Yang Chen-Long, Jing Jun-Jie, Fu Si-Yin, Zhong Yu-Ling, Su Xiu-Zhu, Shi Zhong-Mou, Wu Xiao-Zhi, Yang Fei, Chen Guo-Zhong
Department of Anesthesiology and Perioperative Medicine, Fuzong Clinical Medical College/900th Hospital of the Joint Logistic Support Force, Fujian Medical University, Fuzhou, Fujian, PR China.
Department of Neurosurgery, Fujian Children's Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, PR China.
Neurotoxicology. 2022 Dec;93:173-185. doi: 10.1016/j.neuro.2022.10.001. Epub 2022 Oct 6.
Due to the increasing use of local anesthetic techniques in various healthcare settings, local anesthetic toxicity still occurs. Seizures are the most common symptom of local anesthetic toxicity. The relationship between local anesthetic-induced seizures and the sensation of pain has not been established till now. Here, we assessed the development of pain hypersensitivity after ropivacaine-induced seizures (RIS) and the influence of RIS on incision-induced postsurgical pain and formalin-induced acute inflammatory pain. In addition, the involvement of spinal 5-HT/5-HTR in RIS-induced pain sensitization was investigated. According to a sequential exploratory experimental strategy, we first calculated the 50% seizure dosage of ropivacaine to be 42.66 mg/kg (95% confidence interval: 40.19-45.28 mg/kg). We showed that RIS induced significant bilateral mechanical pain hypersensitivity that lasted around 5 days, accompanied by an increase in spinal 5-HT. Moreover, RIS considerably protracted postsurgical pain and enhanced formalin-induced spontaneous flinching in the second phase. Depletion of spinal 5-HT with intrathecal injection of 5,7-dihydroxytryptamine (5,7-DHT) reduced RIS-induced pain hypersensitivity and prevented the prolonging of postsurgical pain following RIS. Likewise, blocking spinal 5-HT3R by intrathecal administration of ondansetron reversed RIS-induced pain hypersensitivity and attenuated the pronociception of RIS in the formalin test. Our findings revealed that acute RIS led to pain hypersensitivity and had pronociceptive effects on incision-induced postsurgical pain and formalin-induced acute inflammatory pain. Moreover, our data implied that RIS-induced pain sensitization depends on spinal 5-HT/5-HTR signaling. Thus, targeting the descending serotonergic facilitation system should be an important element of the precise treatment for local anesthetic toxicity.
由于局部麻醉技术在各种医疗环境中的使用日益增加，局部麻醉药毒性仍然会发生。癫痫发作是局部麻醉药毒性最常见的症状。迄今为止，局部麻醉药诱发的癫痫发作与疼痛感觉之间的关系尚未确立。在此，我们评估了罗哌卡因诱发癫痫发作（RIS）后痛觉过敏的发展情况以及RIS对切口诱发的术后疼痛和福尔马林诱发的急性炎性疼痛的影响。此外，还研究了脊髓5-羟色胺/5-羟色胺受体（5-HT/5-HTR）在RIS诱发的疼痛敏化中的作用。根据顺序探索性实验策略，我们首先计算出罗哌卡因的50%癫痫发作剂量为42.66mg/kg（95%置信区间：40.19-45.28mg/kg）。我们发现，RIS诱发了显著的双侧机械性痛觉过敏，持续约5天，同时伴有脊髓5-羟色胺水平升高。此外，RIS显著延长了术后疼痛，并增强了福尔马林诱发的第二相自发退缩反应。鞘内注射5,7-二羟色胺（5,7-DHT）耗尽脊髓5-羟色胺可降低RIS诱发的痛觉过敏，并防止RIS后术后疼痛延长。同样，鞘内注射昂丹司琼阻断脊髓5-HT3R可逆转RIS诱发的痛觉过敏，并减弱RIS在福尔马林试验中的促痛觉感受作用。我们的研究结果表明，急性RIS导致痛觉过敏，并对切口诱发的术后疼痛和福尔马林诱发的急性炎性疼痛具有促痛觉感受作用。此外，我们的数据表明，RIS诱发的疼痛敏化依赖于脊髓5-HT/5-HTR信号传导。因此，针对下行5-羟色胺能易化系统应是局部麻醉药毒性精准治疗的重要环节。
