BDNF 信号阻断可减轻 IBS 样大鼠模型中的慢性内脏高敏感。

Blockade of BDNF signalling attenuates chronic visceral hypersensitivity in an IBS-like rat model.

机构信息

School of basic Medical Sciences, Laboratory of Pain Research, Fujian Medical University, Fuzhou, China.

Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Medical University, Fuzhou, China.

出版信息

Eur J Pain. 2020 Apr;24(4):839-850. doi: 10.1002/ejp.1534. Epub 2020 Feb 5.

DOI:10.1002/ejp.1534

PMID:31976585

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7154558/

Abstract

BACKGROUND

Irritable bowel syndrome (IBS) is a common functional disease characterized by chronic abdominal pain and changes in bowel movements. Effective therapy for visceral hypersensitivity in IBS patients remains challenging. This study investigated the roles of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) and the effect of ANA-12 (a selective antagonist of TrkB) on chronic visceral hypersensitivity in an IBS-like rat model.

METHODS

An IBS-like rat model was established through neonatal maternal separation (NMS), and visceral hypersensitivity was assessed by electromyographic (EMG) responses of the abdominal external oblique muscles to colorectal distention (CRD). Different doses of ANA-12 were injected intrathecally to investigate the effect of that drug on visceral hypersensitivity, and the open field test was performed to determine whether ANA-12 had side effects on movement. Thoracolumbar spinal BDNF, TrkB receptor and Protein kinase Mζ (PKMζ) expression were measured to investigate their roles in chronic visceral hypersensitivity. Whole-cell recordings were made from thoracolumbar superficial dorsal horn (SDH) neurons of lamina II.

RESULTS

The expression of BDNF and TrkB was enhanced in the thoracolumbar spinal cord of the NMS animals. ANA-12 attenuated visceral hypersensitivity without side effects on motricity in NMS rats. PKMζ expression significantly decreased after the administration of ANA-12. The frequency of spontaneous excitatory postsynaptic currents (sEPSCs) increased in the thoracolumbar SDH neurons of lamina II in NMS rats. The amplitude and frequency of sEPSCs were reduced after perfusion with ANA-12 in NMS rats.

CONCLUSIONS

Neonatal maternal separation caused visceral hypersensitivity and increased synaptic activity by activating BDNF-TrkB-PKMζ signalling in the thoracolumbar spinal cord of adult rats. PKMζ was able to potentiate AMPA receptor (AMPAR)-mediated sEPSCs in NMS rats. ANA-12 attenuated visceral hypersensitivity and synaptic activity by blocking BDNF/TrkB signalling in NMS rats.

SIGNIFICANCE

ANA-12 attenuates visceral hypersensitivity via BDNF-TrkB-PKMζ signalling and reduces synaptic activity through AMPARs in NMS rats. This knowledge suggests that ANA-12 could represent an interesting novel therapeutic medicine for chronic visceral hypersensitivity.

摘要

背景

肠易激综合征（IBS）是一种常见的功能性疾病，其特征为慢性腹痛和肠道运动改变。对于 IBS 患者内脏高敏性的有效治疗仍具有挑战性。本研究旨在探讨脑源性神经营养因子（BDNF）和酪氨酸激酶受体 B（TrkB）的作用，以及 ANA-12（TrkB 的选择性拮抗剂）对 IBS 样大鼠模型中慢性内脏高敏性的影响。

方法

通过新生期母鼠分离（NMS）建立 IBS 样大鼠模型，并通过腹壁外斜肌的肌电图（EMG）反应评估内脏高敏性对结肠扩张（CRD）的反应。鞘内注射不同剂量的 ANA-12，以研究该药物对内脏高敏性的影响，并进行旷场试验以确定 ANA-12 是否对运动有副作用。测量胸腰段脊髓 BDNF、TrkB 受体和蛋白激酶 Mζ（PKMζ）的表达，以探讨其在慢性内脏高敏性中的作用。进行胸腰段浅层背角（SDH）II 层的全细胞膜片钳记录。

结果

NMS 动物的胸腰段脊髓中 BDNF 和 TrkB 的表达增强。ANA-12 减轻了 NMS 大鼠的内脏高敏性，且对运动无副作用。给予 ANA-12 后 PKMζ 的表达显著降低。在 NMS 大鼠的胸腰段 SDH 神经元中，自发性兴奋性突触后电流（sEPSC）的频率增加。在 NMS 大鼠中，用 ANA-12 灌流后，sEPSC 的幅度和频率降低。