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Li D, Li YC, Zhu ZY, Zhang FC, Zhao QY, Jiang JH, Shen B, Tang Y, Xu GY. The paraventricular thalamus mediates visceral pain and anxiety-like behaviors via two distinct pathways. Neuron 2025:S0896-6273(25)00302-2. [PMID: 40345185 DOI: 10.1016/j.neuron.2025.04.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 03/06/2025] [Accepted: 04/18/2025] [Indexed: 05/11/2025]
Abstract
Chronic visceral pain (CVP) often accompanies emotional disorders. However, the lack of suitable animal models has hindered research into their underlying molecular and neural circuitry mechanisms. Early-life stress is a key factor in developing both visceral hypersensitivity and emotional disorders, yet its pathological mechanisms are not well understood. This study showed that adult offspring of prenatal maternal stress (PMS)-exposed mice exhibited visceral hypersensitivity and anxiety-like behaviors. Glutamatergic neurons in the anterior paraventricular thalamus (aPVT) responded to visceral pain, while those in the posterior PVT (pPVT) were more responsive to anxiety. The aPVT-basolateral amygdala (BLA) and pPVT-central amygdala (CeA) circuits regulated CVP and anxiety, respectively. Notably, increased Cacna1e expression in aPVT enhanced both visceral pain and anxiety, while Grin2a upregulation in pPVT facilitated only anxiety. These findings highlight the distinct roles of aPVTGlu-BLAGlu-CeAGABA and pPVTGlu-CeAGABA circuits, providing insights for therapeutic approaches in CVP and anxiety comorbidity.
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Affiliation(s)
- Di Li
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, Jiangsu, P.R. China
| | - Yong-Chang Li
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, Jiangsu, P.R. China
| | - Zheng-Yan Zhu
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, Jiangsu, P.R. China
| | - Fu-Chao Zhang
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, Jiangsu, P.R. China
| | - Qiu-Ying Zhao
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, Jiangsu, P.R. China
| | - Jia-Hui Jiang
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, Jiangsu, P.R. China
| | - Biyu Shen
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, Jiangsu, P.R. China; Department of Nursing, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University School of Nursing, Shanghai 200127, P.R. China
| | - Yong Tang
- International Collaborative Centre on Big Science Plan for Purine Signaling, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan, P.R. China
| | - Guang-Yin Xu
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, Jiangsu, P.R. China.
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Liu T, Ma M, Wu Y, Asif IM, Chen D, Liu L, Zhang M, Chen Y, Li B, Wang L. Protective Effects of Fucoidan on Iodoacetamide-Induced Functional Dyspepsia via Modulation of 5-HT Metabolism and Microbiota. Int J Mol Sci 2025; 26:3273. [PMID: 40244137 PMCID: PMC11989908 DOI: 10.3390/ijms26073273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 02/26/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025] Open
Abstract
As the major polysaccharide in brown algae, fucoidan possesses broad biological abilities and has been reported to improve gastrointestinal health. Functional dyspepsia, a common non-organic disease, is a complex of symptoms mainly characterized by pathogenesis, such as visceral hypersensitivity, gastric dysmotility, and inflammation. To date, the effects of fucoidan in regulating functional dyspepsia with visceral sensitivity remains unclear. In the current study, iodoacetamide was employed to establish a mouse model of visceral hypersensitivity. Meanwhile, fucoidan was orally administrated for fourteen days. Indicators were conducted to evaluate the potential of fucoidan as the ingredient of complementary and alternative medicine for functional dyspepsia, such as levels of serum hormones, expression of receptors, and gut microbial profile. The results show that oral administration of fucoidan led to significant reductions in the secretion of 5-hydroxytryptamine, cortisol, and corticosterone. Additionally, it decreased the expression of 5-hydroxytryptamine-3 receptors, with regulation of 5-hydroxytryptamine metabolism and improvement of gut microbial imbalance. The above results suggest fucoidan could ameliorate visceral hypersensitivity by modulating 5-HT metabolism and microbiota. The current findings indicate that fucoidan has potential as a biological component in the adjuvant treatment of functional dyspepsia and for its expanded utilization in the food and medical fields.
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Affiliation(s)
- Tianxu Liu
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (T.L.); (M.M.)
- Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
- Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
| | - Muyuan Ma
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (T.L.); (M.M.)
- Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
| | - Yonglin Wu
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (T.L.); (M.M.)
- Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
| | - Ismail Muhammad Asif
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (T.L.); (M.M.)
- Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
| | - Daosen Chen
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (T.L.); (M.M.)
- Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
| | - Lichong Liu
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (T.L.); (M.M.)
- Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
| | - Minghui Zhang
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (T.L.); (M.M.)
- Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
| | - Yijie Chen
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (T.L.); (M.M.)
- Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
| | - Bin Li
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (T.L.); (M.M.)
- Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
| | - Ling Wang
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; (T.L.); (M.M.)
- Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
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Zhang FC, Weng RX, Li D, Li YC, Dai XX, Hu S, Sun Q, Li R, Xu GY. A vagus nerve dominant tetra-synaptic ascending pathway for gastric pain processing. Nat Commun 2024; 15:9824. [PMID: 39537596 PMCID: PMC11561356 DOI: 10.1038/s41467-024-54056-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
Gastric pain has limited treatment options and the mechanisms within the central circuitry remain largely unclear. This study investigates the central circuitry in gastric pain induced by noxious gastric distension (GD) in mice. Here, we identified that the nucleus tractus solitarius (NTS) serves as the first-level center of gastric pain, primarily via the vagus nerve. The prelimbic cortex (PL) is engaged in the perception of gastric pain. The lateral parabrachial nucleus (LPB) and the paraventricular thalamic nucleus (PVT) are crucial regions for synaptic transmission from the NTS to the PL. The glutamatergic tetra-synaptic NTS-LPB-PVT-PL circuitry is necessary and sufficient for the processing of gastric pain. Overall, our finding reveals a glutamatergic tetra-synaptic NTS-LPB-PVT-PL circuitry that transmits gastric nociceptive signaling by the vagus nerve in mice. It provides an insight into the gastric pain ascending pathway and offers potential therapeutic targets for relieving visceral pain.
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Affiliation(s)
- Fu-Chao Zhang
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
| | - Rui-Xia Weng
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Di Li
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
| | - Yong-Chang Li
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
| | - Xiao-Xuan Dai
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
| | - Shufen Hu
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
| | - Qian Sun
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Rui Li
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Guang-Yin Xu
- Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
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Zhou JZ, Chen H, Xu WL, Fu Z, Zhou S, Zhu WJ, Zhang ZH. Auricular Vagal Nerve Stimulation Inhibited Central Nerve Growth Factor/Tropomyosin Receptor Kinase A/Phospholipase C-Gamma Signaling Pathway in Functional Dyspepsia Model Rats With Gastric Hypersensitivity. Neuromodulation 2024; 27:273-283. [PMID: 36801128 DOI: 10.1016/j.neurom.2023.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 01/12/2023] [Accepted: 01/18/2023] [Indexed: 02/18/2023]
Abstract
OBJECTIVE Functional dyspepsia (FD), which has a complicated pathophysiologic process, is a common functional gastrointestinal disease. Gastric hypersensitivity is the key pathophysiological factor in patients with FD with chronic visceral pain. Auricular vagal nerve stimulation (AVNS) has the therapeutic effect of reducing gastric hypersensitivity by regulating the activity of the vagus nerve. However, the potential molecular mechanism is still unclear. Therefore, we investigated the effects of AVNS on the brain-gut axis through the central nerve growth factor (NGF)/ tropomyosin receptor kinase A (TrkA)/phospholipase C-gamma (PLC-γ) signaling pathway in FD model rats with gastric hypersensitivity. MATERIALS AND METHODS We established the FD model rats with gastric hypersensitivity by means of colon administration of trinitrobenzenesulfonic acid on ten-day-old rat pups, whereas the control rats were given normal saline. AVNS, sham AVNS, K252a (an inhibitor of TrkA, intraperitoneally), and K252a + AVNS were performed on eight-week-old model rats for five consecutive days. The therapeutic effect of AVNS on gastric hypersensitivity was determined by the measurement of abdominal withdrawal reflex response to gastric distention. NGF in gastric fundus and NGF, TrkA, PLC-γ, and transient receptor potential vanilloid 1 (TRPV1) in the nucleus tractus solitaries (NTS) were detected separately by polymerase chain reaction, Western blot, and immunofluorescence tests. RESULTS It was found that a high level of NGF in gastric fundus and an upregulation of the NGF/TrkA/PLC-γ signaling pathway in NTS were manifested in model rats. Meanwhile, both AVNS treatment and the administration of K252a not only decreased NGF messenger ribonucleic acid (mRNA) and protein expressions in gastric fundus but also reduced the mRNA expressions of NGF, TrkA, PLC-γ, and TRPV1 and inhibited the protein levels and hyperactive phosphorylation of TrkA/PLC-γ in NTS. In addition, the expressions of NGF and TrkA proteins in NTS were decreased significantly after the immunofluorescence assay. The K252a + AVNS treatment exerted a more sensitive effect on regulating the molecular expressions of the signal pathway than did the K252a treatment. CONCLUSION AVNS can regulate the brain-gut axis effectively through the central NGF/TrkA/PLC-γ signaling pathway in the NTS, which suggests a potential molecular mechanism of AVNS in ameliorating visceral hypersensitivity in FD model rats.
