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Ribolsi M, Marchetti L, Olmi LM, Cicala M, Savarino E. Esophageal chest pain resembles heartburn in reflux metrics and response to proton pump inhibitor therapy. Neurogastroenterol Motil 2025; 37:e14953. [PMID: 39485991 DOI: 10.1111/nmo.14953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/14/2024] [Accepted: 10/19/2024] [Indexed: 11/03/2024]
Abstract
BACKGROUND Gastro-esophageal reflux disease (GERD) is the most common cause for noncardiac chest pain (NCCP), with an estimated prevalence rate ranging between 30% and 60%. Heartburn and NCCP may share common mechanisms. AIMS/METHODS To assess whether particular patterns of impedance-pH variables characterize patients with dominant heartburn, regurgitation, or NCCP and their ability to predict proton pump inhibitor (PPI) response for each symptom, GERD patients, evaluated with high-resolution manometry (HRM) and impedance-pH, were included. RESULTS In total, 109 NCCP, 68 heartburn, and 64 regurgitation patients were included. Pathological reflux episodes were observed in 28%, 19%, and 56% (p < 0.001). Pathological mean nocturnal baseline impedance (MNBI) values were observed in 55%, 53%, and 34% (p < 0.05). Hypomotility was more frequent in NCCP compared to heartburn patients (p < 0.05). When comparing NCCP with heartburn, hypomotility was associated with NCCP perception (OR: 2.34, 95% CI: 1.23-4.43; p < 0.01). When comparing NCCP with regurgitation, >80 refluxes and type 2/3 esophagogastric junction (EGJ) were associated with regurgitation perception (OR: 0.31, 95% CI: 0.16-0.59; p < 0.001, and OR: 0.5, 95% CI: 0.27-0.93; p < 0.05), while pathological MNBI was associated with NCCP perception (OR: 2.34, 95% CI: 1.23-4.43; p < 0.01). 45.5% NCCP patients, 45.6% with heartburn, and 36% with regurgitation responded to PPIs (p < 0.05). At multivariate analysis, pathological MNBI or PSPW index were associated with PPI responsiveness in patients with NCCP or heartburn, while in patients with regurgitation, pathological MNBI was associated with PPI responsiveness and a reflux number >80 to PPI refractoriness. CONCLUSIONS We highlight the usefulness of an accurate clinical and functional evaluation of GERD patients, allowing to discriminate particular characteristics in patients with dominant heartburn, NCCP, or regurgitation, which may benefit of distinct therapeutic strategies.
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Affiliation(s)
- Mentore Ribolsi
- Department of Digestive Diseases, Campus Bio Medico University of Rome, Rome, Italy
| | - Lorenzo Marchetti
- Department of Digestive Diseases, Campus Bio Medico University of Rome, Rome, Italy
| | - Lucrezia Maria Olmi
- Department of Digestive Diseases, Campus Bio Medico University of Rome, Rome, Italy
| | - Michele Cicala
- Department of Digestive Diseases, Campus Bio Medico University of Rome, Rome, Italy
| | - Edoardo Savarino
- Division of Gastroenterology, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
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Ni Bhraonain EP, Turner JA, Hannigan KI, Sanders KM, Cobine CA. Immunohistochemical characterization of interstitial cells and their spatial relationship to motor neurons within the mouse esophagus. Cell Tissue Res 2025; 399:61-84. [PMID: 39607495 DOI: 10.1007/s00441-024-03929-z] [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: 05/24/2024] [Accepted: 10/28/2024] [Indexed: 11/29/2024]
Abstract
Interstitial cells of Cajal (ICC) and PDGFRα+ cells regulate smooth muscle motility in the gastrointestinal (GI) tract, yet their function in the esophagus remains unknown. The mouse esophagus has been described as primarily skeletal muscle; however, ICC have been identified in this region. This study characterizes the distribution of skeletal and smooth muscle cells (SMCs) and their spatial relationship to ICC, PDGFRα+ cells, and intramuscular motor neurons in the mouse esophagus. SMCs occupied approximately 30% of the distal esophagus, but their density declined in more proximal regions. Similarly, ANO1+ intramuscular ICC (ICC-IM) were distributed along the esophagus, with density decreasing proximally. While ICC-IM were closely associated with SMCs, they were also present in regions of skeletal muscle. Intramuscular, submucosal, and myenteric PDGFRα+ cells were densely distributed throughout the esophagus, yet only intramuscular PDGFRα+ cells in the lower esophageal sphincter (LES) and distal esophagus expressed SK3. ICC-IM and PDGFRα+ cells were closely associated with intramuscular nNOS+, VIP+, VAChT+, and TH+ neurons and GFAP+ cells resembling intramuscular enteric glia. These findings suggest that ICC-IM and PDGFRα+ cells may have roles in regulating esophageal motility due to their close proximity to each other and to skeletal muscle and SMCs, although further functional studies are needed to explore their role in this region. The mixed muscular composition and presence of interstitial cells in the mouse distal esophagus is anatomically similar to the transitional zone found in the human esophagus, and therefore, motility studies in the mouse may be translatable to humans.
