High‐Frequency Spinal Stimulation Suppresses Microglial Kaiso‐P2X7 Receptor Axis‐Induced Inflammation to Alleviate Neuropathic Pain in Rats

Objective Neuropathic 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. Methods We 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. Results We 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. Interpretation HF10 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