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Affiliation(s)
- Jing-Zhu Zhou
- Department of Acupuncture and Moxibustion, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
| | - Huan Chen
- Department of Acupuncture and Moxibustion, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Wan-Li Xu
- Department of Acupuncture and Moxibustion, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Zhe Fu
- Department of Acupuncture and Moxibustion, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Shuai Zhou
- Department of Acupuncture and Moxibustion, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Wei-Jian Zhu
- Department of Acupuncture and Moxibustion, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Zhao-Hui Zhang
- Department of Acupuncture and Moxibustion, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
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Wang H, Zhang F, Xu TW, Xu Y, Tian Y, Wu Y, Xu J, Hu S, Xu G. DNMT1 involved in the analgesic effect of folic acid on gastric hypersensitivity through downregulating ASIC1 in adult offspring rats with prenatal maternal stress. CNS Neurosci Ther 2023; 29:1678-1689. [PMID: 36852448 PMCID: PMC10173708 DOI: 10.1111/cns.14131] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/30/2022] [Accepted: 12/10/2022] [Indexed: 03/01/2023] Open
Abstract
AIMS Gastric hypersensitivity (GHS) is a characteristic pathogenesis of functional dyspepsia (FD). DNA methyltransferase 1 (DNMT1) and acid-sensing ion channel 1 (ASIC1) are associated with GHS induced by prenatal maternal stress (PMS). The aim of this study was to investigate the mechanism of DNMT1 mediating the analgesic effect of folic acid (FA) on PMS-induced GHS. METHODS GHS was quantified by electromyogram recordings. The expression of DNMT1, DNMT3a, DNMT3b, and ASIC1 were detected by western blot, RT-PCR, and double-immunofluorescence. Neuronal excitability and proton-elicited currents of dorsal root ganglion (DRG) neurons were determined by whole-cell patch clamp recordings. RESULTS The expression of DNMT1, but not DNMT3a or DNMT3b, was decreased in DRGs of PMS rats. FA alleviated PMS-induced GHS and hyperexcitability of DRG neurons. FA also increased DNMT1 and decreased ASIC1 expression and sensitivity. Intrathecal injection of DNMT1 inhibitor DC-517 attenuated the effect of FA on GHS alleviation and ASIC1 downregulation. Overexpression of DNMT1 with lentivirus not only rescued ASIC1 upregulation and hypersensitivity, but also alleviated GHS and hyperexcitability of DRG neurons induced by PMS. CONCLUSIONS These results indicate that increased DNMT1 contributes to the analgesic effect of FA on PMS-induced GHS by reducing ASIC1 expression and sensitivity.
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Affiliation(s)
- Hong‐Jun Wang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of NeuroscienceSoochow UniversitySuzhouJiangsuChina
- Jiangsu Key Laboratory of Anesthesiology & Jiangsu Key Laboratory of Anesthesia and Analgesia Application TechnologyXuzhou Medical UniversityXuzhouChina
| | - Fu‐Chao Zhang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of NeuroscienceSoochow UniversitySuzhouJiangsuChina
| | - Timothy W. Xu
- Suzhou Academy of Xi'an Jiaotong UniversitySuzhouChina
| | - Yu‐Cheng Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of NeuroscienceSoochow UniversitySuzhouJiangsuChina
| | - Yuan‐Qing Tian
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of NeuroscienceSoochow UniversitySuzhouJiangsuChina
| | - Yan‐Yan Wu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of NeuroscienceSoochow UniversitySuzhouJiangsuChina
| | - Ji‐Tian Xu
- Department of Physiology and NeurobiologyCollege of Basic Medical Sciences, Zhengzhou UniversityZhengzhouChina
| | - Shufen Hu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of NeuroscienceSoochow UniversitySuzhouJiangsuChina
| | - Guang‐Yin Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of NeuroscienceSoochow UniversitySuzhouJiangsuChina
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Alam MJ, Chen JDZ. Electrophysiology as a Tool to Decipher the Network Mechanism of Visceral Pain in Functional Gastrointestinal Disorders. Diagnostics (Basel) 2023; 13:627. [PMID: 36832115 PMCID: PMC9955347 DOI: 10.3390/diagnostics13040627] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/27/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023] Open
Abstract
Abdominal pain, including visceral pain, is prevalent in functional gastrointestinal (GI) disorders (FGIDs), affecting the overall quality of a patient's life. Neural circuits in the brain encode, store, and transfer pain information across brain regions. Ascending pain signals actively shape brain dynamics; in turn, the descending system responds to the pain through neuronal inhibition. Pain processing mechanisms in patients are currently mainly studied with neuroimaging techniques; however, these techniques have a relatively poor temporal resolution. A high temporal resolution method is warranted to decode the dynamics of the pain processing mechanisms. Here, we reviewed crucial brain regions that exhibited pain-modulatory effects in an ascending and descending manner. Moreover, we discussed a uniquely well-suited method, namely extracellular electrophysiology, that captures natural language from the brain with high spatiotemporal resolution. This approach allows parallel recording of large populations of neurons in interconnected brain areas and permits the monitoring of neuronal firing patterns and comparative characterization of the brain oscillations. In addition, we discussed the contribution of these oscillations to pain states. In summary, using innovative, state-of-the-art methods, the large-scale recordings of multiple neurons will guide us to better understanding of pain mechanisms in FGIDs.
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Affiliation(s)
- Md Jahangir Alam
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jiande D. Z. Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
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7
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Decraecker L, Boeckxstaens G, Denadai-Souza A. Inhibition of Serine Proteases as a Novel Therapeutic Strategy for Abdominal Pain in IBS. Front Physiol 2022; 13:880422. [PMID: 35665224 PMCID: PMC9161638 DOI: 10.3389/fphys.2022.880422] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Serine proteases are heavily present in the gastrointestinal tract where they are essential in numerous physiological processes. An imbalance in the proteolytic activity is a central mechanism underlying abdominal pain in irritable bowel syndrome (IBS). Therefore, protease inhibitors are emerging as a promising therapeutic tool to manage abdominal pain in this functional gastrointestinal disorder. With this review, we provide an up-to-date overview of the implications of serine proteases in the development of abdominal pain in IBS, along with a critical assessment of the current developments and prospects of protease inhibitors as a therapeutic tool. In particular, we highlight the current knowledge gap concerning the identity of dysregulated serine proteases that are released by the rectal mucosa of IBS patients. Finally, we suggest a workflow with state-of-the-art techniques that will help address the knowledge gap, guiding future research towards the development of more effective and selective protease inhibitors to manage abdominal pain in IBS.
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Epigenetic upregulation of acid-sensing ion channel 1 contributes to gastric hypersensitivity in adult offspring rats with prenatal maternal stress. Pain 2021; 161:989-1004. [PMID: 31895269 DOI: 10.1097/j.pain.0000000000001785] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Functional dyspepsia is a common functional gastrointestinal disorder. Gastric hypersensitivity (GHS) is a hallmark of this disorder, but the cellular mechanisms remain largely unknown. Stressors during gestational period could have effects on the offspring's tissue structure and function, which may predispose to gastrointestinal diseases. The aim of this study was to test whether prenatal maternal stress (PMS) induces GHS and to investigate role of acid-sensing ion channel (ASIC)/nuclear factor-κB (NF-κB) signaling by examining Asic1 methylation status in adult offspring rats. Gastric hypersensitivity in response to gastric distension was examined by electromyography recordings. Changes in neuronal excitability were determined by whole-cell patch-clamp recording techniques. Demethylation of CpG islands of Asic1 was determined by methylation-specific PCR and bisulfite sequencing assay. Prenatal maternal stress produced GHS in adult offspring rats. Treatment with amiloride, an inhibitor of ASICs, significantly attenuated GHS and reversed hyperexcitability of gastric-specific dorsal root ganglion (DRG) neurons labeled by the dye DiI. Expression of ASIC1 and NF-κBp65 was markedly enhanced in T7 to T10 DRGs. Furthermore, PMS led to a significant demethylation of CpG islands in the Asic1 promoter. A chromatin immunoprecipitation assay showed that PMS also enhanced the ability of NF-κBp65 to bind the promoter of Asic1 gene. Blockade of NF-κB using lentiviral-p65shRNA reversed upregulation of ASIC1 expression, GHS, and the hyperexcitability of DRG neurons. These data suggest that upregulation of ASIC1 expression is attributed to Asic1 promoter DNA demethylation and NF-κB activation, and that the enhanced interaction of the Asic1 and NF-κBp65 contributes to GHS induced by PMS.
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9
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Duan S, Kondo T, Miwa H, Yang Y, Wang S, Kanda H, Kogure Y, Imamura N, Fujimura T, Kono T, Fukushima M, Tozawa K, Tomita T, Oshima T, Fukui H, Yamamoto S, Noguchi K, Dai Y. Eosinophil-associated microinflammation in the gastroduodenal tract contributes to gastric hypersensitivity in a rat model of early-life adversity. Am J Physiol Gastrointest Liver Physiol 2021; 320:G206-G216. [PMID: 33174456 DOI: 10.1152/ajpgi.00313.2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Gastric hypersensitivity is a major pathophysiological feature of functional dyspepsia (FD). Recent clinical studies have shown that a large number of patients with FD present with gastroduodenal microinflammation, which may be involved in the pathophysiology of FD. However, no animal model reflecting this clinical characteristic has been established. The underlying mechanism between microinflammation and FD remains unknown. In this study, using a maternal separation (MS)-induced FD model, we aimed to reproduce the gastroduodenal microinflammation and reveal the interaction between gastroduodenal microinflammation and gastric hypersensitivity. The MS model was established by separating newborn Sprague-Dawley rats for 2 h a day from postnatal day 1 to day 10. At 7-8 wk of age, electromyography was used to determine the visceromotor response to gastric distention (GD) and immunohistochemistry was performed to detect distension-associated neuronal activation as well as immunohistological changes. Our results demonstrated that MS-induced FD rats underwent gastric hypersensitivity with GD at 60 and 80 mmHg, which are related to increased p-ERK1/2 expression in the dorsal horn of T9-T10 spinal cords. Eosinophils, but not mast cells, were significantly increased in the gastroduodenal tract, and the coexpression rate of CD11b and major basic protein significantly increased in MS rats. Treatment with dexamethasone reversed gastric hypersensitivity in MS-induced FD rats by inhibiting eosinophil infiltration. These findings indicated that neonatal MS stress induces eosinophil-associated gastroduodenal microinflammation and gastric hypersensitivity in adulthood in rats. Microinflammation contributes to gastric hypersensitivity; therefore, anti-inflammatory therapy may be effective in treating patients with FD with gastroduodenal microinflammation.NEW & NOTEWORTHY We showed for the first time that neonatal MS stress-induced FD rats undergo gastroduodenal eosinophil-associated microinflammation in adulthood. Suppression of microinflammation attenuated gastric hypersensitivity in MS rats. These findings established a functional link between microinflammation and gastric hypersensitivity, which may provide a potential clue for the clinical treatment of FD.
