Nrf2 Activation Mediates Antiallodynic Effect of Electroacupuncture on a Rat Model of Complex Regional Pain Syndrome Type-I through Reducing Local Oxidative Stress and Inflammation.

Xiaojie Li,Xiaomei Shao,Boyi Liu,Junfan Fang,Jie Wang,Jianqiao Fang,Yan Tai,Qimiao Hu,Junying Du,Huimin Nie,Boyu Liu,Chengyu Yin,Sachchida Nand Rai

doi:10.1155/2022/8035109

Abstract

Complex regional pain syndrome type-I (CRPS-I) represents a type of neurovascular condition featured by severe pain in affected extremities. Few treatments have proven effective for CRPS-I. Electroacupuncture (EA) is an effective therapy for pain relief. We explored the mechanism through which EA ameliorates pain in a rat CRPS-I model. The chronic postischemic pain (CPIP) model was established using Sprague-Dawley rats to mimic CRPS-I. We found that oxidative stress-related biological process was among the predominant biological processes in affected hindpaw of CPIP rats. Oxidative stress occurred primarily in local hindpaw but not in the spinal cord or serum of model rats. Antioxidant N-acetyl cysteine (NAC) attenuated mechanical allodynia and spinal glia overactivation in CPIP model rats, whereas locally increasing oxidative stress is sufficient to induce chronic pain and spinal glia overactivation in naive rats. EA exerted remarkable antiallodynia on CPIP rats by reducing local oxidative stress via enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Pharmacological blocking Nrf2 abolished antioxidative and antiallodynic effects of EA. EA reduced spinal glia overactivation, attenuated the upregulation of inflammatory cytokines, reduced the enhanced TRPA1 channel activity in dorsal root ganglion neurons innervating the hindpaws, and improved blood flow dysfunction in hindpaws of CPIP rats, all of which were mimicked by NAC treatment. Thus, we identified local oxidative injury as an important contributor to pathogenesis of animal CRPS-I model. EA targets local oxidative injury by enhancing endogenous Nrf2-mediated antioxidative mechanism to relieve pain and inflammation. Our study indicates EA can be an alternative option for CRPS-I management.

Highlights

Complex regional pain syndrome type-I (CRPS-I) is a debilitating pain condition that usually affects the extremities of the patients [1]
We and others contributed to this field by identifying a number of pivotal mechanisms contributing to CRPS-I pathogenesis, including peripheral NMDA and TRPA1/TRPV1 channels, the chemokine CXCL12/CXCR4 signaling, NLRP3 inflammasome, and CSF1 in the spinal cord [10,11,12,13,14]
We aimed to explore potential genes or biological process involved in mediating the pain response of chronic postischemic pain (CPIP) model rats

Summary

Introduction

Complex regional pain syndrome type-I (CRPS-I) is a debilitating pain condition that usually affects the extremities of the patients [1]. It can be triggered by an initial injury, including surgery, ischemia, and fracture, and can progress into a chronic stage that significantly affects the patients’ daily activity [2, 3]. The CPIP model exhibited a number of key Oxidative Medicine and Cellular Longevity features that mimic clinical symptoms of CRPS-I, such as chronic thermal, mechanical, and chemical pain hypersensitivities in affected hind limbs, followed with microvascular injury and abnormalities in regional blood flow [8, 9]. We and others contributed to this field by identifying a number of pivotal mechanisms contributing to CRPS-I pathogenesis, including peripheral NMDA and TRPA1/TRPV1 channels, the chemokine CXCL12/CXCR4 signaling, NLRP3 inflammasome, and CSF1 in the spinal cord [10,11,12,13,14]

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