Fang Junfan, Xu Yashuang, Qiu Mengting, Zhong Liyan, Ye Ru, Guan Lu, Ren Junhui, Guo Zi, He Xiaofen, Shao Xiaomei, Liang Yi, Fang Jianqiao, Du Junying
Department of Neurobiology and Acupuncture Research, The Third School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
Key Laboratory for Research of Acupuncture Treatment and Transformation of Emotional Diseases, The Third School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
Chin Med. 2025 Sep 2;20(1):143. doi: 10.1186/s13020-025-01202-1.
Evidence indicates that the interplay between pain and anxiety poses clinical challenges for the evaluation and management of chronic pain, yet effective therapies for these comorbidities are limited. This study aimed to elucidate the effects and mechanisms of electroacupuncture (EA) on pain-anxiety comorbidities.
Mice injected with Complete Freund's adjuvant (CFA) in the ipsilateral hind paw developed persistent inflammatory pain and anxiety-like behaviors, as assessed by the von Frey, open field, elevated plus maze, and novelty-suppressed feeding tests. EA was administered 12-17d after CFA injection with once daily. rAAV virus and chemogenetics were used to manipulate parvalbumin (PV) interneurons and astrocytes excitation in the anterior cingulate cortex (ACC). Immunofluorescence, morphological analysis, patch clamp and in vivo fiber Ca imaging were used to examine the activation of PV interneurons and astrocytes. The effect of EPCPX (antagonist of A1R) and chemogenetics activated astrocytes on EA analgesia were observed in a subset of mice prior to EA.
EA administration alleviated pain and anxiety-like behaviors in CFA mice, activated PV interneurons, and inhibited astrocytes activation in the ACC. Furthermore, both PV interneurons activation and astrocyte inhibition in the ACC elicited effects similar to those elicited by EA on pain and anxiety. Chemogenetic activation of ACC astrocytes reversed the effects of EA. Additionally, astrocyte activation in the ACC suppressed PV interneurons and induced pain-anxiety like behaviors in mice. Adenosine A1 receptors, crucial for mediating the interaction between astrocytes and PV interneurons in the ACC, were also found to be involved in the effects of EA on pain-anxiety comorbidity.
These findings reveal that EA alleviates the pain and anxiety comorbidity through a potential mechanism involving the activation of PV interneurons, which are modulated by the inhibition of astrocytes in the ACC, thus providing a promising therapeutic strategy for persistent pain and concurrent anxiety.
有证据表明，疼痛与焦虑之间的相互作用给慢性疼痛的评估和管理带来了临床挑战，然而针对这些共病的有效疗法有限。本研究旨在阐明电针（EA）对疼痛-焦虑共病的影响及机制。
通过von Frey、旷场、高架十字迷宫和新奇抑制摄食试验评估，在同侧后爪注射完全弗氏佐剂（CFA）的小鼠出现了持续性炎性疼痛和焦虑样行为。在CFA注射后12 - 17天每天进行一次EA治疗。使用重组腺相关病毒（rAAV）病毒和化学遗传学方法来调控前扣带回皮质（ACC）中小清蛋白（PV）中间神经元和星形胶质细胞的兴奋性。采用免疫荧光、形态学分析、膜片钳和体内光纤钙成像技术检测PV中间神经元和星形胶质细胞的激活情况。在一部分小鼠进行EA治疗前，观察EPCPX（A1R拮抗剂）和化学遗传学激活的星形胶质细胞对EA镇痛作用的影响。
EA治疗减轻了CFA小鼠的疼痛和焦虑样行为，激活了ACC中的PV中间神经元，并抑制了星形胶质细胞的激活。此外，ACC中PV中间神经元的激活和星形胶质细胞的抑制所产生的效果与EA对疼痛和焦虑的作用相似。ACC星形胶质细胞的化学遗传学激活逆转了EA的作用。此外，ACC中星形胶质细胞的激活抑制了PV中间神经元，并在小鼠中诱导出疼痛-焦虑样行为。还发现腺苷A1受体在介导ACC中星形胶质细胞与PV中间神经元之间的相互作用中起关键作用，并且参与了EA对疼痛-焦虑共病的影响。
这些发现揭示，EA通过一种潜在机制减轻疼痛和焦虑共病，该机制涉及激活PV中间神经元，而PV中间神经元受到ACC中星形胶质细胞抑制的调节，从而为持续性疼痛和并发焦虑提供了一种有前景的治疗策略。
