Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ.
Department of Anesthesiology, Daping Hospital, Institute of Surgery Research, Third Military Medical University (Army Medical University), Chongqing, China.
Int J Cancer. 2019 Oct 15;145(8):2122-2134. doi: 10.1002/ijc.32155. Epub 2019 Feb 5.
Antineoplastic drugs induce dramatic transcriptional changes in dorsal root ganglion (DRG) neurons, which may contribute to chemotherapy-induced neuropathic pain. K 1.1 controls neuronal excitability by setting the resting membrane potential. Here, we report that systemic injection of the chemotherapy agent paclitaxel time-dependently downregulates the expression of K 1.1 mRNA and its coding K 1.1 protein in the DRG neurons. Rescuing this downregulation mitigates the development and maintenance of paclitaxel-induced mechanical allodynia and heat hyperalgesia. Conversely, in the absence of paclitaxel administration, mimicking this downregulation decreases outward potassium current and increases excitability in the DRG neurons, leading to the enhanced responses to mechanical and heat stimuli. Mechanically, the downregulation of DRG K 1.1 mRNA is attributed to paclitaxel-induced increase in DRG DNMT3a, as blocking this increase reverses the paclitaxel-induced the decrease of DRG K 1.1 and mimicking this increase reduces DRG K 1.1 expression. In addition, paclitaxel injection increases the binding of DNMT3a to the K 1.1 gene promoter region and elevates the level of DNA methylation within this region in the DRG. These findings suggest that DNMT3a-triggered downregulation of DRG K 1.1 may contribute to chemotherapy-induced neuropathic pain.
抗肿瘤药物会引起背根神经节（DRG）神经元显著的转录变化，这可能导致化疗引起的神经性疼痛。K 1.1 通过设定静息膜电位来控制神经元的兴奋性。在这里，我们报告称，化疗药物紫杉醇的全身注射会随时间下调 DRG 神经元中 K 1.1 mRNA 的表达及其编码的 K 1.1 蛋白。挽救这种下调可以减轻紫杉醇引起的机械性痛觉过敏和热痛觉过敏的发展和维持。相反，在没有紫杉醇给药的情况下，模拟这种下调会减少 DRG 中的外向钾电流并增加其兴奋性，从而导致对机械和热刺激的反应增强。从机制上讲，DRG K 1.1 mRNA 的下调归因于紫杉醇诱导的 DRG DNMT3a 增加，因为阻断这种增加可逆转紫杉醇诱导的 DRG K 1.1 减少，并模拟这种增加会降低 DRG K 1.1 的表达。此外，紫杉醇注射增加了 DRG 中 DNMT3a 与 K 1.1 基因启动子区域的结合，并提高了该区域内的 DNA 甲基化水平。这些发现表明，DRG K 1.1 由 DNMT3a 触发的下调可能导致化疗引起的神经性疼痛。
