The analgesic effects of ulinastatin either as a single agent or in combination with sufentanil: A novel therapeutic potential for postoperative pain
The analgesic effects of ulinastatin either as a single agent or in combination with sufentanil: A novel therapeutic potential for postoperative pain
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乌司他丁作为单一药物或与舒芬太尼联合使用的镇痛作用：术后疼痛的新治疗潜力。
DOI：
10.1016/j.ejphar.2021.174267
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发表时间：
2021-06-22
影响因子：
5
通讯作者：
Wu，Xiao-Zhi
中科院分区：
文献类型：
--
作者：
Guo，Zhi-Bin;Tang，Li;Wu，Xiao-Zhi
乌司他丁是一种广谱蛋白酶抑制剂，具有良好的抗炎和细胞保护作用，广泛应用于各种炎症相关疾病的治疗。然而，乌司他丁是否能缓解术后疼痛仍不清楚。在这项研究中，我们评估了乌司他丁单用或与舒芬太尼合用在经验证的大鼠足底切口术后疼痛的临床前模型中的镇痛效果。我们发现，这些大鼠后爪的切口手术诱导了持续至少10天的同侧机械性疼痛超敏反应。单次腹腔注射乌司他丁可以剂量依赖的方式阻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性阈值没有影响。此外，反复注射乌司他丁可持续减轻切口引起的机械疼痛超敏反应，促进手术恢复。在反复注射乌司他丁的过程中，大鼠没有产生任何镇痛耐受性。当大鼠随后被同侧足底前列腺素E2注射时，单次注射乌司他丁也足以抑制切口诱导的痛觉刺激的开始和维持。此外，乌司他丁和舒芬太尼联合使用可显著增强舒芬太尼对术后疼痛的镇痛作用，其机制并非直接影响阿片受体。这些发现表明，乌司他丁对术后疼痛有显著的镇痛作用，可能是一种新的药物治疗药物，无论是单独治疗还是作为辅助治疗。
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, repeatedi.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 singlei.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.