Inactivation of Kaiso-P2X7R as a key mechanism for high frequency spinal cord stimulation to mitigate inflammatory response in neuropathic pain

Abstract

Neuropathic pain, caused by a lesion or disease affecting the somatosensory system, is an important clinical entity and has substantial impacts on patients’ quality of life, as well as high economic burdens on individuals and society. Although many drugs have been developed based on various molecular mechanisms of neuropathic pain, the treatment outcomes are unsatisfactory. Epidural spinal cord stimulation (SCS) is an emerging physical therapy for chronic pain, which can be divided into Conventional SCS (Con SCS) and 1-10 kHz High-frequency SCS (HF10 SCS). HF10 SCS exhibits more efficient and prolonged analgesic effects compared to Con SCS. As this stimulation approach has just been approved, the molecular mechanisms underlying the analgesic effects are still unclear. Therefore, it is critical to understand the underlying mechanisms of these existing methods and lay the foundation for better therapeutic applications of neuromodulation in the future. We established a new strategy for HF10 SCS with optimized frequency and stimulation duration, which produced long-lasting pain relief when compared to Con SCS. To explore the differential regulatory axis between Con SCS and HF10 SCS, we performed transcriptome analysis followed by functional validation. HF10 SCS significantly suppressed inflammatory progression and favored M2-type microglial polarization. In addition, we found that transcriptional factor Kaiso was specifically downregulated by HF10 SCS, whereas restoration of Kaiso in HF10 SCS resulted in early pain refractoriness, and activation of inflammatory signaling and P2X7R, which are required for pain production and implicated in M1 microglial polarization. On the other hand, the knockdown of P2X7R prolonged the analgesic effects of Con SCS without affecting Kaiso expression. In summary, our data demonstrate that Kaiso-P2X7R-microglial M1/M2 shift is the key regulatory axis that determines the inflammatory response to neuropathic pain, and HF10 SCS exhibits better analgesic effects than Con SCS via specific inactivation of the Kaiso-P2X7R-microglial M1/M2 axis. These findings provide a clinical basis and guidance for patients who undergo neuromodulation therapy to treat chronic pain.