Ulinastatin Exhibits Antinociception in Rat Models of Acute Somatic and Visceral Pain Through Inhibiting the Local and Central Inflammation.
Ulinastatin Exhibits Antinociception in Rat Models of Acute Somatic and Visceral Pain Through Inhibiting the Local and Central Inflammation.
复制标题
乌司他丁通过抑制局部和中枢炎症，在急性躯体和内脏疼痛大鼠模型中表现出镇痛作用。
DOI：
10.2147/jpr.s303595
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发表时间：
2021
影响因子：
2.7
通讯作者：
Chen GZ
中科院分区：
文献类型：
--
作者：
Zhan MX;Tang L;Lu YF;Wu HH;Guo ZB;Shi ZM;Yang CL;Zou YQ;Yang F;Chen GZ
乌司他丁是一种广谱丝氨酸蛋白酶抑制剂，临床上已广泛应用于多种疾病的治疗。然而，到目前为止，乌司他丁的抗伤害性作用的实验研究仍然较少，乌司他丁缓解疼痛的潜在机制仍然不清楚。本研究旨在寻找乌司他丁对急性躯体和内脏疼痛的镇痛作用的证据。采用福尔马林扭体法和醋酸扭体法评价乌司他丁对急性躯体痛和内脏痛的镇痛作用。通过苏木精-伊红（H&E）染色和免疫组织化学染色检测外周炎性细胞浸润和脊髓胶质细胞活化，验证乌司他丁的镇痛机制。我们发现，腹膜内（i. p.）乌司他丁给药前和给药后均能以剂量相关的方式减少足底福尔马林注射后的退缩总数和舔体持续时间。然而，乌司他丁的抑制作用仅存在于福尔马林诱导的自发性疼痛反应的第二阶段（阶段2），在第一阶段（阶段1）没有效果。乌司他丁腹腔给药也可改善福尔马林诱导的水肿和溃疡。此外，腹腔注射乌司他丁也能够延迟醋酸诱导的扭体反应的发生，并剂量依赖性地减少扭体反应的总数。我们进一步证明，乌司他丁分别在福尔马林和乙酸试验中显著减少损伤足爪和腹膜组织中的局部炎性细胞浸润。足跖福尔马林和腹腔注射乙酸诱导的脊髓背角小胶质细胞和星形胶质细胞活化也被腹腔注射乌司他丁显著抑制。本研究首次为乌司他丁通过抑制外周和脊髓炎症反应减轻急性躯体和内脏疼痛提供了新的证据。
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.