Blockade of BK channels attenuates chronic visceral hypersensitivity in an IBS-like rat model

Fan, Fudong; Chen, Y; Chen, Z; Guan, Le Luo; Ye, Z; Tang, Ying; Chen, A; Lin, Chun

doi:10.1177/17448069211040364

Cited by 9 publications

(5 citation statements)

References 37 publications

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“…Animal models of IBS were often established by recapitulating early-life stress, such as motherinfant separation (Moloney et al, 2015), unpredictable electrical stimulation (Louwies and Greenwood-Van Meerveld, 2020), and neonatal CRD (Chen et al, 2014;Gil et al, 2016;Fan et al, 2021). Our previous study indicated that neonatal CRD induced visceral hypersensitivity after adulthood (Chen et al, 2014;Fan et al, 2021). In this study, we focused not only on visceral pain but also on emotional comorbidity in ELS rats.…”

Section: Discussionmentioning

confidence: 99%

“…The approval number is SCXK (Fujian) 2012-0001. ELS rats were established by colorectal dilation (CRD) stimulation of 60 mmHg pressure for 1 min using a 2.5 mm × 20 mm human vascular reconstruction balloon (Chen et al, 2014;Fan et al, 2021). The stimulation was performed once a day from the 8th to the 14th day after birth.…”

Section: Animalmentioning

confidence: 99%

“…Male rats (8 weeks old) were anesthetized with light isoflurane. Abdominal electromyography (EMG) response to CRD stimulation was measured to assess visceral hypersensitivity as previously described (Chen et al, 2014;Fan et al, 2021). CRD induces abdominal contractions, and this visceromotor response is used to assess visceral pain.…”

Section: Assessment Of Visceral Hypersensitivitymentioning

confidence: 99%

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Contribution of Amygdala Histone Acetylation in Early Life Stress-Induced Visceral Hypersensitivity and Emotional Comorbidity

Guan

Tang

et al. 2022

Front. Neurosci.

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Patients with irritable bowel syndrome (IBS) experience not only enhanced visceral pain but also emotional comorbidities, such as anxiety and depression. Early life stress (ELS) is a high-risk for the development of IBS. Literatures have reported an important epigenetic modulation in sustaining extrinsic phenotypes. The amygdala is closely related to the regulation of visceral functions and emotional experiences. In this study, we hypothesized that ELS-induced reprogramming inappropriate adaptation of histone acetylation modification in the amygdala may result in visceral hypersensitivity and anxiety-like behaviors in ELS rats. To test this hypothesis, the model of ELS rats was established by neonatal colorectal dilatation (CRD). Visceral hypersensitivity was assessed based on the electromyography response of the abdominal external oblique muscle to CRD. Emotional comorbidities were examined using the elevated plus maze test, open field test, and sucrose preference test. Trichostatin A (TSA) and C646 were microinjected into the central amygdala (CeA) individually to investigate the effects of different levels of histone acetylation modification on visceral hypersensitivity and emotion. We found neonatal CRD resulted in visceral hypersensitivity and anxiety-like behaviors after adulthood. Inhibiting histone deacetylases (HDACs) in the CeA by TSA enhanced visceral sensitivity but did not affect anxiety-like behaviors, whereas inhibiting HAT by C646 attenuated visceral hypersensitivity in ELS rats. Interestingly, CeA treatment with TSA induced visceral sensitivity and anxiety-like behaviors in the control rats. Western blot showed that the expressions of acetylated 9 residue of Histone 3 (H3K9) and protein kinase C zeta type (PKMζ) were higher in the ELS rats compared to those of the controls. The administration of the PKMζ inhibitor ZIP into the CeA attenuated visceral hypersensitivity of ELS rats. Furthermore, the expression of amygdala PKMζ was enhanced by TSA treatment in control rats. Finally, western blot and immunofluorescence results indicated the decrease of HDAC1 and HDAC2 expressions, but not HDAC3 expression, contributed to the enhancement of histone acetylation in ELS rats. Our results support our hypothesis that amygdala-enhanced histone acetylation induced by stress in early life results in visceral hypersensitivity and anxiety-like behaviors in ELS rats, and reversing the abnormal epigenetic mechanisms may be crucial to relieve chronic symptoms in ELS rats.

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Section: Discussionmentioning

confidence: 99%

Section: Animalmentioning

confidence: 99%

Section: Assessment Of Visceral Hypersensitivitymentioning

confidence: 99%

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Contribution of Amygdala Histone Acetylation in Early Life Stress-Induced Visceral Hypersensitivity and Emotional Comorbidity

Guan

Tang

et al. 2022

Front. Neurosci.

