Gallic acid alleviates visceral hyperalgesia following maternal separation in mice by inhibiting EphrinB2/EphB2 signaling mediated activation of neurons and glial cells

作者：Shufen Guo, Yu Wang, Han Zheng, Hong-qin Tu, Yaming Xi, Dan Li, Zhengliang Ma, Wei Zhang, Jiaping Ruan · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1698744 · 被引用次数：1 · 研究领域：Pain Mechanisms and Treatments、Axon Guidance and Neuronal Signaling、Neuropeptides and Animal Physiology

Background: Early life stress (ELS) causes functional gastrointestinal issues linked to visceral hyperalgesia. Activation of spinal neurons and glial cells is key to the development and persistence of visceral hyperalgesia. Our previous research has shown that EphrinB2/EphB2 signaling in the spinal cord facilitates this hyperalgesia through neuron and glial cell activation. Gallic acid (GA), a natural compound with recognized anti-inflammatory and analgesic effects, may attenuate visceral hyperalgesia. This study investigates whether GA mitigates visceral hyperalgesia induced by ELS in mice via inhibiting EphrinB2/EphB2-mediated activation of neurons and glial cells. Methods: We employed a maternal separation (MS)-induced ELS model and recorded abdominal withdrawal reflex (AWR) scores following colorectal distension (CRD) in adult mice. Molecular docking analysis was used to evaluate the binding stability of GA with the EphrinB2-EphB2 complex or EphrinB2 alone. After CRD, we assessed EphrinB2 and EphB2 expression, glial and neuronal activation, and synaptic plasticity in the spinal cord of MS mice, with or without GA treatment. C-fos levels were measured via immunohistochemistry, and protein expression was quantified by Western blotting. EphrinB2/EphB2 co-expression with neurons or glial cells was examined by double-labeling, and a 3D reconstruction confirmed cell type-specific expression. Results: Molecular docking confirmed that GA binds stably to EphrinB2-EphB2 complex or ...