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Affiliation(s)
- Shaoqi Duan
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.,Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan.,Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Japan
| | - Takashi Kondo
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroto Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.,Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Japan
| | - Yanjing Yang
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan.,Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Japan.,Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Japan
| | - Shenglan Wang
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan.,School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine (BUCM), Beijing, China
| | - Hirosato Kanda
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan.,Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Japan.,Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yoko Kogure
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan
| | - Nobuko Imamura
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tadahiro Fujimura
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tomoaki Kono
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Masashi Fukushima
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Katsuyuki Tozawa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Toshihiko Tomita
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tadayuki Oshima
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hirokazu Fukui
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Satoshi Yamamoto
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan
| | - Koichi Noguchi
- Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Japan.,Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yi Dai
- Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan.,Traditional Medicine Research Center, Chinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM), Kobe, Japan.,Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Japan
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10
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Ouyang X, Li S, Zhou J, Chen JDZ. Electroacupuncture Ameliorates Gastric Hypersensitivity via Adrenergic Pathway in a Rat Model of Functional Dyspepsia. Neuromodulation 2020; 23:1137-1143. [DOI: 10.1111/ner.13154] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 02/27/2020] [Accepted: 03/16/2020] [Indexed: 12/15/2022]
Affiliation(s)
- Xiaojun Ouyang
- Veterans Research and Education Foundation, Oklahoma City VA Health Care System OK USA
- Institute of Geriatrics, Jiangsu Province Official Hospital Nanjing Jiangsu China
| | - Shiying Li
- Veterans Research and Education Foundation, Oklahoma City VA Health Care System OK USA
- Division of Gastroenterology and Hepatology Johns Hopkins University Baltimore MD USA
| | - Jingzhu Zhou
- Veterans Research and Education Foundation, Oklahoma City VA Health Care System OK USA
- Department of Acupuncture and Moxibustion The First Affiliated Hospital of Nanjing Medical University Nanjing Jiangsu China
| | - Jiande DZ Chen
- Division of Gastroenterology and Hepatology Johns Hopkins University Baltimore MD USA
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11
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Accarie A, Vanuytsel T. Animal Models for Functional Gastrointestinal Disorders. Front Psychiatry 2020; 11:509681. [PMID: 33262709 PMCID: PMC7685985 DOI: 10.3389/fpsyt.2020.509681] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 10/22/2020] [Indexed: 12/12/2022] Open
Abstract
Functional gastrointestinal disorders (FGID), such as functional dyspepsia (FD) and irritable bowel syndrome (IBS) are characterized by chronic abdominal symptoms in the absence of an organic, metabolic or systemic cause that readily explains these complaints. Their pathophysiology is still not fully elucidated and animal models have been of great value to improve the understanding of the complex biological mechanisms. Over the last decades, many animal models have been developed to further unravel FGID pathophysiology and test drug efficacy. In the first part of this review, we focus on stress-related models, starting with the different perinatal stress models, including the stress of the dam, followed by a discussion on neonatal stress such as the maternal separation model. We also describe the most commonly used stress models in adult animals which brought valuable insights on the brain-gut axis in stress-related disorders. In the second part, we focus more on models studying peripheral, i.e., gastrointestinal, mechanisms, either induced by an infection or another inflammatory trigger. In this section, we also introduce more recent models developed around food-related metabolic disorders or food hypersensitivity and allergy. Finally, we introduce models mimicking FGID as a secondary effect of medical interventions and spontaneous models sharing characteristics of GI and anxiety-related disorders. The latter are powerful models for brain-gut axis dysfunction and bring new insights about FGID and their comorbidities such as anxiety and depression.
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Affiliation(s)
- Alison Accarie
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Tim Vanuytsel
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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12
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Nerve growth factor and Tropomyosin receptor kinase A are increased in the gastric mucosa of patients with functional dyspepsia. BMC Gastroenterol 2019; 19:221. [PMID: 31856738 PMCID: PMC6924065 DOI: 10.1186/s12876-019-1133-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Accepted: 12/02/2019] [Indexed: 01/19/2023] Open
Abstract
Background Nerve growth factor (NGF) and enteric glial cells (EGCs) are associated with visceral hypersensitivity and gastrointestinal motility disorder, which may represent the pathogenesis of functional dyspepsia (FD). This study aimed to investigate the expression of NGF, its high affinity receptor tropomyosin receptor kinase A (TrkA) and the EGC activation marker glial fibrillary acidic protein (GFAP) in the gastric mucosa of patients with FD and the association of these proteins with dyspeptic symptoms. Methods Gastric mucosal biopsies taken from 27 FD patients (9 epigastric pain syndrome (EPS) patients, 7 postprandial distress syndrome (PDS) patients and 11 EPS overlap PDS patients) and 26 control subjects were used for analysis. The expression of NGF, TrkA and GFAP was examined, and the association of these proteins with dyspeptic symptoms, including epigastric pain, postprandial fullness, early satiation and epigastric burning, was analysed. Results The expression levels of NGF, TrkA, and GFAP in the gastric mucosa were significantly higher in the EPS group, the PDS group, and the EPS overlap PDS group than in the healthy control group. There was no significant difference between the FD subgroups. TrkA colocalized with GFAP, which indicated that TrkA was localized to EGCs, and the expression of TrkA in EGCs was significantly higher in the FD group than in the control group. Changes in the expression of NGF, TrkA, and GFAP were positively correlated with epigastric pain, postprandial fullness and early satiation but had no significant relationship with epigastric burning. Conclusions The increased expression of gastric NGF, TrkA and GFAP might be involved in FD pathophysiology and symptom perception.
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13
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Dong Y, Li S, Yin J, Chen JDZ. Ameliorating effects of optimized gastric electrical stimulation and mechanisms involving nerve growth factor and opioids in a rodent model of gastric hypersensitivity. Neurogastroenterol Motil 2019; 31:e13551. [PMID: 30790401 DOI: 10.1111/nmo.13551] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 12/09/2018] [Accepted: 12/20/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Gastric electrical stimulation (GES) has been applied to treat gastric motility disorders for decades. This study was designed to investigate the effects and mechanisms of GES for visceral hypersensitivity in a rodent model of functional dyspepsia (FD). METHODS Male Sprague-Dawley rat pups at 10-days old received 0.1% iodoacetamide (IA) daily for 6 days. The experiments were performed when the rats reached 8-11 weeks of age, and visceral hypersensitivity was established. Then, GES parameters were optimized and the chronic effects of GES on gastric hypersensitivity were assessed by electromyogram (EMG). Naloxone (3 mg/kg), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP, 1 mg/kg), and anti-NGF (16 μg/kg) were individually intraperitoneally injected to investigate opioid and nerve growth factor (NGF) mechanisms. Tissues were analyzed for NGF expression. KEY RESULTS In the IA-treated rats, the visceromotor response to gastric distension was significantly increased, and both acute GES with optimized stimulation parameters (0.25 seconds on, 0.25 seconds off, 100 Hz, 0.25 ms, 6 mA) and chronic GES (7 days, 2 hours/day) normalized gastric hypersensitivity. The inhibitory effect of GES on gastric hypersensitivity was blocked by naloxone and CTOP. Anti-NGF normalized EMG responses in IA-treated rats. The expressions of NGF in the tissues of IA-treated rats were dramatically increased, and these increases were suppressed with GES. CONCLUSIONS AND INFERENCES GES with optimized parameters improves gastric hypersensitivity induced by neonatal treatment of IA mediated peripherally by suppressing NGF and via the opioid mechanism involving the µ receptor. GES as a potential therapy for treating visceral pain may be explored in clinical studies.
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Affiliation(s)
- Yan Dong
- Veterans Research and Education Foundation, VA Medical Center, Oklahoma City, Oklahoma.,Institute of Chinese Traditional Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shiying Li
- Veterans Research and Education Foundation, VA Medical Center, Oklahoma City, Oklahoma.,Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jieyun Yin
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jiande D Z Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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14
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Strober W. Neonatal Colonic Inflammation: An Epigenetic Trigger of Adult Disease. Cell Mol Gastroenterol Hepatol 2018; 6:115-116. [PMID: 29928678 PMCID: PMC6007811 DOI: 10.1016/j.jcmgh.2018.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Affiliation(s)
- Warren Strober
- Mucosal Immunity Section, National Institutes of Health, Bethesda, Maryland
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15
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Neonatal Colonic Inflammation Epigenetically Aggravates Epithelial Inflammatory Responses to Injury in Adult Life. Cell Mol Gastroenterol Hepatol 2018; 6:65-78. [PMID: 29928672 PMCID: PMC6008258 DOI: 10.1016/j.jcmgh.2018.02.014] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 02/01/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Early life adversity is considered a risk factor for the development of gastrointestinal diseases, including inflammatory bowel disease. We hypothesized that early life colonic inflammation causes susceptibility to aggravated overexpression of interleukin (IL)1β. METHODS We developed a 2-hit rat model in which neonatal inflammation (NI) and adult inflammation (AI) were induced by trinitrobenzene sulfonic acid. RESULTS Aggravated immune responses were observed in NI + AI rats, including a sustained up-regulation of IL1β and other cytokines. In parallel with exacerbated loss of inhibitor of kappa B alpha expression, NI + AI rats showed hyperacetylation of histone H4K12 and increased V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A binding on the IL1B promoter, accompanied by high levels of norepinephrine/epinephrine. Propranolol, a β-blocker, markedly ameliorated the inflammatory response and IL1β overexpression by mitigating against epigenetic modifications. Adrenalectomy abrogated NI-induced disease susceptibility whereas yohimbine sensitized the epithelium for exacerbated immune response. The macrophages of NI rats produced more IL1β than controls after exposure to lipopolysaccharide (LPS), suggesting hypersensitization; incubation with LPS plus Foradil (Sigma, St. Louis, MO), a β2-agonist, induced a greater IL1β expression than LPS alone. Epinephrine and Foradil also exacerbated LPS-induced IL1β activation in human THP-1-derived macrophages, by increasing acetylated H4K12, and these increases were abrogated by propranolol. CONCLUSIONS NI sensitizes the colon epithelium for exacerbated IL1β activation by increasing stress hormones that induce histone hyperacetylation, allowing greater access of nuclear factor-κB to the IL1B promoter and rendering the host susceptible to aggravated immune responses. Our findings suggest that β blockers have a therapeutic potential for inflammatory bowel disease susceptibility and establish a novel paradigm whereby NI induces epigenetic susceptibility to inflammatory bowel disease.