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Affiliation(s)
- Emer P Ni Bhraonain
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, 1664 N. Virginia St., MS 352, Reno, NV, 89557, USA
| | - Jack A Turner
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, 1664 N. Virginia St., MS 352, Reno, NV, 89557, USA
| | - Karen I Hannigan
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, 1664 N. Virginia St., MS 352, Reno, NV, 89557, USA
| | - Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, 1664 N. Virginia St., MS 352, Reno, NV, 89557, USA
| | - Caroline A Cobine
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, 1664 N. Virginia St., MS 352, Reno, NV, 89557, USA.
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Lei WY, Hung JS, Wong MW, Liu TT, Yi CH, Gyawali CP, Chen CL. Effects of capsaicin on esophageal peristalsis in humans using high resolution manometry. Neurogastroenterol Motil 2024; 36:e14942. [PMID: 39385495 DOI: 10.1111/nmo.14942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 09/25/2024] [Accepted: 09/30/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND Capsaicin-containing red pepper sauce suspension augments esophageal contraction amplitude on conventional manometry. This study used high-resolution manometry (HRM) to investigate if capsaicin infusion modulates segmental esophageal smooth muscle peristalsis in healthy adults. METHODS Sixteen healthy volunteers (mean age 37 years, 14 male) underwent HRM for the evaluation of primary peristalsis and secondary peristalsis using slow and rapid air distensions. Both primary and secondary peristalsis were assessed following infusions of capsaicin-containing red pepper sauce and saline. KEY RESULTS Capsaicin infusion significantly increased heartburn symptoms compared to saline infusion (p < 0.001), and significantly decreased threshold volumes of secondary peristalsis during rapid air distensions (p = 0.02). The frequency of secondary peristalsis during rapid air distensions was significantly increased by capsaicin infusion (p = 0.03). Neither capsaicin infusion (p = 0.06) nor saline infusion (p = 0.27) altered threshold volume during slow air distensions. Capsaicin infusion significantly increased distal contractile integral (DCI) of primary peristalsis (p = 0.04), particularly in the proximal smooth muscle segment (p = 0.048). It enhanced secondary peristalsis during rapid air distensions (p = 0.003) but not during slow air distension (p = 0.23). Saline infusion significantly increased DCI of secondary peristalsis during rapid air distension (p = 0.01). CONCLUSIONS AND INFERENCES Augmentation of distension-induced secondary peristalsis can be modulated by activation of capsaicin-sensitive afferents similar to mechanosensitive afferents. Capsaicin-induced augmentation of primary peristalsis isolates to the cholinergic-mediated proximal smooth muscle segment, which warrants study in ineffective esophageal motility to determine therapeutic potential.
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Affiliation(s)
- Wei-Yi Lei
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Jui-Sheng Hung
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Ming-Wun Wong
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Tso-Tsai Liu
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Chih-Hsun Yi
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - C Prakash Gyawali
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Chien-Lin Chen
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
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Choi Y, Kim N, Lee DH. The Efficacy and Safety of NOVAponin ( Dolichos lablab Linne Extract Powder) in Mild Functional Dyspepsia: A Single-center, Randomized, Double-Blind, Placebo-controlled Study. J Neurogastroenterol Motil 2024; 30:468-479. [PMID: 39397624 PMCID: PMC11474556 DOI: 10.5056/jnm23180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 02/21/2024] [Accepted: 03/10/2024] [Indexed: 10/15/2024] Open
Abstract
Background/Aims NOVAponin, a functional health food derived from Dolichos lablab Linne extract improves gastric mucosal injury and increases regeneration and proliferation. This study aims to investigate the efficacy and safety of NOVAponin in individuals with mild functional dyspepsia (FD). Methods In this single-center, double-blind, randomized clinical trial, 131 patients with FD meeting the Rome IV criteria were enrolled. Changes in the gastrointestinal symptom rating scale (GSRS), FD-related quality of life (FD-QoL), gastrointestinal symptom (GIS) scores, inflammatory and anti-inflammatory markers, and adverse effects before and after administration were compared. Results After 12 weeks of administration, GSRS upper abdominal symptom scores were significantly improved in the test group compared to the control group (-5.30 ± 0.60 vs -2.35 ± 0.56, P < 0.001). GSRS upper abdominal symptom scores (-5.13 ± 0.55 vs -1.92 ± 0.44, P < 0.001), GSRS total scores (-7.02 ± 0.91 vs -3.33 ± 0.73, P < 0.001), GIS total scores (-11.21 ± 0.53 vs -6.65 ± 0.70, P < 0.001) after 6 weeks of administration, GSRS total scores (-7.54 ± 0.94 v. -3.31 ± 0.85, P < 0.001), GIS total scores (-11.90 ± 0.52 vs -7.61 ± 0.73, P < 0.001), and FD-QoL total scores (-11.41 ± 1.75 vs -5.55 ± 1.20, P = 0.007) after 12 weeks of administration also showed significant differences between groups. The differences were slightly more pronounced in epigastric pain syndrome subtypes and in females than the others, although more females were assigned to the test group. There were no significant changes in inflammatory and anti-inflammatory markers or adverse reactions. Conclusion NOVAponin significantly improved mild FD symptoms especially in epigastric pain syndrome subtype and in females, and was found to be safe.
