Preconditioning by Voluntary Wheel Running Attenuates Later Neuropathic Pain via Nuclear Factor E2-Related Factor 2 Antioxidant Signaling in Rats

Authors

Suzanne M Green-Fulgham
Michael E Harland
Jayson B Ball
Jiahe Li
Michael J Lacagnina
Heather D'Angelo
Renee A Dreher
Kendal F Willcox
Sabina A Lorca
Andrew J Kwilasz
Steven F Maier
Linda R Watkins
Peter M Grace

Publication Date

10-1-2022

Journal

Pain

Abstract

Animal and human studies have shown that exercise prior to nerve injury prevents later chronic pain, but the mechanisms of such preconditioning remain elusive. Given that exercise acutely increases the formation of free radicals, triggering antioxidant compensation, we hypothesized that voluntary running preconditioning would attenuate neuropathic pain by supporting redox homeostasis after sciatic nerve injury in male and female rats. We show that 6 weeks of voluntary wheel running suppresses neuropathic pain development induced by chronic constriction injury across both sexes. This attenuation was associated with reduced nitrotyrosine immunoreactivity-a marker for peroxynitrite-at the sciatic nerve injury site. Our data suggest that prior voluntary wheel running does not reduce the production of peroxynitrite precursors, as expression levels of inducible nitric oxide synthase and NADPH oxidase 2 were unchanged. Instead, voluntary wheel running increased superoxide scavenging by elevating expression of superoxide dismutases 1 and 2. Prevention of neuropathic pain was further associated with the activation of the master transcriptional regulator of the antioxidant response, nuclear factor E2-related factor 2 (Nrf2). Six weeks of prior voluntary wheel running increased Nrf2 nuclear translocation at the sciatic nerve injury site; in contrast, 3 weeks of prior wheel running, which failed to prevent neuropathic pain, had no effect on Nrf2 nuclear translocation. The protective effects of prior voluntary wheel running were mediated by Nrf2, as suppression was abolished across both sexes when Nrf2 activation was blocked during the 6-week running phase. This study provides insight into the mechanisms by which physical activity may prevent neuropathic pain. Preconditioning by voluntary wheel running, terminated prior to nerve injury, suppresses later neuropathic pain in both sexes, and it is modulated through the activation of Nrf2-antioxidant signaling.

Keywords

Animals, Antioxidants, Female, Hyperalgesia, Male, Motor Activity, NADPH Oxidase 2, NF-E2-Related Factor 2, Neuralgia, Nitric Oxide Synthase Type II, Peripheral Nerve Injuries, Peroxynitrous Acid, Rats, Rats, Sprague-Dawley, Sciatic Neuropathy, Superoxides

Comments

PMID: 35486864