Activation of TGR5 in the injured nerve site according to a prevention protocol mitigates partial sciatic nerve ligation–induced neuropathic pain by alleviating neuroinflammation

神经病理性疼痛 神经炎症 坐骨神经 医学 周围神经损伤 神经损伤 坐骨神经损伤 麻醉 药理学 神经科学 炎症 内科学 生物
作者
Wen-Ge Shi,Yao Yao,Yajing Liang,Jie Lei,Shi‐Yang Feng,Zixian Zhang,Yue Tian,Jie Cai,Guo‐Gang Xing,Kai‐Yuan Fu
出处
期刊:Pain [Ovid Technologies (Wolters Kluwer)]
标识
DOI:10.1097/j.pain.0000000000003460
摘要

Abstract 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.

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