Kilohertz High-Frequency Alternating Current Ameliorate Hyperalgesia and Inhibit the Glial Activation by Modulating TRPV1 and NMDAR2B Signaling Pathways in Chronic Constriction Injury of Sciatic Nerve Mice

Abstract

Abstract In recent years, there has been increasing interest in the use of kilohertz frequency alternating current (KHFAC) to block peripheral nerves. However, there is still a lack of direct data and mechanistic studies on the treatment of neuropathic pain by KHFAC. Based on this, we applied a high-frequency bipolar rectangular stimulus pulse to chronic constriction injury of sciatic nerve mice (CCI), and explored the optimal stimulation frequency and current by recording the compound muscle action potential (CMAP). We found that KHFAC could significantly alleviate the mechanical and thermal allodynia in neuropathic pain mice without any effect of movement function following 7 days of high-frequency electrical stimulation of the sciatic nerve. KHFAC inhibited the expression of TRPV1 and NMDAR2B, which could also inhibit the activation of astrocytes and microglia in the spinal cord. The administration of TRPV1 pathway activator could partially reverse the antinociceptive effects of KHFAC, while TRPV1 pathway inhibitor could achieve analgesic effects similar to KHFAC. Therefore, we believe that KHFAC inhibits the activation of spinal dorsal horn glial cells, especially astrocytes and microglia, through nociceptive afferent fibers by inhibiting the activation of TRPV1/NMDAR2B signaling pathway. In summary, KHFAC has a potential to be a novel intervention for the treatment of neuropathic pain.