Involvement of Spinal Neuroplastin 65 in Neuropathic Pain by GABAA Receptor α2 Subunit Regulation.

IF 4.6 2区医学 Q1 ANESTHESIOLOGY

Anesthesia and analgesia Pub Date : 2024-11-01 Epub Date: 2024-03-20 DOI:10.1213/ANE.0000000000006964

Li Xu, Yu Wang, Yang Jiao, Yulin Huang, Rui Xu, Xiaoping Gu, Wei Zhang, Zhengliang Ma

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引用次数: 0

Abstract

Background: Neuropathic pain (NP) is a highly challenging condition with complex pathological mechanisms, and the spinal gamma aminobutyric acid A receptor receptor plays a crucial role in its progression. Recent studies have revealed a potential interaction between neuroplastin 65 (NP65) and gamma aminobutyric acid A receptor α2 subunit (GABAAR-α2) on the cell surface. We hypothesize that NP65 is involved in the pathogenesis of NP by regulating the level of GABAAR-α2.

Methods: A chronic constrictive injury (CCI) pain model was established in male Sprague-Dawley rats to verify the change in spinal NP65 expression. Alterations in pain behavior and GABAAR-α2 protein expression were observed after intrathecal injection of NP65 overexpressing adeno-associated virus (AAV) in CCI rats. In vitro investigations on Neuroblastoma 2a cells, the effect of NP65 on GABAAR-α2 expression via the calcineurin-nuclear factor of activated T-cell 4 (CaN-NFATc4) signaling pathway was evaluated by manipulating NP65 expression.

Results: The expression level of NP65 protein and mRNA in the CCI group were significantly decreased ( P < .05; analysis of variance [ANOVA]). After intrathecal injection of NP65, overexpression of AAV and pain behavior in CCI rats were significantly alleviated, and levels of GABAAR-α2 were upregulated. In vitro experiments verified alterations in the expression of GABAAR-α2, CaN, and phosphorylated NFATc4 on the application of NP65 with plasmid or small interfering RNA, respectively. After the application of the specific CaN inhibitor cyclosporine A (CsA), the changes in NP65 expression did not produce subsequent alterations in the expression of GABAAR-α2, CaN, or phosphorylated NFATc4 proteins.

Conclusions: NP65 modulates the level of GABAAR-α2 through the CaN-NFATc4 signaling pathway, which may serve as the underlying mechanism of NP.

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脊髓神经弹性蛋白 65 通过 GABAA 受体 α2 亚基调节参与神经性疼痛的发生

背景：神经病理性疼痛（NP）是一种病理机制复杂的高难度疾病，脊髓γ氨基丁酸A受体在其发展过程中起着至关重要的作用。最近的研究发现，神经弹性蛋白 65（NP65）与细胞表面的γ-氨基丁酸 A 受体α2 亚基（GABAAR-α2）之间存在潜在的相互作用。我们假设 NP65 通过调节 GABAAR-α2 的水平参与了 NP 的发病机制：方法：在雄性 Sprague-Dawley 大鼠中建立慢性收缩性损伤（CCI）疼痛模型，以验证脊髓 NP65 表达的变化。方法：在雄性 Sprague-Dawley 大鼠体内注射过表达 NP65 的腺相关病毒（AAV）后，观察到 CCI 大鼠疼痛行为和 GABAAR-α2 蛋白表达的改变。在神经母细胞瘤 2a 细胞的体外研究中，通过操纵 NP65 的表达，评估了 NP65 通过钙神经素-活化 T 细胞核因子 4（CaN-NFATc4）信号通路对 GABAAR-α2 表达的影响：结果：CCI 组 NP65 蛋白和 mRNA 的表达水平显著下降（P < .05；方差分析 [ANOVA]）。鞘内注射 NP65 后，AAV 的过表达和 CCI 大鼠的疼痛行为明显缓解，GABAAR-α2 水平上调。体外实验分别验证了质粒或小干扰 RNA 应用 NP65 时 GABAAR-α2、CaN 和磷酸化 NFATc4 表达的改变。在使用特异性 CaN 抑制剂环孢素 A（CsA）后，NP65 表达的变化并不会导致 GABAAR-α2、CaN 或磷酸化 NFATc4 蛋白表达的随之改变：结论：NP65 通过 CaN-NFATc4 信号通路调节 GABAAR-α2 的水平，这可能是 NP 的基本机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Anesthesia and analgesia 医学-麻醉学

CiteScore

9.90

自引率

7.00%

发文量

817

审稿时长

2 months

期刊介绍： Anesthesia & Analgesia exists for the benefit of patients under the care of health care professionals engaged in the disciplines broadly related to anesthesiology, perioperative medicine, critical care medicine, and pain medicine. The Journal furthers the care of these patients by reporting the fundamental advances in the science of these clinical disciplines and by documenting the clinical, laboratory, and administrative advances that guide therapy. Anesthesia & Analgesia seeks a balance between definitive clinical and management investigations and outstanding basic scientific reports. The Journal welcomes original manuscripts containing rigorous design and analysis, even if unusual in their approach.