Activation of the bile acid receptors TGR5 and FXR in the spinal dorsal horn alleviates neuropathic pain

Aims: Beyond digestion, bile acids have been recognized as signaling molecules with broad paracrine and endocrine functions by activating plasma membrane receptor (Takeda G protein-coupled receptor 5, TGR5) and the nuclear farnesoid X receptor (FXR). The present study investigated the role of bile acids in alleviating neuropathic pain by activating TGR5 and FXR.Method: Neuropathic pain was induced by spared nerve injury (SNI) of the sciatic nerve. TGR5 or FXR agonist was injected intrathecally. Pain hypersensitivity was measured with Von Frey test. The amount of bile acids was detected using a bile acid assay kit. Western blotting and immunohistochemistry were used to assess molecular changes.Results: We found that bile acids were downregulated, whereas the expression of cytochrome P450 cholesterol 7ahydroxylase (CYP7A1), a rate-limiting enzyme for bile acid synthesis, was upregulated exclusively in microglia in the spinal dorsal horn after SNI. Furthermore, the expression of the bile acid receptors TGR5 and FXR was increased in glial cells and GABAergic neurons in the spinal dorsal horn on day 7 after SNI. Intrathecal injection of either TGR5 or FXR agonist on day 7 after SNI alleviated the established mechanical allodynia in mice, and the effects were blocked by TGR5 or FXR antagonist. Bile acid receptor agonists inhibited the activation of glial cells and ERK pathway in the spinal dorsal horn. All of the above effects of TGR5 or FXR agonists on mechanical allodynia, on the activation of glial cells, and on ERK pathway were abolished by intrathecal injection of the GABA(A) receptor antagonist bicuculline.Conclusion: These results suggest that activation of TGR5 or FXR counteracts mechanical allodynia. The effect was mediated by potentiating function of GABA(A) receptors, which then inhibited the activation of glial cells and neuronal sensitization in the spinal dorsal horn.

Automated summary

This study investigates the role of bile acids in alleviating neuropathic pain by activating TGR5 and FXR. The results show that bile acids are downregulated and the expression of CYP7A1 is upregulated in microglia after nerve injury. Furthermore, the expression of TGR5 and FXR is increased in glial cells and GABAergic neurons. Activation of TGR5 or FXR can alleviate mechanical allodynia, and this effect is mediated through potentiation of GABA(A) receptors and inhibition of glial cells activation.