Pulsed radiofrequency attenuates mechanical hypersensitivity in neuropathic pain rats by activating the Nrf2-regulated CaMKII/NF-κB signaling pathway

Background: Pulsed radio frequency (PRF) is a novel therapeutic method for treating neuropathic pain (NP). This study aimed to elucidate the role of NF-E2-Related Factor 2 (Nrf2) in pain signal transduction associated with the mechanism of PRF analgesia action.

Methods: Establishing the spared nerve injury (SNI) rat model and PRF treated model (45 V5 minutes, 45 V15 minutes, 90 V15 minutes), the authors used behavioral testing, western blotting, and enzyme-linked immunosorbent assay methods to verify the analgesic effect of PRF. Secondly, behavioral testing and biomarker analyses were performed in SNI rats that received intrathecally injected calmodulin-dependent protein kinase type II (CaMKII) antagonist, Calcitonin gene-related peptide (CGRP) antagonist, or Nrf2 activator.

Results: High-voltage, long-duration PRF significantly alleviated mechanical hypersensitivity in SNI rats. On the 9th day after PRF therapy, Nrf2 and heme oxygenase 1 (HO-1) expression were markedly upregulated, otherwise, CaMKII, phosphorylated level of CaMKII (p-CaMKII), NF-kappa B (NF-κB) p65, and CGRP content were downregulated. Otherwise, intrathecal CaMKII antagonist, CaMKII, p-CaMKII expression, and CGRP content were decreased. Intrathecal Nrf2 activator led to overexpression of Nrf2, while the expression of p-CaMKII, CaMKII, NF-κB p65, and CGRP content were significantly reduced. Additionally, administration of intrathecal CGRP antagonist decreased CGRP content. After the intrathecal injection of these three drugs, the SNI rats' mechanical hypersensitivity was ameliorated.

Conclusions: A novel therapeutic method employing high-voltage, long-duration PRF markedly ameliorated neuropathy, relieving central sensitization by activating the Nrf2 expression-regulated CaMKII/NF-κB signaling pathway blocking CA²⁺ pain signal transmission.

Calmodulin-dependent protein kinase type II; Central Sensitization; NF-E2-Related Factor 2; NF-Kappa B; Neuropathic Pain; Pulsed Radiofrequency.