Fang Jaden Y, Yamamoto Hideaki, Romman Adam, Koutrouvelis Aristides P, Yamamoto Satoshi
Anesthesiology, University of Texas Medical Branch, Galveston, USA.
Biological Sciences, University of California San Diego, San Diego, USA.
Cureus. 2025 Jun 8;17(6):e85567. doi: 10.7759/cureus.85567. eCollection 2025 Jun.
Spinal cord stimulation (SCS) is a widely used neuromodulation therapy for chronic neuropathic pain, including failed back surgery syndrome and complex regional pain syndrome, but its mechanisms of action remain incompletely defined. This systematic review examined 40 unique preclinical animal studies to classify spinal mechanisms underlying SCS-induced analgesia. A comprehensive database search including PubMed, MEDLINE, and Cochrane was conducted through October 2024 following PRISMA guidelines. Studies were included if they investigated SCS effects on spinal cord cells such as dorsal horn neurons, dorsal column fibers, interneurons, or glia, and excluded if they involved brain structures. Mechanisms were categorized into three domains: inhibition of ascending nociceptive transmission (n = 22), enhancement of descending inhibition (n = 5), and neuroimmune modulation via microglial and astrocytic pathways (n = 13). SCS was shown to enhance inhibitory signaling, reduce excitatory neurotransmitter release, and modulate dorsal horn activity at molecular and electroneurophysiological levels. It also promoted descending inhibition via serotonergic, opioid, and cholinergic mechanisms. Neuroimmune effects included suppression of proinflammatory cytokines and modulation of microglial and astrocyte activity, often through MAPK-related signaling. Risk of bias was assessed using the SYRCLE tool, revealing a variable methodological quality. The experimental frameworks utilized either neuropathic or inflammatory pain models, which exhibit substantial clinical relevance to chronic pain phenomena. Collectively, these findings suggest that SCS exerts analgesic effects through integrated spinal mechanisms involving neuronal inhibition, descending modulation, and glial suppression. However, the exclusive reliance on animal models limits direct clinical translatability, and future studies are needed to validate whether these mechanistic insights reliably extend to human physiology and therapeutic outcomes. This review provides a mechanistic framework to guide translational strategies for optimizing SCS therapy.
脊髓刺激（SCS）是一种广泛应用于慢性神经性疼痛的神经调节疗法，包括腰椎手术失败综合征和复杂性区域疼痛综合征，但其作用机制仍未完全明确。本系统评价对40项独特的临床前动物研究进行了分析，以分类SCS诱导镇痛的脊髓机制。按照PRISMA指南，在2024年10月之前对包括PubMed、MEDLINE和Cochrane在内的综合数据库进行了检索。如果研究调查了SCS对脊髓细胞（如背角神经元、背柱纤维、中间神经元或神经胶质细胞）的影响，则纳入研究；如果研究涉及脑结构，则排除。机制分为三个领域：抑制伤害性上行传导（n = 22）、增强下行抑制（n = 5）以及通过小胶质细胞和星形胶质细胞途径进行神经免疫调节（n = 13）。研究表明，SCS在分子和电神经生理学水平上增强抑制性信号传导、减少兴奋性神经递质释放并调节背角活动。它还通过5-羟色胺能、阿片样物质能和胆碱能机制促进下行抑制。神经免疫效应包括抑制促炎细胞因子以及调节小胶质细胞和星形胶质细胞的活性，这通常通过丝裂原活化蛋白激酶相关信号传导来实现。使用SYRCLE工具评估偏倚风险，结果显示方法学质量存在差异。实验框架采用了神经性或炎症性疼痛模型，这些模型与慢性疼痛现象具有重要的临床相关性。总体而言，这些发现表明SCS通过涉及神经元抑制、下行调节和神经胶质抑制的综合脊髓机制发挥镇痛作用。然而，仅依赖动物模型限制了直接的临床可转化性，未来需要进行研究以验证这些机制性见解是否能可靠地扩展到人体生理学和治疗结果。本综述提供了一个机制框架，以指导优化SCS治疗的转化策略。
