Cargando…

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

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 activatio...

Descripción completa

Detalles Bibliográficos
Autores principales: Kong, Erliang, Wang, Hongqian, Wang, Xiaoqiang, Zhang, Yan, Zhang, Jinmin, Yu, Weifeng, Feng, Xudong, Sun, Yuming, Wu, Feixiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047141/
https://www.ncbi.nlm.nih.gov/pubmed/33869168
http://dx.doi.org/10.3389/fcell.2021.605855
_version_ 1783678985607053312
author Kong, Erliang
Wang, Hongqian
Wang, Xiaoqiang
Zhang, Yan
Zhang, Jinmin
Yu, Weifeng
Feng, Xudong
Sun, Yuming
Wu, Feixiang
author_facet Kong, Erliang
Wang, Hongqian
Wang, Xiaoqiang
Zhang, Yan
Zhang, Jinmin
Yu, Weifeng
Feng, Xudong
Sun, Yuming
Wu, Feixiang
author_sort Kong, Erliang
collection PubMed
description 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-HT(3) 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.
format Online
Article
Text
id pubmed-8047141
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-80471412021-04-16 Bilirubin Induces Pain Desensitization in Cholestasis by Activating 5-Hydroxytryptamine 3A Receptor in Spinal Cord Kong, Erliang Wang, Hongqian Wang, Xiaoqiang Zhang, Yan Zhang, Jinmin Yu, Weifeng Feng, Xudong Sun, Yuming Wu, Feixiang Front Cell Dev Biol Cell and Developmental Biology 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-HT(3) 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. Frontiers Media S.A. 2021-04-01 /pmc/articles/PMC8047141/ /pubmed/33869168 http://dx.doi.org/10.3389/fcell.2021.605855 Text en Copyright © 2021 Kong, Wang, Wang, Zhang, Zhang, Yu, Feng, Sun and Wu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Kong, Erliang
Wang, Hongqian
Wang, Xiaoqiang
Zhang, Yan
Zhang, Jinmin
Yu, Weifeng
Feng, Xudong
Sun, Yuming
Wu, Feixiang
Bilirubin Induces Pain Desensitization in Cholestasis by Activating 5-Hydroxytryptamine 3A Receptor in Spinal Cord
title Bilirubin Induces Pain Desensitization in Cholestasis by Activating 5-Hydroxytryptamine 3A Receptor in Spinal Cord
title_full Bilirubin Induces Pain Desensitization in Cholestasis by Activating 5-Hydroxytryptamine 3A Receptor in Spinal Cord
title_fullStr Bilirubin Induces Pain Desensitization in Cholestasis by Activating 5-Hydroxytryptamine 3A Receptor in Spinal Cord
title_full_unstemmed Bilirubin Induces Pain Desensitization in Cholestasis by Activating 5-Hydroxytryptamine 3A Receptor in Spinal Cord
title_short Bilirubin Induces Pain Desensitization in Cholestasis by Activating 5-Hydroxytryptamine 3A Receptor in Spinal Cord
title_sort bilirubin induces pain desensitization in cholestasis by activating 5-hydroxytryptamine 3a receptor in spinal cord
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047141/
https://www.ncbi.nlm.nih.gov/pubmed/33869168
http://dx.doi.org/10.3389/fcell.2021.605855
work_keys_str_mv AT kongerliang bilirubininducespaindesensitizationincholestasisbyactivating5hydroxytryptamine3areceptorinspinalcord
AT wanghongqian bilirubininducespaindesensitizationincholestasisbyactivating5hydroxytryptamine3areceptorinspinalcord
AT wangxiaoqiang bilirubininducespaindesensitizationincholestasisbyactivating5hydroxytryptamine3areceptorinspinalcord
AT zhangyan bilirubininducespaindesensitizationincholestasisbyactivating5hydroxytryptamine3areceptorinspinalcord
AT zhangjinmin bilirubininducespaindesensitizationincholestasisbyactivating5hydroxytryptamine3areceptorinspinalcord
AT yuweifeng bilirubininducespaindesensitizationincholestasisbyactivating5hydroxytryptamine3areceptorinspinalcord
AT fengxudong bilirubininducespaindesensitizationincholestasisbyactivating5hydroxytryptamine3areceptorinspinalcord
AT sunyuming bilirubininducespaindesensitizationincholestasisbyactivating5hydroxytryptamine3areceptorinspinalcord
AT wufeixiang bilirubininducespaindesensitizationincholestasisbyactivating5hydroxytryptamine3areceptorinspinalcord