Stretch-Induced BDNF in Colon Smooth Muscle Plays a Critical Role in Obstruction Associated Visceral Hypersensitivity by Altering K v Function in Primary Sensory Neurons

Lin, You-Min; Fu, Yu; Radhakrishnan, Ravi S.; Huang, Li‐Chun; Shi, Xuan-Zheng P.

doi:10.1016/s0016-5085(17)30986-1

Cited by 4 publications

(5 citation statements)

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“…Furthermore, research in BDNF +/− mice has confirmed that colonic BDNF expression contributes to visceral hypersensitivity in IBS mice (Wang et al, ). BDNF mRNA and protein expression are also increased in the smooth muscle cells of a rat model of bowel obstruction (Lin, Fu, Radhakrishnan, Huang, & Shi, ). Apart from the increase in colonic BDNF expression, the expression of BDNF in the spinal cord and DRG is high in colitis (Qiao, Gulick, Bowers, Kuemmerle, & Grider, ).…”

Section: Discussionmentioning

confidence: 99%

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

Fan

Tang

Dai

et al. 2020

European Journal of Pain

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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.

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Section: Discussionmentioning

confidence: 99%

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

Fan

Tang

Dai

et al. 2020

European Journal of Pain

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“…Our study in the rat model of BO found that the dorsal root ganglia (DRG) neurons projecting to the distended colon showed abnormal hyper-excitability with decreased resting membrane potential and rheobase, and increased number of action potentials (Lin et al, 2017b ). We tested whether mechano-transcription of pain mediators in the gut contribute to visceral hypersensitivity in BO (Lin et al, 2017a , b ).…”

Section: Pathophysiological Role Of Mechano-transcription In Abdominamentioning

confidence: 99%

“…Thus, mechano-transcription of NGF in colon SMC may play a critical role in visceral hypersensitivity in BO, by acting on TTX-r Na + channels in sensory neurons. Recent study found that mechanical stretch also induces up-regulation of BDNF in SMC, and BDNF may contribute to sensory neuron hyper-excitability in BO by suppressing A-type K + currents (Lin et al, 2017a ).…”

Section: Pathophysiological Role Of Mechano-transcription In Abdominamentioning

confidence: 99%

Mechanical Regulation of Gene Expression in Gut Smooth Muscle Cells

Shi

2017

Front. Physiol.

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Intraluminal contents and their movement along the gastrointestinal tract create shear stress and mechanical stretch on the gut wall. While the shear stress is important in the initiation of immediate physiological responses, the circumferential mechanical stretch, such as that in obstructive bowel disorders, exerts long-lasting impacts on bowel functions by mainly affecting the deeper muscularis externae. Recent studies demonstrate that mechanical stretch alters gene transcription in gut smooth muscle cells (SMC), and the stretch-altered gene expression (mechano-transcription) may play a critical role in pathogenesis of motility dysfunction and abdominal pain in obstruction. Specifically, stretch-induced cyclo-oxygenase-2 and other pro-inflammatory mediators in gut SMC account for impairments of muscle contractility. Mechano-transcription of pain mediators such as nerve growth factor may contribute to visceral hypersensitivity, by sensitizing primary sensory neurons. This review aims to highlight the novel findings of mechano-transcription in the gut, and to discuss the signaling mechanisms and pathophysiological significance of mechano-transcription.

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“…Expression of BDNF mRNA and protein was also increased dramatically in the colonic smooth muscle of the oral dilated segment, but not in the non-dilated segment aboral to obstruction ( Lin et al, 2017a ; Fu et al, 2018 ). There was an eightfold increase in BDNF mRNA expression in colonic smooth muscle on day 3 in BO.…”

Section: Pathophysiological Role Of Mechanical Stress-induced Neurotrmentioning

confidence: 94%

“…Administration of inhibitor of BDNF receptor (Trk B) ANA-12 blocked BO-associated changes of neuronal excitability, K v activity, and gene expression in obstruction. This is associated with improvement of referred hyperalgesia ( Lin et al, 2017a ). Thus, mechano-transcription of BDNF in gut SMC contributes to visceral hypersensitivity in BO mainly by suppressing A-type K + currents and gene expression in the primary sensory neurons ( Figure 2 ).…”

Section: Pathophysiological Role Of Mechanical Stress-induced Neurotrmentioning

confidence: 99%

Novel Insights Into the Mechanisms of Abdominal Pain in Obstructive Bowel Disorders

Shi

Lin

Hegde

2018

Front. Integr. Neurosci.

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Obstructive bowel disorders (OBD) are characterized by lumen distention due to mechanical or functional obstruction in the gut. Abdominal pain is one of the main symptoms in OBD. In this article, we aim to critically review the potential mechanisms for acute and chronic pain in bowel obstruction (BO). While clustered contractions and associated increase of intraluminal pressure may account for colicky pain in simple obstruction, ischemia may be involved in acute pain in severe conditions such as closed loop obstruction. Recent preclinical studies discovered that visceral sensitivity is increased in BO, and visceral hypersensitivity may underlie the mechanisms of chronic abdominal pain in BO. Mounting evidence suggests that lumen distension, as a circumferential mechanical stretch, alters gene expression (mechano-transcription) in the distended bowel, and mechano-transcription of nociceptive and inflammatory mediators plays a critical role in the development of visceral hypersensitivity in BO. Mechano-transcription of nerve growth factor (NGF) in gut smooth muscle cells is found to increase voltage-gated Na+ channel (Nav) activity of the primary sensory neurons by up-regulating expression of TTX-resistant Nav1.8, whereas mechanical stretch-induced brain-derived neurotrophic factor (BDNF) reduces Kv currents especially A-type (IA) currents by down-regulating expression of specific IA subtypes such as Kv1.4. The NGF and BDNF mediated changes in gene expression and channel functions in the primary sensory neurons may constitute the main mechanisms of visceral hypersensitivity in OBD. In addition, mechanical stretch-induced COX-2 and other inflammatory mediators in the gut may also contribute to abdominal pain by activating and sensitizing nociceptors.

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Stretch-Induced BDNF in Colon Smooth Muscle Plays a Critical Role in Obstruction Associated Visceral Hypersensitivity by Altering K v Function in Primary Sensory Neurons

Cited by 4 publications

References 0 publications

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

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

Mechanical Regulation of Gene Expression in Gut Smooth Muscle Cells

Novel Insights Into the Mechanisms of Abdominal Pain in Obstructive Bowel Disorders

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