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Key Words
- AI, adult inflammation
- ChIP, chromatin immunoprecipitation
- Ctl, control
- Early Life Adversity
- Epinephrine
- H4K12ac, acetylated HRK12
- HDAC, histone deacetylase
- Histone Acetylation
- IBD, inflammatory bowel disease
- IL, interleukin
- Inflammatory Bowel Disease
- IκB, inhibitor of kappa B alpha
- LPS, lipopolysaccharide
- MPO, myeloperoxidase
- NF-κB
- NF-κB, nuclear factor-κB
- NI, neonatal inflammation
- PCR, polymerase chain reaction
- PMA, phorbol 12-myristate 13-acetate
- RNAP II, RNA polymerase II
- RelA, V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A
- TNBS, 2,4,6-trinitrobenzene sulfonic acid
- Tnf, tumor necrosis factor
- mRNA, messenger RNA
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Ye Y, Wang XR, Zheng Y, Yang JW, Yang NN, Shi GX, Liu CZ. Choosing an Animal Model for the Study of Functional Dyspepsia. Can J Gastroenterol Hepatol 2018; 2018:1531958. [PMID: 29623262 PMCID: PMC5830275 DOI: 10.1155/2018/1531958] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Accepted: 11/16/2017] [Indexed: 02/06/2023] Open
Abstract
Functional dyspepsia (FD) is a common functional gastrointestinal disorder with pain or discomfort in the upper abdomen as the main characteristic. The prevalence of FD worldwide varies between 5% and 11%. This condition adversely affects attendance and productivity in the workplace. Emerging evidence is beginning to unravel the pathophysiologies of FD, and new data on treatment are helping to guide evidence-based practice. In order to better understand the pathophysiologies of FD and explore better treatment options, various kinds of animal models of FD have been developed. However, it is unclear which of these models most closely mimic the human disease. This review provides a comprehensive overview of the currently available animal models of FD in relationship to the clinical features of the disease. The rationales, methods, merits, and disadvantages for modelling specific symptoms of FD are discussed in detail.
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Affiliation(s)
- Yang Ye
- Acupuncture and Moxibustion Department, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Xue-Rui Wang
- Acupuncture and Moxibustion Department, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing, China
| | - Yang Zheng
- Acupuncture and Moxibustion Department, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing, China
| | - Jing-Wen Yang
- Acupuncture and Moxibustion Department, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing, China
| | - Na-Na Yang
- Acupuncture and Moxibustion Department, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Guang-Xia Shi
- Acupuncture and Moxibustion Department, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing, China
| | - Cun-Zhi Liu
- Acupuncture and Moxibustion Department, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing, China
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Jing FC, Zhang J, Feng C, Nian YY, Wang JH, Hu H, Yang BD, Sun XM, Zheng JY, Yin XR. Potential rat model of anxiety-like gastric hypersensitivity induced by sequential stress. World J Gastroenterol 2017; 23:7594-7608. [PMID: 29204059 PMCID: PMC5698252 DOI: 10.3748/wjg.v23.i42.7594] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 10/04/2017] [Accepted: 10/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To establish a rat model of anxiety-like gastric hypersensitivity (GHS) of functional dyspepsia (FD) induced by novel sequential stress.
METHODS Animal pups were divided into two groups from postnatal day 2: controls and the sequential-stress-treated. The sequential-stress-treated group received maternal separation and acute gastric irritation early in life and restraint stress in adulthood; controls were reared undisturbed with their mothers. Rats in both groups were followed to adulthood (8 wk) at which point the anxiety-like behaviors and visceromotor responses to gastric distention (20-100 mmHg) and gastric emptying were tested. Meanwhile, alterations in several anxiety-related brain-stomach modulators including 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), brain-derived neurotrophic factor (BDNF) and nesfatin-1 in the rat hippocampus, plasma and gastric fundus and the 5-HT1A receptor (5-HT1AR) in the hippocampal CA1 subfield and the mucosa of the gastric fundus were examined.
RESULTS Sequential-stress-treated rats simultaneously demonstrated anxiety-like behaviors and GHS in dose-dependent manner compared with the control group. Although rats in both groups consumed similar amount of solid food, the rate of gastric emptying was lower in the sequential-stress-treated rats than in the control group. Sequential stress significantly decreased the levels of 5-HT (51.91 ± 1.88 vs 104.21 ± 2.88, P < 0.01), GABA (2.38 ± 0.16 vs 5.01 ± 0.13, P < 0.01) and BDNF (304.40 ± 10.16 vs 698.17 ± 27.91, P < 0.01) in the hippocampus but increased the content of nesfatin-1 (1961.38 ± 56.89 vs 1007.50 ± 33.05, P < 0.01) in the same site; significantly decreased the levels of 5-HT (47.82 ± 2.29 vs 89.45 ± 2.61, P < 0.01) and BDNF (257.05 ± 12.89 vs 536.71 ± 20.73, P < 0.01) in the plasma but increased the content of nesfatin-1 in it (1391.75 ± 42.77 vs 737.88 ± 33.15, P < 0.01); significantly decreased the levels of 5-HT (41.15 ± 1.81 vs 89.17 ± 2.31, P < 0.01) and BDNF (226.49 ± 12.10 vs 551.36 ± 16.47, P < 0.01) in the gastric fundus but increased the content of nesfatin-1 in the same site (1534.75 ± 38.52 vs 819.63 ± 38.04, P < 0.01). The expressions of 5-HT1AR in the hippocampal CA1 subfield and the mucosa of the gastric fundus were down-regulated measured by IHC (Optical Density value: Hippocampus 15253.50 ± 760.35 vs 21149.75 ± 834.13; gastric fundus 15865.25 ± 521.24 vs 23865.75 ± 1868.60; P < 0.05, respectively) and WB (0.38 ± 0.01 vs 0.57 ± 0.03, P < 0.01) (n = 8 in each group).
CONCLUSION Sequential stress could induce a potential rat model of anxiety-like GHS of FD, which could be used to research the mechanisms of this intractable disease.
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Affiliation(s)
- Fu-Chun Jing
- Department of Gastroenterology, Second Hospital Affiliated to the Medical School of Xi’an Jiao Tong University, Xi’an 710004, Shaanxi Province, China
- Department of Digestive Diseases, Baoji People’s Hospital Affiliated to the Medical School of Yan’an University, Baoji 721000, Shaanxi Province, China
| | - Jun Zhang
- Department of Gastroenterology, Second Hospital Affiliated to the Medical School of Xi’an Jiao Tong University, Xi’an 710004, Shaanxi Province, China
| | - Chen Feng
- Department of Gastroenterology, Second Hospital Affiliated to the Medical School of Xi’an Jiao Tong University, Xi’an 710004, Shaanxi Province, China
| | - Yuan-Yuan Nian
- Department of Gastroenterology, Second Hospital Affiliated to the Medical School of Xi’an Jiao Tong University, Xi’an 710004, Shaanxi Province, China
| | - Jin-Hai Wang
- Department of Gastroenterology, Second Hospital Affiliated to the Medical School of Xi’an Jiao Tong University, Xi’an 710004, Shaanxi Province, China
| | - Hao Hu
- Department of Pharmacology, Health Science Center, Xi’an Jiao Tong University, Xi’an 710061, Shaanxi Province, China
- Basic Medical Experiment Teaching Center, Health Science Center, Xi’an Jiao Tong University, Xi’an 710061, Shaanxi Province, China
| | - Bao-De Yang
- Department of Pharmacology, Health Science Center, Xi’an Jiao Tong University, Xi’an 710061, Shaanxi Province, China
- Basic Medical Experiment Teaching Center, Health Science Center, Xi’an Jiao Tong University, Xi’an 710061, Shaanxi Province, China
| | - Xiao-Ming Sun
- Department of Pharmacology, Health Science Center, Xi’an Jiao Tong University, Xi’an 710061, Shaanxi Province, China
- Basic Medical Experiment Teaching Center, Health Science Center, Xi’an Jiao Tong University, Xi’an 710061, Shaanxi Province, China
| | - Jian-Yun Zheng
- Department of Pathology, the First Affiliated Hospital of Xi’an Medical University, Xi’an 710077, Shaanxi Province, China
| | - Xiao-Ran Yin
- Department of Gastroenterology, Second Hospital Affiliated to the Medical School of Xi’an Jiao Tong University, Xi’an 710004, Shaanxi Province, China
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19
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Li M, Xue L, Zhu HY, Wang H, Xu X, Zhang PA, Wu G, Xu GY. Protein Kinase C Mediates the Corticosterone-induced Sensitization of Dorsal Root Ganglion Neurons Innervating the Rat Stomach. J Neurogastroenterol Motil 2017; 23:464-476. [PMID: 28343377 PMCID: PMC5503297 DOI: 10.5056/jnm16161] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 12/31/2016] [Accepted: 01/15/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS Gastric hypersensitivity contributes to abdominal pain in patients with functional dyspepsia. Recent studies showed that hormones induced by stress are correlated with visceral hypersensitivity. However, the precise mechanisms underlying gastric hypersensitivity remain largely unknown. The aim of the present study was designed to investigate the roles of corticosterone (CORT) on excitability of dorsal root ganglion (DRG) neurons innervating the stomach. METHODS DRG neurons innervating the stomach were labeled by DiI injection into the stomach wall. Patch clamp recordings were employed to examine neural excitability and voltage-gated sodium channel currents. Electromyograph technique was used to determine the responses of neck muscles to gastric distension. RESULTS Incubation of acutely isolated DRG neurons with CORT significantly depolarized action potential threshold and enhanced the number of action potentials induced by current stimulation of the neuron. Under voltage-clamp mode, incubation of CORT enhanced voltage-gated sodium current density of the recorded neurons. Pre-incubation of GF109203X, an inhibitor of protein kinase C, blocked the CORT-induced hyperexcitability and potentiation of sodium currents. However, pre-incubation of H-89, an inhibitor of protein kinase A, did not alter the sodium current density. More importantly, intraperitoneal injection of CORT produced gastric hypersensitivity of healthy rats, which was blocked by pre-administration of GF109203X but not H-89. CONCLUSIONS Our data strongly suggest that CORT rapidly enhanced neuronal excitability and sodium channel functions, which is most likely mediated by protein kinase C but not protein kinase A signaling pathway in DRG neurons innervating the stomach, thus underlying the gastric hypersensitivity induced by CORT injection.
