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 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
NMS caused visceral hypersensitivity and increased synaptic activity by activating BDNF‐TrkB‐PKMζ signaling 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 signaling in NMS rats.
Significance
ANA‐12 attenuates visceral hypersensitivity via BDNF‐TrkB‐PKMζ signaling 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.
from Wiley: European Journal of Pain: Table of Contents https://ift.tt/2TUMwZT
via IFTTT
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