Spinal cord stimulation prevents paclitaxel-induced mechanical and cold hypersensitivity and modulates spinal gene expression in rats

Introduction: Paclitaxel-induced peripheral neuropathy (PIPN) is a common dose-limiting side effect of this cancer treatment drug. Spinal cord stimulation (SCS) has demonstrated efficacy for attenuating some neuropathic pain conditions. Objective: We aim to examine the inhibitory effect of SCS for the development of PIPN pain in rats. Methods: We examined whether traditional SCS administered during paclitaxel treatment attenuates PIPN-related pain behavior. After SCS, we carried out RNA-seq of the lumbar spinal cord to examine which genes are differentially expressed after PIPN with and without SCS. Results: Compared to rats treated with paclitaxel alone (n=7) or sham SCS (n=6), SCS treatment (n= 11) significantly inhibited the development of paclitaxel-induced mechanical and cold hypersensitivity, without altering open-field exploratory behavior. RNA-seq showed that SCS induced upregulation of 836 genes and downregulation of 230 genes in the spinal cord of paclitaxel-treated rats (n=3), as compared to sham SCS (n=5). SCS upregulated immune responses in paclitaxel-treated rats, including transcription of astrocyte- and microglial-related genes, but repressed transcription of multiple gene networks associated with synaptic plasticity, neuron projection development, g-aminobutyric acid reuptake, and long-term potentiation. Conclusion: Our findings suggest that traditional SCS may attenuate the development of pain-related behaviors in PIPN, partially by causing aggregate inhibition of synaptic plasticity through up- and down-regulation of gene networks in the spinal cord.引言：紫杉醇诱导性周围神经病（Paclitaxel-induced peripheral neuropathy, PIPN）是该抗癌药物常见的剂量限制性不良反应。脊髓电刺激（Spinal cord stimulation, SCS）已被证实对部分神经性疼痛病症具有缓解功效。本研究旨在探讨脊髓电刺激对大鼠紫杉醇诱导性周围神经病疼痛发生的抑制作用。研究目的：考察紫杉醇给药期间实施传统脊髓电刺激是否可减轻紫杉醇诱导性周围神经病相关疼痛行为。研究方法：我们评估了在紫杉醇治疗期间施加的传统脊髓电刺激能否缓解PIPN相关疼痛行为。在完成脊髓电刺激干预后，我们对大鼠腰骶段脊髓进行RNA测序（RNA-seq），以分析存在与不存在脊髓电刺激干预的PIPN大鼠脊髓内的差异表达基因。研究结果：与单纯紫杉醇治疗组（n=7）及假手术脊髓电刺激组（n=6）相比，脊髓电刺激治疗组（n=11）可显著抑制紫杉醇诱导的机械性痛觉超敏与冷痛觉超敏的发生，且不影响大鼠的旷场探索行为。RNA测序结果显示，相较于假手术脊髓电刺激组（n=5），紫杉醇治疗大鼠经脊髓电刺激干预后（n=3），脊髓内有836个基因表达上调、230个基因表达下调。脊髓电刺激可上调紫杉醇治疗大鼠的免疫应答相关通路，包括星形胶质细胞与小胶质细胞相关基因的转录，但同时抑制了多个与突触可塑性、神经元投射发育、γ-氨基丁酸（γ-aminobutyric acid）重摄取以及长时程增强相关的基因网络的转录。研究结论：本研究结果表明，传统脊髓电刺激可减轻紫杉醇诱导性周围神经病的疼痛相关行为的发生，其部分机制可能通过在脊髓内上下调相关基因网络，整体抑制突触可塑性来实现。