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Affiliation(s)
| | | | | | | | | | | | | | - Guang-Yin Xu
- Correspondence: Guang-Yin Xu, MD, PhD, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, 199 Ren-Ai Road, Suzhou 215123, China, Tel: +86-512-6588-2817, Fax: +86-512-6588-3602, E-mail:
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Abstract
INTRODUCTION The etiologies of functional dyspepsia symptoms, including postprandial distress syndrome, remain unknown. We tested the hypothesis that neonatal colon inflammation induces postprandial distress syndrome-like symptoms in adult life that associate with increased activation of vagal afferent pathways and forebrain limbic regions. RESULTS These rats showed a significant decrease in nutrient meal consumption to satiety after an overnight fast, decrease in gastric emptying, decrease in total distance traveled, and decrease in percent distance traveled in midfield versus control rats in open field test, indicating postprandial anxiety- and depression-like behaviors. Adult naïve rats treated with oral iodoacetamide to induce H. pylori-like mild gastritis demonstrated similar postprandial effects as the above rats. CONCLUSIONS We concluded that neonatal colon inflammation is a risk factor for the development of postprandial distress syndrome-like symptoms. While mild gastritis can induce symptoms similar to those of neonatal colon inflammation, gastritis in these rats does not worsen the symptoms.
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21
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Wang FY, Zhong LL, Kang N, Dai L, Lv L, Bian LQ, Chen T, Zhang BH, Bian ZX, Wang XG, Zhu EL, Tang XD. Chinese herbal formula for postprandial distress syndrome: Study protocol of a double-blinded, randomized, placebo-controlled trial. Eur J Integr Med 2016; 8:688-694. [DOI: 10.1016/j.eujim.2016.03.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Winston JH, Sarna SK. Enhanced sympathetic nerve activity induced by neonatal colon inflammation induces gastric hypersensitivity and anxiety-like behavior in adult rats. Am J Physiol Gastrointest Liver Physiol 2016; 311:G32-9. [PMID: 27151940 PMCID: PMC4967178 DOI: 10.1152/ajpgi.00067.2016] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 04/20/2016] [Indexed: 02/08/2023]
Abstract
Gastric hypersensitivity (GHS) and anxiety are prevalent in functional dyspepsia patients; their underlying mechanisms remain unknown largely because of lack of availability of live visceral tissues from human subjects. Recently, we demonstrated in a preclinical model that rats subjected to neonatal colon inflammation show increased basal plasma norepinephrine (NE), which contributes to GHS through the upregulation of nerve growth factor (NGF) expression in the gastric fundus. We tested the hypothesis that neonatal colon inflammation increases anxiety-like behavior and sympathetic nervous system activity, which upregulates the expression of NGF to induce GHS in adult life. Chemical sympathectomy, but not adrenalectomy, suppressed the elevated NGF expression in the fundus muscularis externa and GHS. The measurement of heart rate variability showed a significant increase in the low frequency-to-high frequency ratio in GHS vs. the control rats. Stimulus-evoked release of NE from the fundus muscularis externa strips was significantly greater in GHS than in the control rats. Tyrosine hydroxylase expression was increased in the celiac ganglia of the GHS vs. the control rats. We found an increase in trait but not stress-induced anxiety-like behavior in GHS rats in an elevated plus maze. We concluded that neonatal programming triggered by colon inflammation upregulates tyrosine hydroxylase in the celiac ganglia, which upregulates the release of NE in the gastric fundus muscularis externa. The increase of NE release from the sympathetic nerve terminals concentration dependently upregulates NGF, which proportionately increases the visceromotor response to gastric distention. Neonatal programming concurrently increases anxiety-like behavior in GHS rats.
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Affiliation(s)
- John H. Winston
- 1Division of Gastroenterology, Department of Internal Medicine Enteric Neuromuscular Disorders and Visceral Pain Center, The University of Texas Medical Branch at Galveston, Galveston, Texas; and
| | - Sushil K. Sarna
- 1Division of Gastroenterology, Department of Internal Medicine Enteric Neuromuscular Disorders and Visceral Pain Center, The University of Texas Medical Branch at Galveston, Galveston, Texas; and ,2Department of Neuroscience and Cell Biology Enteric Neuromuscular Disorders and Visceral Pain Center, The University of Texas Medical Branch at Galveston, Galveston, Texas
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Petra AI, Panagiotidou S, Hatziagelaki E, Stewart JM, Conti P, Theoharides TC. Gut-Microbiota-Brain Axis and Its Effect on Neuropsychiatric Disorders With Suspected Immune Dysregulation. Clin Ther 2016; 37:984-95. [PMID: 26046241 DOI: 10.1016/j.clinthera.2015.04.002] [Citation(s) in RCA: 390] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Revised: 04/04/2015] [Accepted: 04/07/2015] [Indexed: 12/15/2022]
Abstract
PURPOSE Gut microbiota regulate intestinal function and health. However, mounting evidence indicates that they can also influence the immune and nervous systems and vice versa. This article reviews the bidirectional relationship between the gut microbiota and the brain, termed the microbiota-gut-brain (MGB) axis, and discusses how it contributes to the pathogenesis of certain disorders that may involve brain inflammation. METHODS Articles were identified with a search of Medline (starting in 1980) by using the key words anxiety, attention-deficit hypersensitivity disorder (ADHD), autism, cytokines, depression, gut, hypothalamic-pituitary-adrenal (HPA) axis, inflammation, immune system, microbiota, nervous system, neurologic, neurotransmitters, neuroimmune conditions, psychiatric, and stress. FINDINGS Various afferent or efferent pathways are involved in the MGB axis. Antibiotics, environmental and infectious agents, intestinal neurotransmitters/neuromodulators, sensory vagal fibers, cytokines, and essential metabolites all convey information to the central nervous system about the intestinal state. Conversely, the hypothalamic-pituitary-adrenal axis, the central nervous system regulatory areas of satiety, and neuropeptides released from sensory nerve fibers affect the gut microbiota composition directly or through nutrient availability. Such interactions seem to influence the pathogenesis of a number of disorders in which inflammation is implicated, such as mood disorder, autism-spectrum disorders, attention-deficit hypersensitivity disorder, multiple sclerosis, and obesity. IMPLICATIONS Recognition of the relationship between the MGB axis and the neuroimmune systems provides a novel approach for better understanding and management of these disorders. Appropriate preventive measures early in life or corrective measures such as use of psychobiotics, fecal microbiota transplantation, and flavonoids are discussed.
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Affiliation(s)
- Anastasia I Petra
- Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, Massachusetts
| | - Smaro Panagiotidou
- Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, Massachusetts
| | - Erifili Hatziagelaki
- Second Department of Internal Medicine, Attikon General Hospital, Athens Medical School, Athens, Greece
| | - Julia M Stewart
- Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, Massachusetts
| | - Pio Conti
- Department of Medical Sciences, Immunology Division, University of Chieti, Via dei Vestini, Chieti, Italy
| | - Theoharis C Theoharides
- Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, Massachusetts; Department of Internal Medicine, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts; Department of Psychiatry, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts.
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Wu B, Xu C, Huang HH. [Expression profiles of brain-derived neurotrophic factor in the spinal dorsal horn of young rats with visceral hypersensitivity]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2016; 18:277-281. [PMID: 26975829 PMCID: PMC7390003 DOI: 10.7499/j.issn.1008-8830.2016.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 01/26/2016] [Indexed: 06/05/2023]
Abstract
OBJECTIVE To explore the relationship between the expression of brain-derived neurotrophic factor (BDNF) in the spinal dorsal horn and the increase in visceral hypersensitivity in young rats by establishing a young rat model of visceral hypersensitivity by neonatal maternal separation (NMS). METHODS Thirty-two newborn Sprague-Dawley rats were randomly and equally divided into four groups by a 2×2 factorial design: control, NMS, colorectal distension (CRD), and NMS+CRD. The newborn rats in the NMS and NMS+CRD groups were subjected to 3-hour daily maternal separation from days 2 to 14 after birth to establish a model of visceral hypersensitivity, while the rats in the control and CRD groups received no treatment after birth. At 6 weeks after birth, the CRD and CRD+NMS groups received CRD stimulation. The streptavidin-biotin complex immunohistochemical method was used to determine the expression of BDNF in the spinal dorsal horn. The immunohistochemical score (IHS) was calculated based on the percentage of BDNF-positive cells and color intensity. The percentage of BDNF-positive cells in the spinal dorsal horn and IHS were analyzed by factorial analysis of variance. RESULTS The expression of BDNF was detected bilaterally in the spinal dorsal horn at different levels in the four groups. The percentage of BDNF-positive cells and IHS were significantly higher in the NMS and NMS+CRD groups than in the control group (P<0.05). The results of factorial analysis of variance indicated that NMS significantly increased the percentage of BDNF-positive cells in the spinal dorsal horn and IHS; a single CRD stimulation had no effects on the IHS of BDNF-positive cells in the spinal dorsal horn; there was no interaction between NMS and a single CRD stimulation. CONCLUSIONS The over-expression of BDNF in the spinal dorsal horn may be involved in high visceral hypersensitivity in young rats induce by NMS.
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Affiliation(s)
- Bin Wu
- Department of Pediatrics, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China.
