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

CNS Neurosci Ther, 2023 · DOI: 10.1111/cns.14154 · Published: January 1, 2023

Simple Explanation

This research investigates how bile acids, signaling molecules in the body, can help reduce neuropathic pain by activating two specific receptors, TGR5 and FXR, in the spinal cord. The study found that after a nerve injury, the levels of bile acids in the spinal cord decrease, while the receptors TGR5 and FXR increase. Activating these receptors with specific drugs reduced pain in mice with nerve damage. The pain-relieving effects of these drugs were linked to reduced activity of certain immune cells (glial cells) and a specific signaling pathway (ERK) in the spinal cord, suggesting a potential mechanism for how bile acids can modulate pain.

Study Duration

Not specified

Participants

177 male C57BL/6 mice

Evidence Level

Not specified

Key Findings

1
Bile acid levels are decreased in the spinal dorsal horn after spared nerve injury (SNI), while CYP7A1 expression is upregulated in microglia.
2
The expression of TGR5 and FXR is increased in glial cells and GABAergic neurons in the spinal dorsal horn after SNI.
3
Activation of TGR5 or FXR with agonists alleviates mechanical allodynia in mice with SNI, and these effects are blocked by antagonists or a GABAA receptor antagonist.

Research Summary

This study investigates the role of bile acids and their receptors, TGR5 and FXR, in alleviating neuropathic pain induced by spared nerve injury (SNI) in mice. The results demonstrate that SNI leads to decreased bile acid levels and increased expression of CYP7A1 (a bile acid synthesis enzyme) and TGR5/FXR in the spinal dorsal horn, along with glial cell activation and ERK phosphorylation. Activation of TGR5 or FXR with specific agonists alleviated neuropathic pain by inhibiting glial cell activation and ERK phosphorylation, an effect that was blocked by a GABAA receptor antagonist, suggesting a mechanism involving GABAA receptor modulation.

Practical Implications

Therapeutic Potential

Bile acid receptor agonists may represent a novel therapeutic strategy for the treatment of neuropathic pain.

GABAergic System Modulation

The involvement of GABAA receptors highlights the potential for therapies targeting the GABAergic system in conjunction with bile acid receptor activation.

Neuroinflammation Target

Reducing neuroinflammation via bile acid receptor activation may be a key mechanism for pain relief.

Study Limitations

1
The study was conducted only on male mice.
2
The specific mechanisms of CYP7A1 upregulation in spinal cord microglia after peripheral nerve injury are unclear.
3
The crosstalk between neurosteroids and bile acid receptors under neuropathic pain conditions requires further investigation.

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