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内侧前额叶皮层GluN2A与GluN2B亚基在慢性疼痛继发焦虑/抑郁样行为中的差异化作用

丁佳俐, 杨惠然, 张玉秋, 曹红^*

复旦大学附属静安区中心医院转化神经科学平台，脑科学研究院，脑功能和脑疾病全国重点实验室，教育部脑科学前沿中心，上海 200032

摘要

本文旨在研究慢性压迫眶下神经(chronic constriction injury of infraorbital nerve, CION)诱导的小鼠疼痛及焦虑/抑郁样行为中，内侧前额叶皮层(medial prefrontal cortex, mPFC) N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptor, NMDAR)不同亚基(GluN2A与GluN2B)及其下游信号通路的差异化作用。采用CION手术建立三叉神经病理性疼痛小鼠模型，行为学测试评估其疼痛阈值及焦虑/抑郁样行为；采用Western blot 检测mPFC脑区GluN2A、GluN2B蛋白表达及ERK/mTOR信号通路关键蛋白变化；并通过mPFC脑区微量注射GluN2A拮抗剂(PEAQX)和GluN2B拮抗剂(Ifenprodil)探究其行为学效应及分子机制。结果显示：CION 可引起小鼠持续性疼痛和焦虑/抑郁样行为，上调mPFC 脑区GluN2B 的表达；与溶剂对照组相比，GluN2A拮抗剂PEAQX显著改善小鼠的焦虑/抑郁样行为，对疼痛无明显影响；GluN2B拮抗剂Ifenprodil 可显著缓解小鼠的疼痛和抑郁样行为，对小鼠焦虑样行为无明显作用。Western blot 分析显示，PEAQX能显著增加磷酸化ERK1/2 的表达，降低总ERK1/2 蛋白的表达，而Ifenprodil 能降低mTOR总蛋白表达，两者对磷酸化mTOR的表达均无显著影响。综上所述，mPFC脑区GluN2A与GluN2B亚基分别通过不同胞内信号通路对小鼠疼痛和焦虑/抑郁样行为发挥差异化作用。本研究为理解慢性疼痛与情感障碍共病的机制提供了新的视角，并为靶向NMDAR特定亚基的治疗策略提供了实验依据。

关键词： 慢性疼痛; 焦虑/抑郁; GluN2A; GluN2B; 内侧前额叶皮层

Differential effects of GluN2A and GluN2B subunits in the medial prefrontal cortex on chronic pain and anxiety/depressive-like behaviors

DING Jia-Li, YANG Hui-Ran, ZHANG Yu-Qiu, CAO Hong^*

Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China

Abstract

This study aimed to investigate the differential roles of GluN2A and GluN2B subunits of N-methyl-D-aspartate receptor (NMDAR) in the medial prefrontal cortex (mPFC) and their downstream signaling pathways in a mouse model of chronic constrictive injury of the infraorbital nerve (CION)-induced pain and anxiety/depression-like behaviors. A mouse model of trigeminal neuropathic pain was established under CION surgery. Behavioral tests were conducted to assess mechanical thresholds and anxiety/ depression-like behaviors. The protein expression levels of GluN2A, GluN2B, ERK and mTOR in the mPFC were detected by Western blot. GluN2A antagonist (PEAQX) and GluN2B antagonist (Ifenprodil) were microinjected into the mPFC to observe their behavioral effects and underlying molecular mechanisms. CION mice developed persistent pain and anxiety/depression-like behaviors, accompanied by increased GluN2B expression in the mPFC. Behavioral results showed that compared with the vehicle group, GluN2A antagonist PEAQX ameliorated anxiety/depression-like behaviors, but not pain hyperalgesia. However, GluN2B antagonist Ifenprodil significantly alleviated pain and depressive-like symptoms instead of anxiety-like behaviors. Western blot analysis revealed that PEAQX significantly increased the expression of phosphorylation of ERK1 and ERK2, while reduced the expression of both total ERK1 and total ERK2. On the other hand, Ifenprodil decreased the expression of total mTOR protein. Neither antagonist had a significant effect on phospho-mTOR levels. Taken together, our findings suggest that GluN2A and GluN2B subunits in the mPFC differentially contribute to chronic pain and anxiety/depressive-like behaviors through their respective intracellular signaling. This study provides novel insights into the mechanisms underlying chronic pain and emotional comorbidity, and offers experimental evidence for developing targeted therapeutic strategies against specific NMDAR subunits.

Key words: chronic pain; anxiety/depression; GluN2A; GluN2B; medial prefrontal cortex

收稿日期：　　录用日期：

通讯作者：曹红　　E-mail:

DOI: 10.13294/j.aps.2025.0107

引用本文：

丁佳俐, 杨惠然, 张玉秋, 曹红. 内侧前额叶皮层GluN2A与GluN2B亚基在慢性疼痛继发焦虑/抑郁样行为中的差异化作用[J]. 生理学报 2026; 78 (1): 195-206.

DING Jia-Li, YANG Hui-Ran, ZHANG Yu-Qiu, CAO Hong. Differential effects of GluN2A and GluN2B subunits in the medial prefrontal cortex on chronic pain and anxiety/depressive-like behaviors. Acta Physiol Sin 2026; 78 (1): 195-206 (in Chinese with English abstract).