Spinal Mechanisms of Pain Modulation by Spinal Cord Stimulation: A Systematic Review.

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.