Astrocytic ERK/STAT1 Signaling Contributes to Maintenance of Stress-Related Visceral Hypersensitivity in Rats

Dong, Zhiyu; Sun, Huihui; Wang, Junwen; Duan, Guangbing; Zhang, Yan; Chen, Ying; Huang, Ying; Xu, Shuchang

doi:10.1016/j.jpain.2022.07.006

Cited by 3 publications

(6 citation statements)

References 47 publications

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“…Cannulation was performed for the experiment of NMDAR activation as previously described 32 . Briefly, two 9.2 mm stainless steel cannulas (24‐gauge, RWD Life Science Co., Ltd. China) were implanted above BLA.…”

Section: Methodsmentioning

confidence: 99%

“…The visceral hypersensitivity model was established by chronic water avoidance stress (WAS) as previously described. 32 Briefly, a platform was placed in the center of a tank, and rats in WAS group were placed on the platform for an hour each day for 10 days with the water surface in the tank 1 cm below the platform top. Rats in Sham‐WAS group were placed on the platform but without water.…”

Section: Methodsmentioning

confidence: 99%

“…Cannulation was performed for the experiment of NMDAR activation as previously described. 32 Briefly, two 9.2 mm stainless steel cannulas (24‐gauge, RWD Life Science Co., Ltd. China) were implanted above BLA. The shEphB2 virus (0.8 μL/side) was infused through a 28‐gauge inner cannula which was connected to a syringe pump.…”

Section: Methodsmentioning

confidence: 99%

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Overexpression of EphB2 in the basolateral amygdala is crucial for inducing visceral pain sensitization in rats subjected to water avoidance stress

Duan,

Wang,

Sun

et al. 2024

CNS Neurosci Ther

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AimsBasolateral amygdala (BLA), as a center for stress responses and emotional regulation, is involved in visceral hypersensitivity of irritable bowel syndrome (IBS) induced by stress. In the present study, we aimed to investigate the role of EphB2 receptor (EphB2) in BLA and explore the underlying mechanisms in this process.MethodsVisceral hypersensitivity was induced by water avoidance stress (WAS). Elevated plus maze test, forced swimming test, and sucrose preference test were applied to assess anxiety‐ and depression‐like behaviors. Ibotenic acid or lentivirus was used to inactivate BLA in either the induction or maintenance stage of visceral hypersensitivity. The expression of protein was determined by quantitative PCR, immunofluorescence, and western blot.ResultsEphB2 expression was increased in BLA in WAS rats. Inactivation of BLA or downregulation of EphB2 in BLA failed to induce visceral hypersensitivity as well as anxiety‐like behaviors. However, during the maintenance stage of visceral pain, visceral hypersensitivity was only partially relieved but anxiety‐like behaviors were abolished by inactivation of BLA or downregulation of EphB2 in BLA. Chronic WAS increased the expression of EphB2, N‐methyl‐D‐aspartate receptors (NMDARs), and postsynaptic density protein (PSD95) in BLA. Downregulation of EphB2 in BLA reduced NMDARs and PSD95 expression in WAS rats. However, activation of NMDARs after the knockdown of EphB2 expression still triggered visceral hypersensitivity and anxiety‐like behaviors.ConclusionsTaken together, the results suggest that EphB2 in BLA plays an essential role in inducing visceral hypersensitivity. In the maintenance stage, the involvement of EphB2 is crucial but not sufficient. The increase in EphB2 induced by WAS may enhance synaptic plasticity in BLA through upregulating NMDARs, which results in IBS‐like symptoms. These findings may give insight into the treatment of IBS and related psychological distress.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Overexpression of EphB2 in the basolateral amygdala is crucial for inducing visceral pain sensitization in rats subjected to water avoidance stress

Duan,

Wang,

Sun

et al. 2024

CNS Neurosci Ther

Self Cite

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“…[68–70] Activated by neurotrophins or neuronal activity in the central or peripheral nervous system, ERK plays a critical role in the generation and maintenance of visceral nociceptive sensation by modulating injured sensory activity in primary sensory pathways. [71] Electroacupuncture activates the hypothalamic extracellular signal-regulated kinase 1/2 (ERK1/2)/mitogen-activated protein kinase pathway and attenuates yeast polysaccharide-induced colonic hypersensitivity. [72]…”

