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Lidocaine Alleviates Neuropathic Pain and Neuroinflammation by Inhibiting HMGB1 Expression to Mediate MIP-1α/CCR1 Pathway.
Journal of Neuroimmune Pharmacology ( IF 6.2 ) Pub Date : 2020-04-16 , DOI: 10.1007/s11481-020-09913-y
Mingming Li 1 , Hao Jiang 1 , Kuo Gu 2 , Xuechao Sun 1 , Jing Gu 1 , Chunming Li 2 , Guonian Wang 1, 3
Affiliation  

High mobility group box 1 (HMGB1) released from sensory nerve tissues can induce neuropathic pain. Whether HMGB1 is implicated in the mechanism underlying the effect of lidocaine in pain management remains to be determined. This study aims to explore the effect of lidocaine in a rat model of spared nerve injury (SNI) and the underlying mechanism. An SNI model was established via nerve ligation. Two weeks after the SNI model was established, rats were intrathecally injected with lidocaine, an HMGB1 antibody (HMG Ab), an MIP-1α antibody (MIP-1α Ab), a CCR1 inhibitor (CCR1-RS) or a CCR5 antagonist (CCR5-Mar). Pain behaviors were assessed before and after model establishment to calculate the number of spontaneous flinches (NSF), paw withdrawal threshold (PWT), paw withdrawal thermal latency (PWL) and sciatic function index (SFI). Cell apoptosis and the inflammatory response in the cerebrospinal fluid (CSF) were detected by TUNEL staining and ELISA. The mRNA and protein expression levels of MIP-1α, CCR1 and CCR5 were determined by RT-PCR and Western blotting. The expression levels of HMGB1, MIP-1α, CCR1 and CCR5 were measured by Western blotting and immunofluorescence. Pain behavior testing in SNI rats showed that SNI rats exhibited an increased NSF and a decreased PWT, PWL and SFI. Cell apoptosis in the spinal dorsal horn and the generation of inflammatory cytokines were enhanced in SNI rats, and the expression levels of HMGB1, MIP-1α, CCR1 and CCR5 were upregulated. HMGB1 cytoplasmic translocation, the coexpression of MIP-1α with NeuN, and the coexpression of CCR1 and CCR5 with OX42 were also observed in SNI rats. Neuropathic pain and neuroinflammation were suppressed by the intrathecal injection of lidocaine, HMG Ab, MIP-1α Ab, CCR1-RS or CCR5-Mar. Lidocaine inhibited the expression levels of HMGB1, MIP-1α, CCR1 and CCR5, and the HMGB1 antibody suppressed the expression of MIP-1α, CCR1 and CCR5. Lidocaine attenuates neuropathic pain and neuroinflammation by inhibiting HMGB1 to regulate the MIP-1α/CCR1/CCR5 pathway. Graphical Abstract.

中文翻译:

Lidocaine 通过抑制 HMGB1 表达介导 MIP-1α/CCR1 通路来减轻神经性疼痛和神经炎症。

从感觉神经组织释放的高迁移率族框 1 (HMGB1) 可诱发神经性疼痛。HMGB1 是否与利多卡因在疼痛管理中的作用机制有关仍有待确定。本研究旨在探讨利多卡因在大鼠神经损伤(SNI)模型中的作用及其潜在机制。通过神经结扎建立SNI模型。SNI模型建立两周后,大鼠鞘内注射利多卡因、HMGB1抗体(HMG Ab)、MIP-1α抗体(MIP-1α Ab)、CCR1抑制剂(CCR1-RS)或CCR5拮抗剂(CCR5) -三月)。模型建立前后对疼痛行为进行评估,计算自发退缩次数(NSF)、缩爪阈值(PWT)、缩爪热潜伏期(PWL)和坐骨神经功能指数(SFI)。通过TUNEL染色和ELISA检测脑脊液(CSF)中的细胞凋亡和炎症反应。通过RT-PCR和Western印迹测定MIP-1α、CCR1和CCR5的mRNA和蛋白表达水平。通过蛋白质印迹和免疫荧光法测量HMGB1、MIP-1α、CCR1和CCR5的表达水平。SNI 大鼠的疼痛行为测试表明,SNI 大鼠表现出增加的 NSF 和降低的 PWT、PWL 和 SFI。SNI大鼠脊髓背角细胞凋亡和炎症细胞因子的产生增强,HMGB1、MIP-1α、CCR1和CCR5的表达水平上调。在 SNI 大鼠中还观察到 HMGB1 细胞质易位、MIP-1α 与 NeuN 的共表达以及 CCR1 和 CCR5 与 OX42 的共表达。鞘内注射利多卡因、HMG Ab、MIP-1α Ab、CCR1-RS 或 CCR5-Mar 可抑制神经性疼痛和神经炎症。利多卡因抑制 HMGB1、MIP-1α、CCR1 和 CCR5 的表达水平,HMGB1 抗体抑制 MIP-1α、CCR1 和 CCR5 的表达。利多卡因通过抑制 HMGB1 调节 MIP-1α/CCR1/CCR5 通路来减轻神经性疼痛和神经炎症。图形概要。
更新日期:2020-04-21
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