1. 2025;28;E371-E384Spinal Cord Stimulation for Chronic Neuropathic Pain: Research Progress in Molecular and Circuit Mechanisms
   Narrative Review
   Yi Kang, MD, Yidan Tang, PhD, Jun Gao, PhD, Yong Qiu, MD, Weishuang Kong, PhD, Tao Zhu, MD, and Guo Chen, MD.

BACKGROUND: Spinal cord stimulation (SCS) is an effective surgical intervention for treating chronic neuropathic pain conditions that are refractory to other management options, such as opioids, physical therapy, nerve blocks, or radiofrequency ablation. It is currently clinically approved as the main therapeutic procedure for persistent low back pain. As we understand these mechanisms better, SCS could have novel clinical applications. For this reason, an accurate understanding of research progress into the molecular and circuit mechanisms of SCS is indispensable for enhancing its effectiveness, safety, and future applications.

OBJECTIVES: This review aims to systematically discuss the molecular mechanisms of spinal cord electrical stimulation, from its action sites and transmitter interactions to the supraspinal circuit, to reveal the biological basis behind these mechanisms further and provide a more solid theoretical foundation and scientific basis for the clinical application of SCS.

STUDY DESIGN: Narrative review.

METHODS: Our research was conducted in PubMed, Ovid MEDLINE, and Embase. Boolean operators were used to combine MeSH (Medical Subject Headings) terms and keywords such as “spinal cord stimulation,” “chronic neuropathic pain,” “electric stimulation therapy,” “analgesic mechanism,” “spinal cord dorsal horn,” “central sensitization,” “neural circuits,” and “neurotransmitter function”.

RESULTS: Numerous retrospective clinical studies and randomized controlled trials have yielded results supporting the remarkable efficacy and broad development prospects of SCS. However, the effectiveness and safety of SCS in certain diseases are still insufficiently studied, and the related molecular mechanisms are not well developed. We present a comprehensive, up-to-date overview and elaboration of the neurophysiological, biochemical, anti-inflammatory, and neurocirculatory mechanisms that have been associated with the use of spinal cord electrical stimulation for treating chronic pain.

LIMITATIONS: There exists an inconsistency in SCS animal experimental models.

CONCLUSIONS: Our findings from available studies include the molecular mechanisms involved in SCS on chronic pain, new paradigms for spinal cord electrical stimulation therapy, and explain their underlying biological processes, as well as the pros and cons of SCS in terms of its effectiveness in clinical use. With a better understanding of SCS’s mechanisms, we may gain a more in-depth understanding of the current insights about the analgesic mechanisms of action underlying SCS for chronic neuropathic pain treatment.

KEY WORDS: Spinal cord stimulation, analgesic mechanism, chronic neuropathic pain, electric stimulation therapy, spinal cord dorsal horn, central sensitization, neural circuits, neurotransmitter function