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Affiliation(s)
- Yonghoon Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Zou J, Li J, Wang X, Tang D, Chen R. Neuroimmune modulation in liver pathophysiology. J Neuroinflammation 2024; 21:188. [PMID: 39090741 PMCID: PMC11295927 DOI: 10.1186/s12974-024-03181-w] [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: 12/11/2023] [Accepted: 07/19/2024] [Indexed: 08/04/2024] Open
Abstract
The liver, the largest organ in the human body, plays a multifaceted role in digestion, coagulation, synthesis, metabolism, detoxification, and immune defense. Changes in liver function often coincide with disruptions in both the central and peripheral nervous systems. The intricate interplay between the nervous and immune systems is vital for maintaining tissue balance and combating diseases. Signaling molecules and pathways, including cytokines, inflammatory mediators, neuropeptides, neurotransmitters, chemoreceptors, and neural pathways, facilitate this complex communication. They establish feedback loops among diverse immune cell populations and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems within the liver. In this concise review, we provide an overview of the structural and compositional aspects of the hepatic neural and immune systems. We further explore the molecular mechanisms and pathways that govern neuroimmune communication, highlighting their significance in liver pathology. Finally, we summarize the current clinical implications of therapeutic approaches targeting neuroimmune interactions and present prospects for future research in this area.
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Affiliation(s)
- Ju Zou
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Jie Li
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Xiaoxu Wang
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Ruochan Chen
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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Khoury P, Wechsler JB. Role of Mast Cells in Eosinophilic Gastrointestinal Diseases. Immunol Allergy Clin North Am 2024; 44:311-327. [PMID: 38575226 PMCID: PMC11220468 DOI: 10.1016/j.iac.2024.01.004] [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] [Indexed: 04/06/2024]
Abstract
Mast cells play a central role in the pathogenesis of eosinophilic gastrointestinal disorders (EGIDs), including eosinophilic esophagitis. Their interactions with immune and structural cells, involvement in tissue remodeling, and contribution to symptoms make them attractive targets for therapeutic intervention. More is being discovered regarding the intricate interplay of mast cells and eosinophils. Recent studies demonstrating that depletion of eosinophils is insufficient to improve symptoms of EGIDs have raised the question of whether other cells may play a role in symptomatology and pathogenesis of EGIDs.
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Affiliation(s)
- Paneez Khoury
- Human Eosinophil Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 12C103, Bethesda, MD 20892, USA.
