Zhang Hui, Zhai XiaoJing, Zhang WenWen, He Yu, Yu BeiBei, Liu He, Meng XiaoWen, Ji FuHai
Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, 215006, China; Institute of Anesthesiology, Soochow University, Suzhou City, Jiangsu Province, 215006, China; Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, 221002, China.
Jiangsu Province Key Laboratory of Anesthesiology Xuzhou Medical University, Xuzhou City, Jiangsu Province, 221004, China; Department of Pain, The Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, 221002, China.
Exp Cell Res. 2025 Feb 1;445(1):114383. doi: 10.1016/j.yexcr.2024.114383. Epub 2024 Dec 17.
Neuropathic pain, a debilitating condition stemming from nervous system injuries, has profound impacts on quality of life. The medial prefrontal cortex (mPFC) plays a crucial role in the modulation of pain perception and emotional response. This study explores the involvement of Slingshot Homolog 1 (SSH1) protein in neuropathic pain and related emotional and cognitive dysfunctions in a mouse model of spared nerve injury (SNI).
SNI was induced in C57BL/6J mice. SSH1's role was investigated via its overexpression and knockdown using lentiviral vectors in the mPFC. Behavioral assays (thermal and mechanical allodynia, open field test, elevated plus maze, tail suspension test, Y-maze, and novel object recognition were conducted to assess pain sensitivity, anxiety, depression, and cognitive function. Tissue samples underwent Hematoxylin and Eosin staining, Western blotting, immunofluorescence, co-immunoprecipitation, and enzyme-linked immunosorbent assay for inflammatory markers.
SNI mice displayed significant reductions in neuronal density and dendritic integrity in the mPFC, alongside heightened pain perception and emotional disturbances, as compared to sham controls. Overexpression of SSH1 ameliorated these alterations, improving mechanical and thermal thresholds, reducing anxiety and depressive behaviors, and enhancing cognitive performance. Conversely, SSH1 knockdown exacerbated these phenotypes. Molecular investigations revealed that SSH1 modulates pain processing and neuronal health in the mPFC partially through the dephosphorylation of Cofilin and LIM domain kinase 1 (LIMK1), as evidenced by changes in their phosphorylation states and interaction patterns.
SSH1 plays a pivotal role in the modulation of neuropathic pain and associated neuropsychological disturbances in the mPFC of mice. Manipulating SSH1 expression can potentially reverse the neurophysiological and behavioral abnormalities induced by SNI, highlighting a promising therapeutic target for treating neuropathic pain and its complex comorbidities.
神经性疼痛是一种由神经系统损伤引起的使人衰弱的病症，对生活质量有深远影响。内侧前额叶皮质（mPFC）在疼痛感知和情绪反应的调节中起关键作用。本研究在 spared nerve injury（SNI）小鼠模型中探讨了 Slingshot Homolog 1（SSH1）蛋白在神经性疼痛及相关情绪和认知功能障碍中的作用。
在 C57BL/6J 小鼠中诱导 SNI。通过在 mPFC 中使用慢病毒载体对 SSH1 进行过表达和敲低来研究其作用。进行行为学检测（热和机械性异常性疼痛、旷场试验、高架十字迷宫、悬尾试验、Y 迷宫和新物体识别）以评估疼痛敏感性、焦虑、抑郁和认知功能。对组织样本进行苏木精和伊红染色、蛋白质免疫印迹、免疫荧光、免疫共沉淀以及炎症标志物的酶联免疫吸附测定。
与假手术对照组相比，SNI 小鼠的 mPFC 中神经元密度和树突完整性显著降低，同时疼痛感知增强和情绪紊乱。SSH1 的过表达改善了这些改变，提高了机械和热阈值，减少了焦虑和抑郁行为，并增强了认知表现。相反，SSH1 的敲低加剧了这些表型。分子研究表明，SSH1 部分通过对丝切蛋白（Cofilin）和 LIM 结构域激酶 1（LIMK1）的去磷酸化来调节 mPFC 中的疼痛处理和神经元健康，其磷酸化状态和相互作用模式的变化证明了这一点。
SSH1 在调节小鼠 mPFC 中的神经性疼痛及相关神经心理障碍中起关键作用。操纵 SSH1 的表达可能会逆转由 SNI 诱导的神经生理和行为异常，突出了其作为治疗神经性疼痛及其复杂合并症的有前景的治疗靶点。
