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胆红素通过激活脊髓中的5-羟色胺3A受体诱导胆汁淤积时的疼痛脱敏。

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

作者信息

Kong Erliang, Wang Hongqian, Wang Xiaoqiang, Zhang Yan, Zhang Jinmin, Yu Weifeng, Feng Xudong, Sun Yuming, Wu Feixiang

机构信息

Department of Anesthesiology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.

Department of Anesthesiology, The 988th Hospital of Joint Logistic Support Force of PLA, Zhengzhou, China.

出版信息

Front Cell Dev Biol. 2021 Apr 1;9:605855. doi: 10.3389/fcell.2021.605855. eCollection 2021.

DOI:10.3389/fcell.2021.605855
PMID:33869168
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8047141/
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 ) 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-HT receptors, and the affinity and binding mode of bilirubin to 5-HT receptor were determined. Effects of bilirubin on γ-aminobutyric acid (GABA) pathway and the interactions with 5-HT 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 receptor and GABA receptor antagonists could reverse the increased pain threshold in BDL rats. Further, 5-HT and GABA 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 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 receptor by lentivirus.

CONCLUSION

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

摘要

背景

胆汁淤积患者常伴有痛觉脱敏，导致围手术期严重并发症。本研究旨在探讨胆汁淤积时胆红素通过激活脊髓背角（SDH）中的5-羟色胺3A（5-HT）受体介导痛觉脱敏的机制。

方法

通过胆管结扎（BDL）建立大鼠胆汁淤积模型。在BDL后或鞘内注射胆红素的情况下，在有或没有激动剂（mCPBG）和拮抗剂（昂丹司琼、荷包牡丹碱或CGP55845）的情况下测量大鼠的痛阈。测定5-HT受体的表达以及胆红素与5-HT受体的亲和力和结合模式。测试胆红素对γ-氨基丁酸（GABA）途径的影响以及与5-HT受体的相互作用。

结果

BDL大鼠血清和脑脊液中的胆红素均显著升高，同时痛阈上调。5-HT受体拮抗剂和GABA受体拮抗剂均可逆转BDL大鼠升高的痛阈。此外，BDL大鼠或胆红素干预后5-HT和GABA受体表达增加。分子对接表明，胆红素进入5-HT受体中预先形成的疏水口袋并形成潜在氢键。胆红素还增加了脑脊液中的GABA浓度和脊髓中GABA能自发抑制性突触后电流，并直接诱导了通过慢病毒过表达5-HT受体的HEK293细胞中的内向电流。

结论

总之，胆红素通过激活脊髓中的5-HT受体在胆汁淤积中诱导痛觉脱敏。5-HT受体的激活可能通过作用于GABA途径来调节痛阈。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/bf54641341fb/fcell-09-605855-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/4f9f3ce4a40e/fcell-09-605855-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/71b4977a29cb/fcell-09-605855-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/467e0f40b108/fcell-09-605855-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/f3f68d8e228f/fcell-09-605855-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/14e5974f3e2c/fcell-09-605855-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/ff610ee505e5/fcell-09-605855-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/0ec5cf976f13/fcell-09-605855-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/bf54641341fb/fcell-09-605855-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/4f9f3ce4a40e/fcell-09-605855-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/71b4977a29cb/fcell-09-605855-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/467e0f40b108/fcell-09-605855-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/f3f68d8e228f/fcell-09-605855-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/14e5974f3e2c/fcell-09-605855-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/ff610ee505e5/fcell-09-605855-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/0ec5cf976f13/fcell-09-605855-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e4/8047141/bf54641341fb/fcell-09-605855-g008.jpg

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Attenuation of hyperalgesia responses via the modulation of 5-hydroxytryptamine signalings in the rostral ventromedial medulla and spinal cord in a 6-hydroxydopamine-induced rat model of Parkinson's disease.在6-羟基多巴胺诱导的帕金森病大鼠模型中，通过调节延髓头端腹内侧和脊髓中的5-羟色胺信号通路减轻痛觉过敏反应。
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