Application of ultrahigh frequency transcutaneous electrical nerve stimulation for alleviation of neuropathic pain and neuroinflammation modulation in rat sciatic nerve chronic constriction injury

Abstract

Abstract A challenging complication in patients with peripheral compressive neuropathy is neuropathic pain. Excessive neuroinflammation and neuropeptide buildup at the injury site worsen neuropathic pain and impair function. Currently, non-invasive modulation like transcutaneous electrical nerve stimulation (TENS) showed therapeutic promise with positive results. However, underlying regulatory molecular mechanism for peripheral neuropathic pain remains complex and unexplored. This study aimed to validate the therapeutic effect of ultrahigh frequency (UHF)-TENS in chronic constriction injury of rat sciatic nerve. The efficacy and safety of UHF-TENS were examined including mechanistical exploration. Alleviation of mechanical allodynia was achieved through the application of UHF-TENS, which lasted for 3 days for a one-session therapy, without additional damage on the myelinated axon structure. Significant reduction of pain-related neuropeptides, MEK, c-Myc, c-FOS, COX2, and substance P, were observed in the injured DRG neurons. RNA sequencing of differential gene expression of the sensory neurons revealed a significant downregulation in Cables, Pik3r1, Vps4b, Tlr7, and Ezh2 after nerve injury, while upregulation was observed in Nfkbie and Cln3. UHF-TENS effectively and safely relieved neuropathic pain without causing further nerve damage. The decreased production of pain-related neuropeptides within the DRG neurons provided the therapeutic benefit. Possible molecular mechanisms by UHF-TENS might result from the modulation of the NF-κB complex, toll-like receptor-7, and phosphoinositide 3-kinase/Akt signaling in sensory neurons. This results suggest the neuromodulatory effects of UHF-TENS in rat sciatic nerve chronic constriction injury, in terms of alleviation of neuropathic pain, amelioration of pain-related neuropeptides, and regulation of neuroinflammatory gene expression. In combination with related molecular medication, UHF-TENS would be a new modality to potentiate the treatment of neuropathic pain in the future.