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Wu B, Xu C, Huang HH. [Expression profiles of brain-derived neurotrophic factor in the spinal dorsal horn of young rats with visceral hypersensitivity]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2016; 18:277-81. [PMID: 26975829 PMCID: PMC7390003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 01/26/2016] [Indexed: 08/01/2024]
Abstract
OBJECTIVE To explore the relationship between the expression of brain-derived neurotrophic factor (BDNF) in the spinal dorsal horn and the increase in visceral hypersensitivity in young rats by establishing a young rat model of visceral hypersensitivity by neonatal maternal separation (NMS). METHODS Thirty-two newborn Sprague-Dawley rats were randomly and equally divided into four groups by a 2×2 factorial design: control, NMS, colorectal distension (CRD), and NMS+CRD. The newborn rats in the NMS and NMS+CRD groups were subjected to 3-hour daily maternal separation from days 2 to 14 after birth to establish a model of visceral hypersensitivity, while the rats in the control and CRD groups received no treatment after birth. At 6 weeks after birth, the CRD and CRD+NMS groups received CRD stimulation. The streptavidin-biotin complex immunohistochemical method was used to determine the expression of BDNF in the spinal dorsal horn. The immunohistochemical score (IHS) was calculated based on the percentage of BDNF-positive cells and color intensity. The percentage of BDNF-positive cells in the spinal dorsal horn and IHS were analyzed by factorial analysis of variance. RESULTS The expression of BDNF was detected bilaterally in the spinal dorsal horn at different levels in the four groups. The percentage of BDNF-positive cells and IHS were significantly higher in the NMS and NMS+CRD groups than in the control group (P<0.05). The results of factorial analysis of variance indicated that NMS significantly increased the percentage of BDNF-positive cells in the spinal dorsal horn and IHS; a single CRD stimulation had no effects on the IHS of BDNF-positive cells in the spinal dorsal horn; there was no interaction between NMS and a single CRD stimulation. CONCLUSIONS The over-expression of BDNF in the spinal dorsal horn may be involved in high visceral hypersensitivity in young rats induce by NMS.
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Affiliation(s)
- Bin Wu
- Department of Pediatrics, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China.
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Charrua A, Pinto R, Birder LA, Cruz F. Sympathetic nervous system and chronic bladder pain: a new tune for an old song. Transl Androl Urol 2016; 4:534-42. [PMID: 26816852 PMCID: PMC4708549 DOI: 10.3978/j.issn.2223-4683.2015.09.06] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Chronic bladder pain (CBP) patients present with pelvic pain or discomfort during bladder filling, for at least a period of 6 months, which may be accompanied by lower urinary tract symptoms such as frequency, nocturia, and urgency. However, both the etiology of CBP and pathophysiological mechanisms are not well described. A number of clinical and basic animal model findings support involvement of sympathetic nervous system in chronic pain syndromes such as CBP. Examples include sympathetic overactivity and high plasma or urinary catecholamine levels that have a high correlation with nociceptive symptoms. In this review, we explored the current evidence in support of the involvement of sympathetic overactivity in CBP. As bladder inflammation often occurs among subgroups of CBP patients, we discuss the possible role of sympathetic nervous system in mastocytosis as well examples examples of animal models that further support the involvement of sympathetic dysfunction in CBP. As there is substantive evidence for cross-organ sensitization in the pelvis can lead to co-morbidity of genitourinary and gastrointestinal dysfunctions, we also include how sympathetic dysfunction may play a role in a number of co-morbid chronic pain syndromes.
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Affiliation(s)
- Ana Charrua
- 1 I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal ; 2 IBMC-Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal ; 3 Department of Renal, Urologic and Infectious diseases, Faculty of Medicine of University of Porto, Porto, Portugal ; 4 Department of Urology, Hospital S. João, Porto, Portugal ; 5 Departments of Medicine and Pharmacology-Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Rui Pinto
- 1 I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal ; 2 IBMC-Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal ; 3 Department of Renal, Urologic and Infectious diseases, Faculty of Medicine of University of Porto, Porto, Portugal ; 4 Department of Urology, Hospital S. João, Porto, Portugal ; 5 Departments of Medicine and Pharmacology-Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Lori Ann Birder
- 1 I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal ; 2 IBMC-Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal ; 3 Department of Renal, Urologic and Infectious diseases, Faculty of Medicine of University of Porto, Porto, Portugal ; 4 Department of Urology, Hospital S. João, Porto, Portugal ; 5 Departments of Medicine and Pharmacology-Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Francisco Cruz
- 1 I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal ; 2 IBMC-Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal ; 3 Department of Renal, Urologic and Infectious diseases, Faculty of Medicine of University of Porto, Porto, Portugal ; 4 Department of Urology, Hospital S. João, Porto, Portugal ; 5 Departments of Medicine and Pharmacology-Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Johnson AC, Greenwood-Van Meerveld B. The Pharmacology of Visceral Pain. ADVANCES IN PHARMACOLOGY 2016; 75:273-301. [PMID: 26920016 DOI: 10.1016/bs.apha.2015.11.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Visceral pain describes pain emanating from the internal thoracic, pelvic, or abdominal organs. Unlike somatic pain, visceral pain is generally vague, poorly localized, and characterized by hypersensitivity to a stimulus such as organ distension. While current therapeutics provides some relief from somatic pain, drugs used for treatment of chronic visceral pain are typically less efficacious and limited by multiple adverse side effects. Thus, the treatment of visceral pain represents a major unmet medical need. Further, more basic research into the physiology and pathophysiology of visceral pain is needed to provide novel targets for future drug development. In concert with chronic visceral pain, there is a high comorbidity with stress-related psychiatric disorders including anxiety and depression. The mechanisms linking visceral pain with these overlapping comorbidities remain to be elucidated. However, persistent stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic visceral pain disorders. We will focus on stress-induced exacerbation of chronic visceral pain and provide supporting evidence that centrally acting drugs targeting the pain and stress-responsive brain regions may represent a valid target for the development of novel and effective therapeutics.
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Affiliation(s)
- Anthony C Johnson
- Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Beverley Greenwood-Van Meerveld
- Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
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Li Q, Winston JH, Sarna SK. Noninflammatory upregulation of nerve growth factor underlies gastric hypersensitivity induced by neonatal colon inflammation. Am J Physiol Regul Integr Comp Physiol 2015; 310:R235-42. [PMID: 26608656 DOI: 10.1152/ajpregu.00342.2015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 11/18/2015] [Indexed: 02/08/2023]
Abstract
Gastric hypersensitivity is one of the key contributors to the postprandial symptoms of epigastric pain/discomfort, satiety, and fullness in functional dyspepsia patients. Epidemiological studies found that adverse early-life experiences are risk factors for the development of gastric hypersensitivity. Preclinical studies found that neonatal colon inflammation elevates plasma norepinephrine (NE), which upregulates expression of nerve growth factor (NGF) in the muscularis externa of the gastric fundus. Our goal was to investigate the cellular mechanisms by which NE upregulates the expression of NGF in gastric hypersensitive (GHS) rats, which were subjected previously to neonatal colon inflammation. Neonatal colon inflammation upregulated NGF protein, but not mRNA, in the gastric fundus of GHS rats. Western blotting showed upregulation of p110γ of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phosphoinositide-dependent kinase-1 (PDK1), pAKT(Ser473), and phosphorylated 4E-binding protein (p4E-BP1)(Thr70), suggesting AKT activation and enhanced NGF protein translation. AKT inhibitor MK-2206 blocked the upregulation of NGF in the fundus of GHS rats. Matrix metalloproteinase 9 (MMP-9), the major NGF-degrading protease, was suppressed, indicating that NGF degradation was impeded. Incubation of fundus muscularis externa with NE upregulated NGF by modulating the protein translation and degradation pathways. Yohimbine, an α2-adrenergic receptor antagonist, upregulated plasma NE and NGF expression by activating the protein translation and degradation pathways in naive rats. In contrast, a cocktail of adrenergic receptor antagonists suppressed the upregulation of NGF by blocking the activation of the protein translation and degradation pathways. Our findings provide evidence that the elevation of plasma NE induces NGF expression in the gastric fundus.
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Affiliation(s)
- Qingjie Li
- Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, Texas; and
| | - John H Winston
- Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, Texas; and
| | - Sushil K Sarna
- Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, Texas; and Department of Neuroscience and Cell Biology, The University of Texas Medical Branch at Galveston, Galveston, Texas
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Liu J, Li F, Tang XD, Ma J, Ma X, Ge DY, Li GM, Wang Y. XiangshaLiujunzi decoction alleviates the symptoms of functional dyspepsia by regulating brain-gut axis and production of neuropeptides. Altern Ther Health Med 2015; 15:387. [PMID: 26508134 PMCID: PMC4623916 DOI: 10.1186/s12906-015-0913-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Accepted: 10/13/2015] [Indexed: 12/15/2022]
Abstract
Background Chinese medicine xiangshaliujunzi decoction (XSLJZD) plays a key role in treating functional dyspepsia (FD), a common clinical gastrointestinal disorder. However, the mechanism of this disease is unclear. Brain–gut axis regulates food intake behaviour, and this regulatory mechanism is mediated by neuropeptides. Brain–gut axis impairment and neuropeptide alteration may be the pathological mechanisms of FD, and brain–gut axis regulation may influence the action of medicine. Methods In our experiment, the effect of XSLJZD on FD was evaluated in terms of food intake, sucrose preference test and electromyogram. Changes in neuropeptides [ghrelin, cholecystokinin (CCK) and vasoactive intestinal polypeptide (VIP)] were detected through immunohistochemistry, real-time PCR and ELISA. Results XSLJZD increased food intake and the percentage of sucrose preference (>75 %). However, the response to gastric detention decreased. Furthermore, XSLJZD increased ghrelin, CCK, VIP proteins and genes in the stomach. XSLJZD also increased ghrelin, CCK and VIP proteins in serum. By contrast, XSLJZD decreased the mRNA expression of these neuropeptides in the hypothalamus. Conclusions XSLJZD alleviated the symptoms of FD by upregulating the production of ghrelin, CCK and VIP and by increasing the levels of these neuropeptides in circulation. This finding can help elucidate the mechanism of FD and can provide further insight into the pharmacokinetics of XSLJZD.
