Department of Anesthesiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation for Cancer Medicine, Guangzhou, Guangdong, 510000, China.
Department of Anesthesiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation for Cancer Medicine, Guangzhou, Guangdong, 510000, China.
Eur J Pharmacol. 2020 Sep 15;883:173306. doi: 10.1016/j.ejphar.2020.173306. Epub 2020 Jun 27.
Chemotherapy-induced peripheral neuropathy is a serious adverse effect of chemotherapeutic agents such as paclitaxel. JTC-801, a nociceptin/orphanin FQ opioid peptide (NOP) receptor antagonist, has been reported to attenuate neuropathic pain in several pain models. However, the therapeutic significance and function of JTC-801 in chemotherapy-induced peripheral neuropathy remain unclear. In this study, we determined the effect of JTC-801 on neuropathic pain induced by paclitaxel, and we explored the potential mechanism in the dorsal root ganglion (DRG). The behavioral test showed that single or multiple systemic administrations of JTC-801 significantly alleviated mechanical allodynia in paclitaxel-treated rats. Using Western blot analysis and immunohistochemistry, we found that paclitaxel increased the expression of phosphatidylinositol 3-kinase (PI3K) and phospho-Akt (p-Akt) in the DRG. Double immunofluorescence staining indicated that p-Akt was expressed in neurons in the DRG. Multiple injections of JTC-801 significantly inhibited the activation of Akt and decreased the expression of inflammatory cytokines. The data suggest that JTC-801 alleviates mechanical allodynia associated with paclitaxel-induced neuropathic pain via the PI3K/Akt pathway.
化疗引起的周围神经病变是紫杉醇等化疗药物的一种严重不良反应。孤啡肽/强啡肽 FQ 型阿片肽（NOP）受体拮抗剂 JTC-801 已被报道可减轻几种疼痛模型中的神经性疼痛。然而，JTC-801 在化疗引起的周围神经病变中的治疗意义和功能仍不清楚。在本研究中，我们确定了 JTC-801 对紫杉醇诱导的神经病理性疼痛的影响，并探讨了其在背根神经节（DRG）中的潜在机制。行为学测试表明，单次或多次系统给予 JTC-801 可显著减轻紫杉醇处理大鼠的机械性痛觉过敏。通过 Western blot 分析和免疫组织化学，我们发现紫杉醇增加了 DRG 中磷酸肌醇 3-激酶（PI3K）和磷酸化 Akt（p-Akt）的表达。双重免疫荧光染色表明，p-Akt 表达于 DRG 中的神经元。多次注射 JTC-801 可显著抑制 Akt 的激活并降低炎症细胞因子的表达。这些数据表明，JTC-801 通过 PI3K/Akt 通路缓解与紫杉醇诱导的神经病理性疼痛相关的机械性痛觉过敏。
