Dang Thu Nguyen, Van Cuong Nguyen, Ochi Ryosuke, Kuwamura Hiroki, Kurose Tomoyuki, Nakamura Yoki, Hisaoka-Nakashima Kazue, Morioka Norimitsu, Nishijo Hisao, Fujita Naoto, Urakawa Susumu
Department of Neurorehabilitation and Emotional Science, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan.
Department of Anesthesiology, Military Hospital 103, Vietnam Military Medical University, No. 261 Phung Hung Street, Ha Dong District, Hanoi 12108, Viet Nam.
Neurobiol Pain. 2025 Feb 27;18:100181. doi: 10.1016/j.ynpai.2025.100181. eCollection 2025 Jul-Dec.
Anxiety-like behavior often emerges in the later stages of neuropathic pain, exacerbating the pain condition and potentially involving parvalbumin-positive (PV) neurons. This study aimed to investigate the effects of voluntary exercise on neuropathic pain-induced anxiety and its relationship with PV neurons, perineuronal nets (PNNs, labeled with Wisteria floribunda agglutinin [WFA]), and microglia in the corticolimbic regions. Male Wistar rats with partial sciatic nerve ligation (PSL) were given access to running wheels either from 3 days (early voluntary exercise [EEx]) or from 4 weeks (late voluntary exercise [LEx]) postoperatively. Nociceptive behaviors were assessed using the von Frey and acetone tests, while anxiety-like behaviors were assessed using the open field and elevated plus maze tests. Brain sections were histologically analyzed using immunohistochemistry and immunofluorescence 8 weeks post-surgery. Both early and late exercise partially restored the paw withdrawal thresholds and the arousal response. PSL-EEx rats did not exhibit anxiety-like behaviors. PSL-LEx rats transiently showed anxiety-like behaviors, but these were eradicated by exercise. PSL altered PV neurons and PNNs in specific corticolimbic subregions. Notably, voluntary exercise restored the densities of PV-strong WFA neurons in the basolateral amygdala, PV-WFA, and PV-WFA neurons in the anterior cingulate cortex, and PV-WFA neurons in the hippocampal cornu ammonis 1. These changes correlated with reduced anxiety-like behaviors. Exercise modulated PSL-induced microglial activation and interacted differently with these neurons. These findings suggest that voluntary exercise prevents and eliminates chronic pain-induced anxiety through neuronal mechanisms other than analgesic effects, potentially involving PV neurons, PNNs, and microglia in the corticolimbic subregions.
焦虑样行为常出现在神经性疼痛的后期，会加剧疼痛状况，并且可能与小白蛋白阳性（PV）神经元有关。本研究旨在探讨自愿运动对神经性疼痛诱发的焦虑的影响及其与PV神经元、神经元周围网（PNNs，用紫藤凝集素[WFA]标记）和皮质边缘区域小胶质细胞的关系。对部分坐骨神经结扎（PSL）的雄性Wistar大鼠，术后3天（早期自愿运动[EEx]）或4周（晚期自愿运动[LEx]）开始让其使用跑步轮。使用von Frey和丙酮试验评估伤害感受行为，同时使用旷场试验和高架十字迷宫试验评估焦虑样行为。术后8周，采用免疫组织化学和免疫荧光对脑切片进行组织学分析。早期和晚期运动均部分恢复了爪部撤离阈值和觉醒反应。PSL-EEx大鼠未表现出焦虑样行为。PSL-LEx大鼠短暂表现出焦虑样行为，但运动消除了这些行为。PSL改变了特定皮质边缘亚区域的PV神经元和PNNs。值得注意的是，自愿运动恢复了基底外侧杏仁核中PV强WFA神经元、前扣带回皮质中PV-WFA和PV-WFA神经元以及海马角回1中PV-WFA神经元的密度。这些变化与焦虑样行为减少相关。运动调节了PSL诱导的小胶质细胞激活，并与这些神经元有不同的相互作用。这些发现表明，自愿运动通过镇痛作用以外的神经元机制预防和消除慢性疼痛诱发的焦虑，可能涉及皮质边缘亚区域的PV神经元、PNNs和小胶质细胞。
