TGR5 protects against pSNL-induced mechanical allodynia by alleviating neuroinflammation in the injured nerves of male mice

Abstract

Abstract Neuropathic pain is a pervasive medical challenge that currently lacks effective treatment solutions. Molecular changes occurring at the site of peripheral nerve damage contribute to the development of peripheral and central sensitization, which are critical components of neuropathic pain. This study aimed to investigate the role of the G protein-coupled bile acid receptor (GPBAR1, also known as TGR5) in the peripheral mechanisms underlying neuropathic pain induced by partial sciatic nerve ligation (pSNL) in male mice. TGR5 was upregulated in injured nerves and colocalized predominantly with macrophages. Peri-sciatic nerve administration of the TGR5-specific agonist INT-777 provided sustained relief from mechanical allodynia. Transcriptome sequencing revealed that pain relief was primarily attributable to reduced neuroinflammation. This finding was corroborated by a reduction in myeloid cells and proinflammatory mediators (including CCL3, CXCL9, IL-6, and TNF-α), accompanied by an increase in the percentage of anti-inflammatory M2 macrophages following INT-777 administration. Furthermore, myeloid cell-specific TGR5 knockdown in the sciatic nerve following pSNL exacerbated both mechanical allodynia and neuroinflammation. This is substantiated by data from the bulk RNA-seq and upregulated expression levels of inflammatory mediators (including CCL3, CCL2, IL-6, TNF-α and IL-1β), as well as increased monocytes/ macrophages in the injured nerve. Besides, the activation of microglia in the ipsilateral dorsal horn of spinal cord induced by pSNL altered when TGR5 in the sciatic nerve was manipulated. In summary, TGR5, present in injured nerves, plays a protective role and offers potential as a target for treating neuropathic pain.