ObjectiveNeuropathic pain poses a persistent challenge in clinical management. Neuromodulation has emerged as a last‐resort therapy. Conventional spinal cord stimulation (Con SCS) often causes abnormal sensations and provides short analgesia, whereas high‐frequency spinal cord stimulation (HF SCS) is a newer therapy that effectively alleviates pain without paresthesia. However, the modes of action of 10kHz HF SCS (HF10 SCS) in pain relief remain unclear. To bridge this knowledge gap, we employed preclinical models that mimic certain features of clinical SCS to explore the underlying mechanisms of HF10 SCS. Addressing these issues would provide the scientific basis for improving and evaluating the effectiveness, reliability, and practicality of different frequency SCS in clinical settings.MethodsWe established a preclinical SCS model to examine its effects in a neuropathic pain rat model. We conducted bulk and single‐cell RNA sequencing in the spinal dorsal horn (SDH) to examine cellular and molecular changes under different treatments. We employed genetic manipulations through intrathecal injection of a lentiviral system to explore the SCS‐mediated signaling axis in pain. Various behavioral tests were performed to evaluate pain conditions under different treatments.ResultsWe found that HF10 SCS significantly reduces immune responses in the SDH by inactivating the Kaiso‐P2X7R pathological axis in microglia, promoting long‐lasting pain relief. Targeting Kaiso‐P2X7R in microglia dramatically improved efficacy of Con SCS treatment, leading to reduced neuroinflammation and long‐lasting pain relief.InterpretationHF10 SCS could improve the immunopathologic state in the SDH, extending its benefits beyond symptom relief. Targeting the Kaiso‐P2X7R axis may enhance Con SCS therapy and offer a new strategy for pain management. ANN NEUROL 2024

中文翻译：

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高频脊髓刺激抑制小胶质细胞 Kaiso-P2X7 受体轴诱发的炎症，减轻大鼠神经病理性疼痛

目的神经病理性疼痛对临床治疗提出了持续的挑战。神经调节已成为最后的治疗手段。传统的脊髓刺激（Con SCS）通常会引起异常感觉并提供短暂的镇痛，而高频脊髓刺激（HF SCS）是一种较新的疗法，可以有效缓解疼痛而不会出现感觉异常。然而，10kHz HF SCS (HF10 SCS) 在缓解疼痛方面的作用方式仍不清楚。为了弥补这一知识差距，我们采用模仿临床 SCS 某些特征的临床前模型来探索 HF10 SCS 的潜在机制。解决这些问题将为提高和评估不同频率SCS在临床环境中的有效性、可靠性和实用性提供科学依据。方法我们建立了临床前SCS模型来检查其在神经病理性疼痛大鼠模型中的效果。我们对脊髓背角 (SDH) 进行了批量和单细胞 RNA 测序，以检查不同治疗下的细胞和分子变化。我们通过鞘内注射慢病毒系统进行基因操作，以探索 SCS 介导的疼痛信号轴。进行了各种行为测试来评估不同治疗下的疼痛状况。结果我们发现，HF10 SCS 通过灭活小胶质细胞中的 Kaiso-P2X7R 病理轴，显着降低 SDH 中的免疫反应，促进持久疼痛缓解。以小胶质细胞中的 Kaiso‐P2X7R 为靶标，可显着提高 Con SCS 治疗的疗效，从而减少神经炎症并持久缓解疼痛。 解释 HF10 SCS 可以改善 SDH 的免疫病理状态，其益处不仅仅限于症状缓解。靶向 Kaiso-P2X7R 轴可能会增强 Con SCS 治疗并提供新的疼痛管理策略。安神经学 2024