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Wang C, Wang Z, Yang Y, Zhu C, Wu G, Yu G, Jian T, Yang N, Shi H, Tang M, He Q, Lan L, Liu Q, Guan Y, Dong X, Duan J, Tang Z. Pirt contributes to uterine contraction-induced pain in mice. Mol Pain 2015; 11:57. [PMID: 26376721 PMCID: PMC4574137 DOI: 10.1186/s12990-015-0054-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 08/21/2015] [Indexed: 12/27/2022] Open
Abstract
Uterine contraction-induced pain (UCP) represents a common and severe form of visceral pain. Nerve fibers that innervate uterine tissue express the transient receptor potential vanilloid channel 1 (TRPV1), which has been shown to be involved in the perception of UCP. The phosphoinositide-interacting regulator of TRP (Pirt) may act as a regulatory subunit of TRPV1. The intraperitoneal injection of oxytocin into female mice after a 6-day priming treatment with estradiol benzoate induces writhing responses, which reflect the presence of UCP. Here, we first compared writhing response between Pirt (+/+) and Pirt (-/-) mice. Second, we examined the innervation of Pirt-expressing nerves in the uterus of Pirt (-/-) mice by immunofluorescence and two-photon microscopy. Third, we identified the soma of dorsal root ganglion (DRG) neurons that innerve the uterus using retrograde tracing and further characterized the neurochemical properties of these DRG neurons. Finally, we compared the calcium response of capsaicin between DRG neurons from Pirt (+/+) and Pirt (-/-) mice. We found that the writhing responses were less intensive in Pirt (-/-) mice than in Pirt (+/+) mice. We also observed Pirt-expressing nerve fibers in the myometrium of the uterus, and that retrograde-labeled cells were small-diameter, unmyelinated, and Pirt-positive DRG neurons. Additionally, we found that the number of capsaicin-responding neurons and the magnitude of evoked calcium response were markedly reduced in DRG neurons from Pirt (-/-) mice. Taken together, we speculate that Pirt plays an important role in mice uterine contraction-induced pain.
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Affiliation(s)
- Changming Wang
- College of Basic Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing, 210023, Jiangsu, China.
| | - Zhongli Wang
- College of Basic Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing, 210023, Jiangsu, China.
| | - Yan Yang
- College of Basic Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing, 210023, Jiangsu, China.
| | - Chan Zhu
- College of Basic Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing, 210023, Jiangsu, China.
| | - Guanyi Wu
- College of Basic Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing, 210023, Jiangsu, China.
| | - Guang Yu
- College of Basic Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing, 210023, Jiangsu, China.
| | - Tunyu Jian
- College of Basic Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing, 210023, Jiangsu, China.
| | - Niuniu Yang
- College of Basic Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing, 210023, Jiangsu, China.
| | - Hao Shi
- College of Basic Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing, 210023, Jiangsu, China.
| | - Min Tang
- College of Basic Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing, 210023, Jiangsu, China.
| | - Qian He
- College of Basic Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing, 210023, Jiangsu, China.
| | - Lei Lan
- College of Life Science, Nanjing Normal University, Nanjing, 210046, Jiangsu, China.
| | - Qin Liu
- Department of Anesthesiology, University of Washington, St. Louis, MO, 63110, USA.
| | - Yun Guan
- Department of Anesthesiology and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA.
| | - Xinzhong Dong
- The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA.
| | - Jinao Duan
- College of Basic Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing, 210023, Jiangsu, China.
| | - Zongxiang Tang
- College of Basic Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing, 210023, Jiangsu, China.
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Greenwood-Van Meerveld B, Prusator DK, Johnson AC. Animal models of gastrointestinal and liver diseases. Animal models of visceral pain: pathophysiology, translational relevance, and challenges. Am J Physiol Gastrointest Liver Physiol 2015; 308:G885-903. [PMID: 25767262 DOI: 10.1152/ajpgi.00463.2014] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 03/11/2015] [Indexed: 02/08/2023]
Abstract
Visceral pain describes pain emanating from the thoracic, pelvic, or abdominal organs. In contrast to somatic pain, visceral pain is generally vague, poorly localized, and characterized by hypersensitivity to a stimulus such as organ distension. Animal models have played a pivotal role in our understanding of the mechanisms underlying the pathophysiology of visceral pain. This review focuses on animal models of visceral pain and their translational relevance. In addition, the challenges of using animal models to develop novel therapeutic approaches to treat visceral pain will be discussed.
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Affiliation(s)
- Beverley Greenwood-Van Meerveld
- Veterans Affairs Medical Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; and Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Dawn K Prusator
- Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Anthony C Johnson
- Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
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Jiang SM, Lei XG, Jia L, Xu M, Wang SB, Liu J, Song M. Unhealthy dietary behavior in refractory functional dyspepsia: a multicenter prospective investigation in China. J Dig Dis 2014; 15:654-9. [PMID: 25283636 DOI: 10.1111/1751-2980.12199] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To determine the association of dietary behavior with refractory functional dyspepsia (RFD) and its subtypes in Chinese patients. METHODS The medical records of patients admitted to the Outpatient Department of Gastroenterology of four hospitals in Mainland China for upper gastrointestinal (GI) symptoms from June to September 2012 were reviewed and their characteristics were collected. Functional dyspepsia (FD) was diagnosed based on the Rome III criteria. RFD was defined as FD with continuous symptoms for at least 6 months that was unresponsive to at least two kinds of medications. Another 100 healthy volunteers were included as controls. The participants' dietary behaviors were investigated using a questionnaire survey. RESULTS Overall, 1341 FD patients were enrolled in the study, including 327 RFD and 1014 non-RFD (NRFD). Unhealthy dietary behaviors were more prevalent in both RFD and NRFD than in the healthy controls. Skipping meals, eating extra meals and a preference to sweet food and gas-producing food were more common in the RFD patients. Compared with NRFD, RFD-epigastric pain syndrome (EPS) patients preferred spicy food, whereas those with postprandial distress syndrome (PDS) preferred sweet food and gas-producing food, and those with both EPS and PDS were found to skip meals and take extra meals more often. Logistic regression analysis showed that skipping meals, eating extra meals and a preference to sweet food and gas-producing food were risk factors for RFD. CONCLUSION Unhealthy dietary behaviors, especially skipping meals, eating extra meals and a preference to sweet food and gas-producing food, were correlated with RFD and its subtypes.
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Affiliation(s)
- Shu Man Jiang
- Department of Gastroenterology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China; Department of Gastroenterology, Guangzhou Nansha Central Hospital, Guangzhou, China
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Abstract
The gastrointestinal tract is innervated by several distinct populations of neurons, whose cell bodies either reside within (intrinsic) or outside (extrinsic) the gastrointestinal wall. Normally, most individuals are unaware of the continuous, complicated functions of these neurons. However, for patients with gastrointestinal disorders, such as IBD and IBS, altered gastrointestinal motility, discomfort and pain are common, debilitating symptoms. Although bouts of intestinal inflammation underlie the symptoms associated with IBD, increasing preclinical and clinical evidence indicates that infection and inflammation are also key risk factors for the development of other gastrointestinal disorders. Notably, a strong correlation exists between prior exposure to gut infection and symptom occurrence in IBS. This Review discusses the evidence for neuroplasticity (structural, synaptic or intrinsic changes that alter neuronal function) affecting gastrointestinal function. Such changes are evident during inflammation and, in many cases, long after healing of the damaged tissues, when the nervous system fails to reset back to normal. Neuroplasticity within distinct populations of neurons has a fundamental role in the aberrant motility, secretion and sensation associated with common clinical gastrointestinal disorders. To find appropriate therapeutic treatments for these disorders, the extent and time course of neuroplasticity must be fully appreciated.
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Li S, Chen JDZ. Down-regulation of A-type potassium channel in gastric-specific DRG neurons in a rat model of functional dyspepsia. Neurogastroenterol Motil 2014; 26:962-70. [PMID: 24758381 DOI: 10.1111/nmo.12350] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2013] [Accepted: 03/28/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND Although without evidence of organic structural abnormalities, pain or discomfort is a prominent symptom of functional dyspepsia and considered to reflect visceral hypersensitivity whose underlying mechanism is poorly understood. Here, we studied electrophysiological properties and expression of voltage-gated potassium channels in dorsal root ganglion (DRG) neurons in a rat model of functional dyspepsia induced by neonatal gastric irritation. METHODS Male Sprague-Dawley rat pups at 10-day old received 0.1% iodoacetamide (IA) or vehicle by oral gavage for 6 days and studied at adulthood. Retrograde tracer-labeled gastric-specific T8 -T12 DRG neurons were harvested for the patch-clamp study in voltage and current-clamp modes and protein expression of K(+) channel in T8 -T12 DRGs was examined by western blotting. KEY RESULTS (1) Gastric specific but not non-gastric DRG neurons showed an enhanced excitability in neonatal IA-treated rats compared to the control: depolarized resting membrane potentials, a lower current threshold for action potential (AP) activation, and an increase in the number of APs in response to current stimulation. (2) The current density of tetraethylammonium insensitive (transiently inactivating A-type current), but not the tetraethylammonium sensitive (slow-inactivating delayed rectifier K(+) currents), was significantly smaller in IA-treated rats (65.4 ± 6.9 pA/pF), compared to that of control (93.1 ± 8.3 pA/pF). (3) Protein expression of KV 4.3 was down-regulated in IA-treated rats. CONCLUSIONS & INFERENCES A-type potassium channels are significantly down-regulated in the gastric-specific DRG neurons in adult rats with mild neonatal gastric irritation, which in part contribute to the enhanced DRG neuron excitabilities that leads to the development of gastric hypersensitivity.
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Affiliation(s)
- S Li
- Veterans Research and Education Foundation, VA Medical Center, Oklahoma City, OK, USA
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Nilius B, Szallasi A. Transient receptor potential channels as drug targets: from the science of basic research to the art of medicine. Pharmacol Rev 2014; 66:676-814. [PMID: 24951385 DOI: 10.1124/pr.113.008268] [Citation(s) in RCA: 382] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2025] Open
Abstract
The large Trp gene family encodes transient receptor potential (TRP) proteins that form novel cation-selective ion channels. In mammals, 28 Trp channel genes have been identified. TRP proteins exhibit diverse permeation and gating properties and are involved in a plethora of physiologic functions with a strong impact on cellular sensing and signaling pathways. Indeed, mutations in human genes encoding TRP channels, the so-called "TRP channelopathies," are responsible for a number of hereditary diseases that affect the musculoskeletal, cardiovascular, genitourinary, and nervous systems. This review gives an overview of the functional properties of mammalian TRP channels, describes their roles in acquired and hereditary diseases, and discusses their potential as drug targets for therapeutic intervention.
