A challenging complication in patients with peripheral compressive neuropathy is neuropathic pain. Excessive neuroinflammation at the injury site worsens neuropathic pain and impairs function. Currently, non-invasive modulation techniques like transcutaneous electrical nerve stimulation (TENS) have shown therapeutic promise with positive results. However, the underlying regulatory molecular mechanism for pain relief remains complex and unexplored. This study aimed to validate the therapeutic effect of ultrahigh frequency (UHF)-TENS in chronic constriction injury of the rat sciatic nerve. Alleviation of mechanical allodynia was achieved through the application of UHF-TENS, lasting for 3 days after one session of therapy and 4 days after two sessions, without causing additional damage to the myelinated axon structure. The entire tissue collection schedule was divided into four time points: nerve exposure surgery, 7 days after nerve ligation, and 1 and 5 days after one session of UHF therapy. Significant reductions in pain-related neuropeptides, MEK, c-Myc, c-FOS, COX2, and substance P, were observed in the injured DRG neurons after UHF therapy. RNA sequencing of differential gene expression in sensory neurons revealed significant downregulation in Cables, Pik3r1, Vps4b, Tlr7, and Ezh2 after UHF therapy, while upregulation was observed in Nfkbie and Cln3. UHF-TENS effectively and safely relieved neuropathic pain without causing further nerve damage. The decreased production of pain-related neuropeptides within the DRG provided the therapeutic benefit. Possible molecular mechanisms behind UHF-TENS may result from the modulation of the NF-κB complex, toll-like receptor-7, and phosphoinositide 3-kinase/Akt signaling pathways. These results suggest the neuromodulatory effects of UHF-TENS in rat sciatic nerve chronic constriction injury, including alleviation of neuropathic pain, amelioration of pain-related neuropeptides, and regulation of neuroinflammatory gene expression. In combination with the regulation of related neuroinflammatory genes, UHF-TENS could become a new modality for enhancing the treatment of neuropathic pain in the future.

中文翻译：

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用于缓解神经病理性疼痛和神经调节的超高频经皮神经电刺激

周围压迫性神经病患者的一个具有挑战性的并发症是神经性疼痛。损伤部位过度的神经炎症会加重神经性疼痛并损害功能。目前，经皮神经电刺激 (TENS) 等非侵入性调制技术已显示出治疗前景并取得积极成果。然而，缓解疼痛的潜在调节分子机制仍然复杂且尚未探索。本研究旨在验证超高频（UHF）-TENS对大鼠坐骨神经慢性压迫损伤的治疗效果。通过应用 UHF-TENS 可以减轻机械性异常性疼痛，一次治疗后持续 3 天，两次治疗后持续 4 天，且不会对有髓轴突结构造成额外损伤。整个组织采集时间表分为四个时间点：神经暴露手术后、神经结扎后7天、以及一次UHF治疗后1天和5天。UHF 治疗后，在受损的 DRG 神经元中观察到与疼痛相关的神经肽、MEK、c-Myc、c-FOS、COX2 和 P 物质显着减少。对感觉神经元差异基因表达的 RNA 测序显示，UHF 治疗后 Cables、Pik3r1、Vps4b、Tlr7 和 Ezh2 显着下调，而 Nfkbie 和 Cln3 上调。UHF-TENS 有效且安全地缓解神经性疼痛，且不会造成进一步的神经损伤。背根神经节内疼痛相关神经肽的产生减少提供了治疗益处。UHF-TENS 背后可能的分子机制可能来自 NF-κB 复合物、Toll 样受体 7 和磷酸肌醇 3-激酶/Akt 信号通路的调节。这些结果表明UHF-TENS对大鼠坐骨神经慢性压迫性损伤具有神经调节作用，包括减轻神经性疼痛、改善疼痛相关神经肽以及调节神经炎症基因表达。结合相关神经炎症基因的调节，UHF-TENS可能成为未来增强神经病理性疼痛治疗的新方式。