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Abstract：
Ulinastatin is a broad-spectrum protease inhibitor widely used for the treatment of various inflammation-related diseases owing to its recognized excellent anti-inflammatory and cytoprotective properties. However, whether ulinastatin can relieve postoperative pain remains unclear. In this study, we evaluated the analgesic effects of ulinastatin administered either as a single agent or in combination with sufentanil in a validated preclinical rat model of postoperative pain induced by plantar incision. We found that incisional surgery on the hind paw of these rats induced sustained ipsilateral mechanical pain hypersensitivity that lasted for at least 10 days. A single intraperitoneal (i.p.) injection of ulinastatin prevented the development and reversed the maintenance of incision-induced mechanical pain hypersensitivity in a dose-dependent manner. However, ulinastatin had no effect on the baseline nociceptive threshold. Moreover, repeated i.p. injections of ulinastatin persistently attenuated incision-induced mechanical pain hypersensitivity and promoted recovery from the surgery. The rats did not develop any analgesic tolerance over the course of repeated injections of ulinastatin. A single i.p. injection of ulinastatin was also sufficient to inhibit the initiation and maintenance of incision-induced hyperalgesic priming when the rats were subsequently challenged with an ipsilateral intraplantar prostaglandin E2 injection. Furthermore, the combined administration of ulinastatin and sufentanil significantly enhanced the analgesic effect of sufentanil on postoperative pain, which involved mechanisms other than a direct influence on opioid receptors. These findings demonstrated that ulinastatin had a significant analgesic effect on postoperative pain and might be a novel pharmacotherapeutic agent for managing postoperative pain either alone or as an adjuvant.
摘要：
乌司他丁是一种广谱蛋白酶抑制剂,由于其公认的优异的抗炎和细胞保护特性,广泛用于治疗各种炎症相关疾病。然而,乌司他丁能否缓解术后疼痛尚不清楚.在这项研究中,我们评估了乌司他丁单药或联合舒芬太尼在足底切口术后疼痛的临床前大鼠模型中的镇痛效果.我们发现，对这些大鼠的后爪进行切开手术可引起持续的同侧机械性疼痛超敏反应，持续至少10天。单次腹膜内（i.p.）注射乌司他丁可以剂量依赖性方式防止切口引起的机械性疼痛超敏反应的发展并逆转其维持。然而,乌司他丁对基线伤害感受阈值无影响.此外，反复静脉注射乌司他丁可减轻切口引起的机械性疼痛过敏，促进手术恢复。在重复注射乌司他丁的过程中，大鼠没有产生任何镇痛耐受性。当大鼠随后用同侧足底内前列腺素E2注射攻击时，单次腹膜内注射乌司他丁也足以抑制切口诱导的痛觉过敏引发的启动和维持。此外，联合应用乌司他丁和舒芬太尼可显著增强舒芬太尼对术后疼痛的镇痛效果,除了直接影响阿片受体外，还涉及其他机制。这些发现表明乌司他丁对术后疼痛具有显着的镇痛作用，并且可能是单独或作为辅助治疗术后疼痛的新型药物治疗剂。
