• Li Xu, Yu Wang, Yang Jiao, Yulin Huang, Rui Xu, Xiaoping Gu, Wei Zhang, and Zhengliang Ma.
• From the Department of Anesthesiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China.
• Anesth. Analg. 2024 Nov 1; 139 (5): 108610961086-1096.

BackgroundNeuropathic 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.MethodsA 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.ResultsThe 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.ConclusionsNP65 modulates the level of GABAAR-α2 through the CaN-NFATc4 signaling pathway, which may serve as the underlying mechanism of NP.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Anesthesia Research Society.

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