Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado, Boulder, CO, United States.
Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Pain. 2022 Oct 1;163(10):1939-1951. doi: 10.1097/j.pain.0000000000002589. Epub 2022 Jan 24.
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.
动物和人体研究表明，神经损伤前的运动可以预防后期的慢性疼痛，但这种预处理的机制仍不清楚。鉴于运动可急性增加自由基的形成，引发抗氧化剂的补偿，我们假设自愿跑步预处理将通过支持坐骨神经损伤后雄性和雌性大鼠的氧化还原稳态来减轻神经性疼痛。我们表明，6 周的自愿轮跑抑制了慢性缩窄性损伤在两性中诱导的神经性疼痛发展。这种衰减与坐骨神经损伤部位的硝基酪氨酸免疫反应性降低有关-过氧亚硝酸盐的标志物。我们的数据表明，先前的自愿轮跑并没有减少过氧亚硝酸盐前体的产生，因为诱导型一氧化氮合酶和 NADPH 氧化酶 2 的表达水平没有改变。相反，自愿轮跑通过提高超氧化物歧化酶 1 和 2 的表达来增加超氧化物的清除。预防神经性疼痛还与抗氧化反应的主要转录调节因子核因子 E2 相关因子 2（Nrf2）的激活有关。6 周的自愿轮跑增加了坐骨神经损伤部位的 Nrf2 核转位；相比之下，3 周的自愿轮跑未能预防神经性疼痛，对 Nrf2 核转位没有影响。先前自愿轮跑的保护作用是通过 Nrf2 介导的，因为在 6 周的跑步阶段抑制 Nrf2 激活时，两性的抑制作用都被消除。这项研究提供了关于身体活动如何预防神经性疼痛的机制的见解。自愿轮跑的预处理，在神经损伤前终止，可抑制两性后期的神经性疼痛，并且通过 Nrf2-抗氧化信号的激活来调节。