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“…The stratified research shows strong links between ion channel dysfunction and AQPs with visceral hypersensitivity in IBS ( Table 1 ). The voltage-gated sodium (Nav) [ 46 , 83 ], calcium (Cav), specifically Cav3.2 [ 8 ], transient receptor potential vanilloid TRPV1, TRPV3, TRPV4, and TRPA1 [ 45 , 77 ], voltage-gated sodium (Nav) (Nav1.1, Nav1.3, Nav1.5, Nav1.6, Nav1.7, Nav1.8, and Nav1.9) [ 5 , 94 ], and big/large-conductance Ca 2+ -activated K (BKCa) channels [ 23 , 95 ] are involved in the genesis of visceral hypersensitivity in IBS.…”

Section: Ion Channels and The Pathophysiology Of Figdsmentioning

confidence: 99%

The Role of Ion Channels in Functional Gastrointestinal Disorders (FGID): Evidence of Channelopathies and Potential Avenues for Future Research and Therapeutic Targets

Maqoud

Tricarico

Mallamaci

et al. 2023

IJMS

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Several gastrointestinal (GI) tract abnormalities, including visceral hypersensitivity, motility, and intestinal permeability alterations, have been implicated in functional GI disorders (FGIDs). Ion channels play a crucial role in all the functions mentioned above. Hormones and natural molecules modulate these channels and represent targets of drugs and bacterial toxins. Mutations and abnormal functional expression of ion channel subunits can lead to diseases called channelopathies. These channelopathies in gastroenterology are gaining a strong interest, and the evidence of co-relationships is increasing. In this review, we describe the correlation status between channelopathies and FGIDs. Different findings are available. Among others, mutations in the ABCC7/CFTR gene have been described as a cause of constipation and diarrhea. Mutations of the SCN5A gene are instead associated with irritable bowel syndrome. In contrast, mutations of the TRPV1 and TRPA genes of the transient receptor potential (TRP) superfamily manifest hypersensitivity and visceral pain in sensory nerves. Recently, mice and humans affected by Cantu syndrome (CS), which is associated with the mutations of the KCNJ8 and ABCC9 genes encoding for the Kir6.1 and SUR2 subunits, showed dysfunction of contractility throughout the intestine and death in the mice after the weaning on solid food. The discovery of a correlation between channelopathies and FIGD opens new avenues for discovering new direct drug targets for specific channelopathies, leading to significant implications for diagnosing and treating functional GI diseases.

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“…The condition is characterized by abdominal pain, in association with defecation or a change in bowel habit. 1 , 2 Emerging evidence showed that IBS, a hitherto enigmatic disorder thought to be predominantly related to psychological factors, has a microorganic basis in a subset of patients with IBS. 3 In the past few years, a microorganic basis for IBS, including small intestinal bacterial overgrowth (SIBO), post-infectious aetiology, altered gut permeability, immune activation and dietary factors is being understood.…”

Section: Introductionmentioning

confidence: 99%

Folic acid attenuates chronic visceral pain by reducing clostridiales abundance and hydrogen sulfide production

Weng

Wei

et al. 2023

Mol Pain

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Background: Irritable bowel syndrome (IBS) related chronic visceral pain affects 20% of people worldwide. The treatment options are very limited. Although the scholarly reviews have appraised the potential effects of the intestinal microbiota on intestinal motility and sensation, the exact mechanism of intestinal microbiota in IBS-like chronic visceral pain remains largely unclear. The purpose of this study is to investigate whether Folic Acid (FA) attenuated visceral pain and its possible mechanisms. Methods: Chronic visceral hyperalgesia was induced in rats by neonatal colonic inflammation (NCI). 16S rDNA analysis of fecal samples from human subjects and rats was performed. Patch clamp recording was used to determine synaptic transmission of colonic-related spinal dorsal horn. Results: Alpha diversity of intestinal flora was increased in patients with IBS, as well as the obviously increased abundance of Clostridiales order (a main bacteria producing hydrogen sulfide). The hydrogen sulfide content was positive correlation with visceral pain score in patients with IBS. Consistently, NCI increased Clostridiales frequency and hydrogen sulfide content in feces of adult rats. Notably, the concentration of FA was markedly decreased in peripheral blood of IBS patients compared with non-IBS human subjects. FA supplement alleviated chronic visceral pain and normalized the Clostridiales frequency in NCI rats. In addition, FA supplement significantly reduced the frequency of sEPSCs of neurons in the spinal dorsal horn of NCI rats. Conclusion: Folic Acid treatment attenuated chronic visceral pain of NCI rats through reducing hydrogen sulfide production from Clostridiales in intestine.

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Blockade of BK channels attenuates chronic visceral hypersensitivity in an IBS-like rat model

Cited by 9 publications

References 37 publications

Contribution of Amygdala Histone Acetylation in Early Life Stress-Induced Visceral Hypersensitivity and Emotional Comorbidity

Contribution of Amygdala Histone Acetylation in Early Life Stress-Induced Visceral Hypersensitivity and Emotional Comorbidity

The Role of Ion Channels in Functional Gastrointestinal Disorders (FGID): Evidence of Channelopathies and Potential Avenues for Future Research and Therapeutic Targets

Folic acid attenuates chronic visceral pain by reducing clostridiales abundance and hydrogen sulfide production

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