尔马林和醋酸试验下受伤爪和腹膜组织中的局部炎症细胞浸润。腹腔内注射乌司他丁也显著抑制了足底注射福尔马林和腹腔内注射醋酸诱导的脊髓背角小胶质细胞和星形胶质细胞活化。
我们的结果首次提供了新的证据表明，乌司他丁可通过抑制外周和脊髓炎症反应减轻急性躯体和内脏疼痛。
