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Activation of TGR5 in the injured nerve site according to a prevention protocol mitigates partial sciatic nerve ligation-induced neuropathic pain by alleviating neuroinflammation.
Pain ( IF 5.9 ) Pub Date : 2024-10-25 , DOI: 10.1097/j.pain.0000000000003460 Wen-Ge Shi,Yao Yao,Ya-Jing Liang,Jie Lei,Shi-Yang Feng,Zi-Xian Zhang,Yue Tian,Jie Cai,Guo-Gang Xing,Kai-Yuan Fu
Pain ( IF 5.9 ) Pub Date : 2024-10-25 , DOI: 10.1097/j.pain.0000000000003460 Wen-Ge Shi,Yao Yao,Ya-Jing Liang,Jie Lei,Shi-Yang Feng,Zi-Xian Zhang,Yue Tian,Jie Cai,Guo-Gang Xing,Kai-Yuan Fu
Neuropathic pain is a pervasive medical challenge currently lacking effective treatment options. Molecular changes at the site of peripheral nerve injury contribute to both peripheral and central sensitization, critical components of neuropathic pain. This study explores the role of the G-protein-coupled bile acid receptor (GPBAR1 or TGR5) in the peripheral mechanisms underlying neuropathic pain induced by partial sciatic nerve ligation in male mice. TGR5 was upregulated in the injured nerve site and predominantly colocalized with macrophages. Perisciatic nerve administration of the TGR5 agonist, INT-777 according to a prevention protocol (50 μg/μL daily from postoperative day [POD] 0 to POD6) provided sustained relief from mechanical allodynia and spontaneous pain, whereas the TGR5 antagonist, SBI-115 worsened neuropathic pain. Transcriptome sequencing linked the pain relief induced by TGR5 activation to reduced neuroinflammation, which was further evidenced by a decrease in myeloid cells and pro-inflammatory mediators (eg, CCL3, CXCL9, interleukin [IL]-6, and tumor necrosis factor [TNF] α) and an increase in CD86-CD206+ anti-inflammatory macrophages at POD7. Besides, myeloid-cell-specific TGR5 knockdown in the injured nerve site exacerbated both neuropathic pain and neuroinflammation, which was substantiated by bulk RNA-sequencing and upregulated expression levels of inflammatory mediators (including CCL3, CCL2, IL-6, TNF α, and IL-1β) and the increased number of monocytes/macrophages at POD7. Furthermore, the activation of microglia in the spinal cord on POD7 and POD14 was altered when TGR5 in the sciatic nerve was manipulated. Collectively, TGR5 activation in the injured nerve site mitigates neuropathic pain by reducing neuroinflammation, while TGR5 knockdown in myeloid cells worsens pain by enhancing neuroinflammation.
中文翻译:
根据预防方案,在受伤的神经部位激活 TGR5 通过减轻神经炎症来减轻部分坐骨神经结扎诱导的神经性疼痛。
神经性疼痛是一种普遍存在的医学挑战,目前缺乏有效的治疗方案。周围神经损伤部位的分子变化有助于外周和中枢敏化,这是神经性疼痛的关键组成部分。本研究探讨了 G 蛋白偶联胆汁酸受体 (GPBAR1 或 TGR5) 在雄性小鼠部分坐骨神经结扎诱导的神经性疼痛的外周机制中的作用。TGR5 在受伤的神经部位上调,主要与巨噬细胞共定位。根据预防方案 (从术后第 [POD] 0 至 POD6 每天 50 μg/μL)给予 TGR5 激动剂 INT-777 的坐骨神经给药可持续缓解机械性异常性疼痛和自发性疼痛,而 TGR5 拮抗剂 SBI-115 加重神经性疼痛。转录组测序将 TGR5 激活诱导的疼痛缓解与神经炎症的减少联系起来,髓系细胞和促炎介质 (例如,CCL3、CXCL9、白细胞介素 [IL]-6 和肿瘤坏死因子 [TNF] α) 的减少以及 POD7 时 CD86-CD206 + 抗炎巨噬细胞的增加进一步证明了这一点。此外,损伤神经部位的髓细胞特异性 TGR5 敲低加剧了神经性疼痛和神经炎症,大量 RNA 测序和炎症介质 (包括 CCL3 、 CCL2 、 IL-6 、 TNF α 和 IL-1β) 的表达水平上调以及 POD7 中单核细胞/巨噬细胞数量的增加证实了这一点。此外,当操纵坐骨神经中的 TGR5 时,POD7 和 POD14 脊髓中小胶质细胞的激活发生改变。 总的来说,受伤神经部位的 TGR5 激活通过减少神经炎症来减轻神经性疼痛,而髓系细胞中的 TGR5 敲除通过增强神经炎症来加剧疼痛。
更新日期:2024-10-25
中文翻译:
根据预防方案,在受伤的神经部位激活 TGR5 通过减轻神经炎症来减轻部分坐骨神经结扎诱导的神经性疼痛。
神经性疼痛是一种普遍存在的医学挑战,目前缺乏有效的治疗方案。周围神经损伤部位的分子变化有助于外周和中枢敏化,这是神经性疼痛的关键组成部分。本研究探讨了 G 蛋白偶联胆汁酸受体 (GPBAR1 或 TGR5) 在雄性小鼠部分坐骨神经结扎诱导的神经性疼痛的外周机制中的作用。TGR5 在受伤的神经部位上调,主要与巨噬细胞共定位。根据预防方案 (从术后第 [POD] 0 至 POD6 每天 50 μg/μL)给予 TGR5 激动剂 INT-777 的坐骨神经给药可持续缓解机械性异常性疼痛和自发性疼痛,而 TGR5 拮抗剂 SBI-115 加重神经性疼痛。转录组测序将 TGR5 激活诱导的疼痛缓解与神经炎症的减少联系起来,髓系细胞和促炎介质 (例如,CCL3、CXCL9、白细胞介素 [IL]-6 和肿瘤坏死因子 [TNF] α) 的减少以及 POD7 时 CD86-CD206 + 抗炎巨噬细胞的增加进一步证明了这一点。此外,损伤神经部位的髓细胞特异性 TGR5 敲低加剧了神经性疼痛和神经炎症,大量 RNA 测序和炎症介质 (包括 CCL3 、 CCL2 、 IL-6 、 TNF α 和 IL-1β) 的表达水平上调以及 POD7 中单核细胞/巨噬细胞数量的增加证实了这一点。此外,当操纵坐骨神经中的 TGR5 时,POD7 和 POD14 脊髓中小胶质细胞的激活发生改变。 总的来说,受伤神经部位的 TGR5 激活通过减少神经炎症来减轻神经性疼痛,而髓系细胞中的 TGR5 敲除通过增强神经炎症来加剧疼痛。