Dataset Information

Bilirubin Induces Pain Desensitization in Cholestasis by Activating 5-Hydroxytryptamine 3A Receptor in Spinal Cord.

ABSTRACT:

Background

Cholestasis patients often suffer from pain desensitization, resulting in serious complications in perioperative period. This study was aim to investigate the mechanism of bilirubin in cholestasis mediating pain desensitization through 5-hydroxytryptamine 3A (5-HT_3A ) receptor activation in spinal dorsal horn (SDH).

Methods

A cholestasis model was established by bile duct ligation (BDL) in rats. Pain thresholds of rats were measured after BDL or intrathecally injecting bilirubin in the presence or absence of agonist (mCPBG) and antagonists (ondansetron, bicuculline, or CGP55845). Expression of 5-HT₃ receptors, and the affinity and binding mode of bilirubin to 5-HT_3A receptor were determined. Effects of bilirubin on γ-aminobutyric acid (GABA) pathway and the interactions with 5-HT_3A receptor were tested.

Results

Bilirubin was elevated significantly in both serum and CSF in BDL rats, accompanied with the up-regulation of pain thresholds. Both of 5-HT_3A receptor and GABA _A receptor antagonists could reverse the increased pain threshold in BDL rats. Further, 5-HT_3A and GABA _A receptor expressions were increased in BDL rats or intervention with bilirubin. Molecular docking suggested that bilirubin entered the hydrophobic pocket pre-formed in 5-HT_3A receptor with potential hydrogen bonding. Bilirubin also increased GABA concentrations in CSF and GABAergic spontaneous inhibitory postsynaptic current in spinal cord, and directly induced inward currents in HEK293 cells which were overexpressed 5-HT_3A receptor by lentivirus.

Conclusion

In conclusion, bilirubin induced pain desensitization in cholestasis by activating 5-HT_3A receptor in spinal cord. The activation of 5-HT_3A receptor might regulate pain threshold by acting on the GABA pathway.

SUBMITTER: Kong E

PROVIDER: S-EPMC8047141 | biostudies-literature |

REPOSITORIES: biostudies-literature

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