Department of Pain Management, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China.
Department of Pain Management, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, China; Zhongshan School of Medicine, Yat-sen University, Guangzhou, China.
Pain Physician. 2023 May;26(3):E213-E222.
Clinically, neuropathic pain is a severe side effect of oxaliplatin chemotherapy, which usually leads to dose reduction or cessation of treatment. Due to the unawareness of detailed mechanisms of oxaliplatin-induced neuropathic pain, it is difficult to develop an effective therapy and limits its clinical use.
The aim of the present study was to identify the role of sirtuin 1 (SIRT1) reduction in epigenetic regulation of the expression of voltage-gated sodium channels 1.7 (Nav1.7) in the dorsal root ganglion (DRG) during oxaliplatin-induced neuropathic pain.
Controlled animal study.
University laboratory.
The von Frey test was performed to evaluate pain behavior in rats. Real-time quantitative polymerase chain reaction, western blotting, electrophysiological recording, chromatin immunoprecipitation, and small interfering RNA (siRNA) were used to illustrate the mechanisms.
In the present study, we found that both the activity and expression of SIRT1 were significantly decreased in rat DRG following oxaliplatin treatment. The activator of SIRT1, resveratrol, not only increased the activity and expression of SIRT1, but also attenuated the mechanical allodynia following oxaliplatin treatment. In addition, local knockdown of SIRT1 by intrathecal injection of SIRT1 siRNA caused mechanical allodynia in naive rats. Besides, oxaliplatin treatment enhanced the action potential firing frequency of DRG neurons and the expression of Nav1.7 in DRG and activation of SIRT1 by resveratrol reversed this effect. Furthermore, blocking Nav1.7 by ProTx II (a selective Nav1.7 channel blocker) reversed oxaliplatin-induced mechanical allodynia. In addition, histone H3 hyperacetylation at the Nav1.7 promoter in DRG of rats following oxaliplatin treatment was significantly suppressed by activation of SIRT1 with resveratrol. Moreover, both the expression of Nav1.7 and histone H3 acetylation at the Nav1.7 promoter were upregulated in the DRG by local knockdown of SIRT1 with SIRT1 siRNA in naive rats.
More underlying mechanism(s) of SIRT1 reduction after oxaliplatin treatment needs to be explored in future research.
These findings suggest that reduction of SIRT1-mediated epigenetic upregulation of Nav1.7 in the DRG contributes to the development of oxaliplatin-induced neuropathic pain in rats. The intrathecal drug delivery treatment of activating SIRT1 might be a novel therapeutic option for oxaliplatin-induced neuropathic pain.
临床上，神经病理性疼痛是奥沙利铂化疗的一种严重副作用，通常导致剂量减少或停止治疗。由于对奥沙利铂诱导的神经病理性疼痛的详细机制认识不足，因此难以开发有效的治疗方法，限制了其临床应用。
本研究旨在确定 SIRT1（沉默调节蛋白 1）减少在背根神经节（DRG）中电压门控钠通道 1.7（Nav1.7）表达的表观遗传调控中的作用，该作用发生在奥沙利铂诱导的神经病理性疼痛中。
对照动物研究。
大学实验室。
利用 von Frey 试验评估大鼠的疼痛行为。实时定量聚合酶链反应、蛋白质印迹、电生理记录、染色质免疫沉淀和小干扰 RNA（siRNA）用于阐明机制。
在本研究中，我们发现奥沙利铂处理后大鼠 DRG 中的 SIRT1 活性和表达均显著降低。SIRT1 的激活剂白藜芦醇不仅增加了 SIRT1 的活性和表达，而且还减轻了奥沙利铂处理后的机械性痛觉过敏。此外，鞘内注射 SIRT1 siRNA 局部敲低 SIRT1 会导致正常大鼠出现机械性痛觉过敏。此外，奥沙利铂处理增强了 DRG 神经元的动作电位发放频率和 Nav1.7 在 DRG 中的表达，而 SIRT1 的激活则逆转了这种作用。此外，用 ProTx II（一种选择性 Nav1.7 通道阻滞剂）阻断 Nav1.7 可逆转奥沙利铂引起的机械性痛觉过敏。此外，奥沙利铂处理后大鼠 DRG 中 Nav1.7 启动子处组蛋白 H3 的乙酰化明显受到 SIRT1 激活的抑制，而 SIRT1 的激活则抑制了 SIRT1 的表达。此外，在正常大鼠中，用 SIRT1 siRNA 局部敲低 SIRT1 会导致 DRG 中 Nav1.7 的表达和 Nav1.7 启动子处组蛋白 H3 的乙酰化上调。
未来的研究需要进一步探讨奥沙利铂治疗后 SIRT1 减少的更多潜在机制。
这些发现表明，DRG 中 SIRT1 介导的表观遗传上调 Nav1.7 的减少导致了大鼠奥沙利铂诱导的神经病理性疼痛的发生。激活 SIRT1 的鞘内药物输送治疗可能是奥沙利铂诱导的神经病理性疼痛的一种新的治疗选择。
