N-Demethylsinomenine Relieves Neuropathic Pain in Male Mice Mainly via Regulating α2-Subtype GABAA Receptors

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-01-03 DOI:10.1111/cns.70197

Weiwei Rong, Xunjia Qian, Yujian Yin, Yipeng Gu, Weiyi Su, Jie-Jia Li, Yue Xu, Hongyan Zhu, Junxu Li, Qing Zhu

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Abstract

Aims

N-Demethylsinomenine (NDSM) demonstrates good analgesic efficacy in preclinical pain models. However, how NDSM exerts analgesic actions remains unknown.

Methods

We examined the analgesic effects of NDSM using both pain-evoked and pain-suppressed behavioral assays in two persistent pain models. Then western blot assay and immunofluorescence staining were used to investigate the effects of NDSM on the expression of the GABA_A receptor α2 subunit (GABRA2) and inflammatory factors in the spinal cord and brain tissues of male spared nerve injury (SNI) mice. Finally, the individual subtypes of GABA_ARs (α1, α2, α3, and α5) were respectively silenced by viral-mediated knockdown to explore the involvement of subtypes of GABA_ARs in the effects of NDSM on the pain-like behaviors in male SNI mice.

Results

NDSM demonstrated significant analgesic effects against chronic pain both in pain-evoked and pain-suppressed behavioral assays. NDSM treatment significantly reversed the SNI induced down-regulation of GABRA2 and up-regulation of TNF-α and IL-1β. The analgesic effects of NDSM were completely blocked by silencing GABRA2 or partially blocked by silencing GABRA3.

Conclusion

This study provided the first evidence that the analgesic effects of NDSM are mediated primarily by GABRA2 and partially by GABRA3, and the inhibition of neuroinflammation also contributes to the analgesic effects of NDSM.

Abstract Image

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n -去甲基青藤碱主要通过调节α2亚型GABAA受体缓解雄性小鼠神经性疼痛。

目的：N-去甲西诺明（NDSM）在临床前疼痛模型中表现出良好的镇痛效果。然而，NDSM 是如何发挥镇痛作用的仍是未知数：方法：我们在两种持续性疼痛模型中使用疼痛诱发和疼痛抑制行为测定法研究了 NDSM 的镇痛效果。方法：我们在两种持续性疼痛模型中使用疼痛诱发和疼痛抑制行为实验研究了 NDSM 的镇痛作用，然后使用 Western 印迹分析和免疫荧光染色研究了 NDSM 对雄性幸免神经损伤（SNI）小鼠脊髓和脑组织中 GABAA 受体 α2 亚基（GABRA2）和炎症因子表达的影响。最后，通过病毒介导的基因敲除分别沉默了GABAARs的各个亚型（α1、α2、α3和α5），以探讨GABAARs亚型参与NDSM对雄性SNI小鼠疼痛样行为的影响：结果：在疼痛诱发和疼痛抑制行为试验中，NDSM对慢性疼痛均表现出明显的镇痛效果。NDSM能明显逆转SNI诱导的GABRA2下调和TNF-α和IL-1β上调。沉默GABRA2可完全阻断NDSM的镇痛作用，沉默GABRA3可部分阻断NDSM的镇痛作用：该研究首次证明了NDSM的镇痛作用主要由GABRA2介导，部分由GABRA3介导，而且神经炎症的抑制也有助于NDSM的镇痛作用。

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

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.