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Affiliation(s)
- Bernd Nilius
- KU Leuven, Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.); and Department of Pathology, Monmouth Medical Center, Long Branch, New Jersey (A.S.)
| | - Arpad Szallasi
- KU Leuven, Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.); and Department of Pathology, Monmouth Medical Center, Long Branch, New Jersey (A.S.)
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Yuan SB, Shi Y, Chen J, Zhou X, Li G, Gelman BB, Lisinicchia JG, Carlton SM, Ferguson MR, Tan A, Sarna SK, Tang SJ. Gp120 in the pathogenesis of human immunodeficiency virus-associated pain. Ann Neurol 2014; 75:837-50. [PMID: 24633867 DOI: 10.1002/ana.24139] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2013] [Revised: 03/11/2014] [Accepted: 03/11/2014] [Indexed: 01/19/2023]
Abstract
OBJECTIVE Chronic pain is a common neurological comorbidity of human immunodeficiency virus (HIV)-1 infection, but the etiological cause remains elusive. The objective of this study was to identify the HIV-1 causal factor that critically contributes to the pathogenesis of HIV-associated pain. METHODS We first compared the levels of HIV-1 proteins in postmortem tissues of the spinal cord dorsal horn (SDH) from HIV-1/acquired immunodeficiency syndrome patients who developed chronic pain (pain-positive HIV-1 patients) and HIV-1 patients who did not develop chronic pain (pain-negative HIV-1 patients). Then we used the HIV-1 protein that was specifically increased in the pain-positive patients to generate mouse models. Finally, we performed comparative analyses on the pathological changes in the models and the HIV-1 patients. RESULTS We found that HIV-1 gp120 was significantly higher in pain-positive HIV-1 patients (vs pain-negative HIV-1 patients). This finding suggested that gp120 was a potential causal factor of the HIV-associated pain. To test this hypothesis, we used a mouse model generated by intrathecal injection of gp120 and compared the pathologies of the model and the pain-positive human HIV-1 patients. The results showed that the mouse model and pain-positive human HIV-1 patients developed extensive similarities in their pathological phenotypes, including pain behaviors, peripheral neuropathy, glial reactivation, synapse degeneration, and aberrant activation of pain-related signaling pathways in the SDH. INTERPRETATION Our findings suggest that gp120 may critically contribute to the pathogenesis of HIV-associated pain.
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Affiliation(s)
- Su-Bo Yuan
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX
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Budzyński J, Kłopocka M. Brain-gut axis in the pathogenesis of Helicobacter pylori infection. World J Gastroenterol 2014; 20:5212-5225. [PMID: 24833851 PMCID: PMC4017036 DOI: 10.3748/wjg.v20.i18.5212] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 01/11/2014] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection is the main pathogenic factor for upper digestive tract organic diseases. In addition to direct cytotoxic and proinflammatory effects, H. pylori infection may also induce abnormalities indirectly by affecting the brain-gut axis, similar to other microorganisms present in the alimentary tract. The brain-gut axis integrates the central, peripheral, enteric and autonomic nervous systems, as well as the endocrine and immunological systems, with gastrointestinal functions and environmental stimuli, including gastric and intestinal microbiota. The bidirectional relationship between H. pylori infection and the brain-gut axis influences both the contagion process and the host’s neuroendocrine-immunological reaction to it, resulting in alterations in cognitive functions, food intake and appetite, immunological response, and modification of symptom sensitivity thresholds. Furthermore, disturbances in the upper and lower digestive tract permeability, motility and secretion can occur, mainly as a form of irritable bowel syndrome. Many of these abnormalities disappear following H. pylori eradication. H. pylori may have direct neurotoxic effects that lead to alteration of the brain-gut axis through the activation of neurogenic inflammatory processes, or by microelement deficiency secondary to functional and morphological changes in the digestive tract. In digestive tissue, H. pylori can alter signaling in the brain-gut axis by mast cells, the main brain-gut axis effector, as H. pylori infection is associated with decreased mast cell infiltration in the digestive tract. Nevertheless, unequivocal data concerning the direct and immediate effect of H. pylori infection on the brain-gut axis are still lacking. Therefore, further studies evaluating the clinical importance of these host-bacteria interactions will improve our understanding of H. pylori infection pathophysiology and suggest new therapeutic approaches.
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Winston JH, Li Q, Sarna SK. Chronic prenatal stress epigenetically modifies spinal cord BDNF expression to induce sex-specific visceral hypersensitivity in offspring. Neurogastroenterol Motil 2014; 26:715-30. [PMID: 24588943 PMCID: PMC3997587 DOI: 10.1111/nmo.12326] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 02/01/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a heterogeneous disorder with abdominal pain as one of the primary symptoms. The etiology of IBS remains unknown. Epidemiological studies found that a subset of these patients have a history of adverse early-life experiences. We tested the hypothesis that chronic prenatal stress (CPS) epigenetically enhances brain-derived neurotrophic factor (BDNF) in spinal cord to aggravate colon sensitivity to colorectal distension (CRD) differentially in male and female offspring. METHODS We used heterotypic intermittent chronic stress (HeICS) protocols in pregnant dams from E11 until delivery. KEY RESULTS Chronic prenatal stress induced significant visceral hypersensitivity (VHS) to CRD in male and female offspring. A second exposure to HeICS in adult offspring exacerbated VHS greater in female offspring that persisted longer than in male offspring. Chronic prenatal stress upregulated BDNF expression in the lumbar-sacral dorsal horn that correlated with the exacerbation of VHS in female, but not in male offspring. The upregulation of BDNF was due to a significant increase in RNA Pol II binding, histone H3 acetylation, and significant decrease in histone deacetylase 1 association with the core promoter of BDNF in female offspring. Other chronic prenatal and neonatal stress protocols were less effective than HeICS. CONCLUSIONS & INFERENCES The development of VHS, which contributes to the symptom of intermittent abdominal pain, is a two-step process, chronic in utero stress followed by chronic stress in adult-life. This two-step process induces aggravated and persistent colon hypersensitivity in female than in male offspring. Our preclinical model explains several clinical features in IBS patients.
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Affiliation(s)
- J H Winston
- Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, TX, USA
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Li Q, Winston JH, Sarna SK. Developmental origins of colon smooth muscle dysfunction in IBS-like rats. Am J Physiol Gastrointest Liver Physiol 2013; 305:G503-12. [PMID: 23886858 PMCID: PMC3798719 DOI: 10.1152/ajpgi.00160.2013] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Epidemiological studies show that subsets of adult and pediatric patients with irritable bowel syndrome (IBS) have prior exposures to psychological or inflammatory stress. We investigated the cellular mechanisms of colonic smooth muscle dysfunction in adult rats subjected to neonatal inflammation. Ten-day-old male rat pups received 2,4,6-trinitrobenzene sulfonic acid to induce colonic inflammation. Colonic circular smooth muscle strips were obtained 6 to 8 wk later. We found that about half of the neonate pups subjected to inflammatory insult showed a significant increase in expression of the pore-forming α1C-subunit of Cav1.2b channels in adult life. These were the same rats in whom Vip mRNA increased in the colon muscularis externae. Additional experiments showed reduced interaction of histone deacetylase (HDAC) 3 with α1C1b promoter that increased the acetylation of histone H3 lysine 9 (H3K9) in the core promoter region. Vasoactive intestinal peptide (VIP) treatment of naïve muscularis externae swiftly recruited CREB-binding protein (CBP) to the α1C1b promoter and dissociated HDAC3 from this region to initiate transcription. The CBP interaction with the α1C1b promoter was transient, but the dissociation of HDAC3 persisted to sustain H3K9 hyperacetylation and increase in transcription. Intraperitoneal treatment of adult naïve rats with butyrate mimicked the effects of neonatal colon inflammation. We concluded that neonatal inflammation upregulates VIP in the colon muscularis externae, which modulates epigenetic events at the α1C1b promoter to activate α1C1b gene transcription. Inflammatory insult in early life may be one of the etiologies of smooth muscle dysfunction in adult life, which contributes to the altered motility function in patients with diarrhea-predominant IBS.
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Affiliation(s)
- Qingjie Li
- Div. of Gastroenterology, The Univ. of Texas Medical Branch at Galveston, 8.102 Medical Research Bldg., Galveston, TX 77555-1083.
| | - John H. Winston
- 1Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Internal Medicine, and
| | - Sushil K. Sarna
- 1Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Internal Medicine, and ,2Department of Neuroscience and Cell Biology, The University of Texas Medical Branch at Galveston, Galveston, Texas
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Neurological and cellular regulation of visceral hypersensitivity induced by chronic stress and colonic inflammation in rats. Neuroscience 2013; 248:469-78. [PMID: 23806714 DOI: 10.1016/j.neuroscience.2013.06.024] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Revised: 06/03/2013] [Accepted: 06/14/2013] [Indexed: 02/06/2023]
Abstract
The role of inflammation in inducing visceral hypersensitivity (VHS) in ulcerative colitis patients remains unknown. We tested the hypothesis that acute ulcerative colitis-like inflammation does not induce VHS. However, it sets up molecular conditions such that chronic stress following inflammation exaggerates single-unit afferent discharges to colorectal distension. We used dextran sodium sulfate (DSS) to induce ulcerative colitis-like inflammation and a 9-day heterotypic chronic stress protocol in rats. DSS upregulated Nav1.8 mRNA in colon-responsive dorsal root ganglion (DRG) neurons, TRPV1 in colonic muscularis externae (ME) and BDNF in spinal cord without affecting the spike frequency in spinal afferents or VMR to CRD. By contrast, chronic stress did not induce inflammation but it downregulated Kv1.1 and Kv1.4 mRNA in DRG neurons, and upregulated TRPA1 and nerve growth factor in ME, which mediated the increase of spike frequency and VMR to CRD. Chronic stress following inflammation exacerbated spike frequency in spinal afferent neurons. TRPA1 antagonist suppressed the sensitization of afferent neurons. DSS-inflammation did not affect the composition or excitation thresholds of low-threshold and high-threshold fibers. Chronic stress following inflammation increased the percent composition of high-threshold fibers and lowered the excitation threshold of both types of fibers. We conclude that not all types of inflammation induce VHS, whereas chronic stress induces VHS in the absence of inflammation.
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