Section: Acupuncture Relieves Vh Via Perception- and Emotion-related ...mentioning

confidence: 99%

“…[68][69][70] Activated by neurotrophins or neuronal activity in the central or peripheral nervous system, ERK plays a critical role in the generation and maintenance of visceral nociceptive sensation by modulating injured sensory activity in primary sensory pathways. [71] Electroacupuncture Table 1 Neuromolecular mechanisms studies of acupuncture for hypersensitivity in functional gastrointestinal disorders.…”

Section: Thalamusmentioning

confidence: 99%

Central mechanisms of acupuncture in relieving visceral hypersensitivity in functional gastrointestinal disorders: A narrative review

Feng,

Wang,

Rong

2023

Sci Tradit Chin Med

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Visceral hypersensitivity (VH), one of the major symptoms of functional gastrointestinal disorders (FGIDs), impacts the social life and quality of life of the patients. Because of the complex pathological mechanism, the drug therapy for VH has unsatisfactory clinical efficacy and induces side effects. Alternative strategies acting on the central nervous system with few side effects are urgently needed. We summarize the central mechanisms of acupuncture in relieving VH to provide theoretical support for the clinical application of acupuncture in the treatment of VH in FGIDs. In this study, we retrieved the related articles from PubMed and Web of Science with the key words of “acupuncture,”“electroacupuncture,” and “visceral hypersensitivity.” According to the sensory conduction, perception, and emotion-related pathways involved in VH, we summarize the central mechanism of acupuncture in relieving VH from the perspectives of molecular biology and neuroimaging. The pathogenesis of VH in FGIDs involves the peripheral and central nervous systems, which are responsible for the transmission and perception of visceral sensations as well as the regulation of emotion. The widespread nature of VH indicates the involvement of the central nervous system. Acupuncture mediates the signaling pathways between the gastrointestinal tract and the brain to regulate gastrointestinal function and relieve VH. Acupuncture relieves VH by integrating multiple pathways and targets. The available studies in this field mainly focus on the regulation of a specific target or chemical transmitter by acupuncture, while the exact connection among these targets remains to be clarified by multilevel and multitarget studies.

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Upregulation of KDM6B in the anterior cingulate cortex contributes to neonatal maternal deprivation-induced chronic visceral pain in mice

Yi,

Lu,

Zhu

et al. 2024

Mol Pain

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Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disease characterized by chronic visceral pain with a complex etiology and challenging treatment. Although accumulating evidence supports the involvement of central nervous system sensitization in the development of visceral pain, the precise molecular mechanisms remain incompletely understood. In this study, we highlight the critical regulatory role of lysine-specific demethylase 6B (KDM6B) in the anterior cingulate cortex (ACC) in chronic visceral pain. To simulate clinical IBS conditions, we utilized the neonatal maternal deprivation (NMD) mouse model. Our results demonstrated that NMD induced chronic visceral pain and anxiety-like behaviors in mice. Notably, the protein expression level of KDM6B significantly increased in the ACC of NMD mice, leading to a reduction in the expression level of H32K7me3. Immunofluorescence staining revealed that KDM6B primarily co-localizes with neurons in the ACC, with minimal presence in microglia and astrocytes. Injecting GSK-J4 (a KDM6B-specific inhibitor) into ACC of NMD mice, resulted in a significant alleviation in chronic visceral pain and anxiety-like behaviors, as well as a remarkable reduction in NR2B expression level. ChIP assay further indicated that KDM6B regulates NR2B expression by influencing the demethylation of H3K27me3. In summary, our findings underscore the critical role of KDM6B in regulating chronic visceral pain and anxiety-like behaviors in NMD mice. These insights provide a basis for further understanding the molecular pathways involved in IBS and may pave the way for targeted therapeutic interventions.

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Astrocytic ERK/STAT1 Signaling Contributes to Maintenance of Stress-Related Visceral Hypersensitivity in Rats

Cited by 3 publications

References 47 publications

Overexpression of EphB2 in the basolateral amygdala is crucial for inducing visceral pain sensitization in rats subjected to water avoidance stress

Overexpression of EphB2 in the basolateral amygdala is crucial for inducing visceral pain sensitization in rats subjected to water avoidance stress

Central mechanisms of acupuncture in relieving visceral hypersensitivity in functional gastrointestinal disorders: A narrative review

Upregulation of KDM6B in the anterior cingulate cortex contributes to neonatal maternal deprivation-induced chronic visceral pain in mice

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