海马大麻素 2 型受体通过小胶质细胞 DUSP6 通路缓解慢性神经病理性疼痛诱发的大鼠认知障碍

IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Lichi Xu, Afang Zhu, Shuxiang Xu, Jiale Zhao, Shujia Song, He Zhu, Yuguang Huang
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引用次数: 0

摘要

大约 50% 的慢性神经病理性疼痛患者会出现认知障碍,这对他们的生活质量产生了负面影响。大麻素 2 型受体(CB2R)可能参与了海马认知过程。然而,它在慢性神经病理性疼痛引起的认知障碍中的作用仍然难以捉摸。研究人员利用裸神经损伤(SNI)诱导大鼠产生慢性神经病理性疼痛,并采用新物体识别试验和Y迷宫试验评估大鼠的认知功能。我们利用免疫荧光、Western 印迹和立体定向海马显微注射来阐明潜在的机制。我们观察到,SNI 大鼠的机械痛阈值降低,认知功能受损。与此同时,海马小胶质细胞倾向于发挥促炎功能。值得注意的是,CB2R 的表达没有发生变化。然而,内源性配体 AEA 和 2-AG 的下调是显而易见的。海马显微注射 CB2R 激动剂可减轻 SNI 大鼠的认知障碍,这与小胶质细胞倾向于发挥抗炎功能有关。此外,SNI 还诱导激活了海马中的 p-ERK/NFκB 通路。激活 CB2R 可以上调小胶质细胞中 DUSP6 的表达,从而逆转这一过程。通过海马腺相关病毒(AAV)显微注射下调小胶质细胞 DUSP6,可抑制 CB2R 激活引起的效应。相反,使用 AAV 过表达海马 DUSP6 可改善 SNI 大鼠的认知缺陷,而服用 CB2R 拮抗剂后仍不受影响。我们的研究结果表明,通过调节 DUSP6/ERK/NFκB 通路,激活海马 CB2R 可减轻慢性神经病理性疼痛引起的认知障碍。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Hippocampal cannabinoid type 2 receptor alleviates chronic neuropathic pain-induced cognitive impairment via microglial DUSP6 pathway in rats

Hippocampal cannabinoid type 2 receptor alleviates chronic neuropathic pain-induced cognitive impairment via microglial DUSP6 pathway in rats

Approximately 50% of patients with chronic neuropathic pain experience cognitive impairment, which negatively impacts their quality of life. The cannabinoid type 2 receptor (CB2R) may be involved in hippocampal cognitive processes. However, its role in chronic neuropathic pain-induced cognitive impairment remains elusive. Spared nerve injury (SNI) was used to induce chronic neuropathic pain in rats, while the novel-object recognition test and the Y-maze test were employed to assess cognitive function. Immunofluorescence, western blotting, and stereotaxic hippocampal microinjection were utilized to elucidate the potential mechanisms. We observed a reduction in mechanical pain threshold and cognitive impairment in SNI rats. This was accompanied by a tendency for hippocampal microglia to adopt pro-inflammatory functions. Notably, no changes were detected in CB2R expression. However, downregulation of the endogenous ligands AEA and 2-AG was evident. Hippocampal microinjection of a CB2R agonist mitigated cognitive impairment in SNI rats, which correlated with a tendency for microglia to adopt anti-inflammatory functions. Additionally, SNI-induced activation of the p-ERK/NFκB pathway in the hippocampus. Activation of CB2R reversed this process by upregulating DUSP6 expression in microglia. The effects elicited by CB2R activation could be inhibited through the downregulation of microglial DUSP6 via hippocampal adeno-associated virus (AAV) microinjection. Conversely, overexpression of hippocampal DUSP6 using AAV ameliorated the cognitive deficits observed in SNI rats, which remained unaffected by the administration of a CB2R antagonist. Our findings demonstrate that activation of hippocampal CB2R can mitigate chronic neuropathic pain-induced cognitive impairment through the modulation of the DUSP6/ERK/NFκB pathway.

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来源期刊
FASEB Journal
FASEB Journal 生物-生化与分子生物学
CiteScore
9.20
自引率
2.10%
发文量
6243
审稿时长
3 months
期刊介绍: The FASEB Journal publishes international, transdisciplinary research covering all fields of biology at every level of organization: atomic, molecular, cell, tissue, organ, organismic and population. While the journal strives to include research that cuts across the biological sciences, it also considers submissions that lie within one field, but may have implications for other fields as well. The journal seeks to publish basic and translational research, but also welcomes reports of pre-clinical and early clinical research. In addition to research, review, and hypothesis submissions, The FASEB Journal also seeks perspectives, commentaries, book reviews, and similar content related to the life sciences in its Up Front section.
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