| | - Joshua B Wechsler
- Simpson-Querrey 10-518, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 E. Chicago Avenue, Box 65, Chicago, IL 60611, USA
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7
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Shah A, Lee YY, Suzuki H, Tan-Loh J, Siah KTH, Gwee KA, Fairlie T, Talley NJ, Ghoshal UC, Wang YP, Kim YS, Holtmann G. A pathophysiologic framework for the overlap of disorders of gut-brain interaction and the role of the gut microbiome. Gut Microbes 2024; 16:2413367. [PMID: 39482844 PMCID: PMC11540069 DOI: 10.1080/19490976.2024.2413367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/24/2024] [Accepted: 10/02/2024] [Indexed: 11/03/2024] Open
Abstract
The International Rome Committee defines Disorders of Gut-Brain Interactions (DGBI) based upon distinct combinations of chronic and/or recurrent unexplained gastrointestinal symptoms. Yet patients often experience overlapping DGBI. Patients with DGBI frequently also suffer from extraintestinal symptoms, including fatigue, sleep disturbances, anxiety, and depression. Patients with overlapping DGBI typically experience more severe GI symptoms and increased psychosocial burden. Concerning the pathophysiology, DGBI are associated with disruptions in gut motility, function of the brain and enteric neurons, immune function, and genetic markers, with recent findings revealing gut microbiome alterations linked to these mechanisms of DGBI. Emerging evidence summarized in this review suggests that the microbiome influences various established disease mechanisms of different DGBI groups. Overall, changes in the gastrointestinal microbiome do not seem to be linked to a specific DGBI subgroup but may play a key role in the manifestation of different DGBI and, subsequently, overlap of DGBI. Understanding these shared mechanisms and the role of the gastrointestinal microbiome, particularly for overlapping DGBI, might aid in developing more precise diagnostic criteria and treatment strategies while developing personalized interventions that target specific mechanisms to improve patient outcomes.
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Affiliation(s)
- Ayesha Shah
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Department of Gastroenterology and Hepatology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia
| | - Yeong Yeh Lee
- School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia
| | - Hidekazu Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Joash Tan-Loh
- Division of Gastroenterology Hepatology, Department of Internal Medicine, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
| | - Kewin Tien Ho Siah
- Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Hospital, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
| | - Kok-Ann Gwee
- Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Hospital, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
| | - Thomas Fairlie
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Department of Gastroenterology and Hepatology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia
| | - Nicholas J. Talley
- School of Medicine and Public Health, and Hunter Medical Research Institute, the University of Newcastle, Newcastle, Australia
| | - Uday C Ghoshal
- Institute of Gastrosciences & Liver Transplantation, Apollo Multispeciality Hospitals, Kolkata, India
| | - Yen-Po Wang
- Endoscopy centre for Diagnosis of Treatment, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yong Sung Kim
- Digestive Disease Research Institute, Wonkwang University College of Medicine, Iksan, Korea
- Good Breath Clinic, Gunpo, Korea
| | - Gerald Holtmann
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Department of Gastroenterology and Hepatology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia
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Wang J, Kumar P, Engelmann C. Comprehensive insights into the multifaceted roles of the transient receptor potential vanilloid 1 channel in the digestive system. Life Sci 2023; 334:122207. [PMID: 37883862 DOI: 10.1016/j.lfs.2023.122207] [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: 08/09/2023] [Revised: 10/11/2023] [Accepted: 10/23/2023] [Indexed: 10/28/2023]
Abstract
The transient receptor potential vanilloid (TRPV) channel, a family of calcium transporters comprising six distinct members (TRPV1-6), takes on a paramount role in maintaining intracellular Ca2+ homeostasis in mammalian cells. Notably, TRPV1, among its counterparts, has emerged as the subject of extensive scrutiny, owing to its pervasive presence in diverse cellular, tissue, and organ settings. This ubiquitous distribution underscores its fundamental involvement in the genesis of pain, making it a central focus in pain-related research. However, recent investigations have unveiled that TRPV1's functional significance transcends the realm of pain modulation, extending its influence to encompass a wide spectrum of physiological and pathological processes. The ambit of TRPV1's influence encompasses not only pain responses but also embraces the intricate domains of nervous system disorders, cancer metastasis, as well as afflictions pertaining to the skin and heart. Moreover, compelling evidence now demonstrates that TRPV1 also wields substantial sway in the domain of digestive diseases, further highlighting its versatility and far-reaching impact on human health. Therefore, this comprehensive review endeavors to delve into the multifaceted roles played by TRPV1 in the various organs constituting the digestive system.
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Affiliation(s)
- Juan Wang
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Pavitra Kumar
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
| | - Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany.
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Sawada A, Sifrim D, Fujiwara Y. Esophageal Reflux Hypersensitivity: A Comprehensive Review. Gut Liver 2023; 17:831-842. [PMID: 36588526 PMCID: PMC10651372 DOI: 10.5009/gnl220373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/01/2022] [Accepted: 10/18/2022] [Indexed: 01/03/2023] Open
Abstract
Reflux hypersensitivity (RH) is one of the phenotypes of gastroesophageal reflux disease. The latest Rome IV defines RH as a condition with typical reflux symptoms and positive reflux-symptom association despite normal acid exposure. Subsequently, the Lyon consensus proposed detailed cutoff values for the criteria on the basis of experts' consensus. Rome IV brought a clear-cut perspective into the pathophysiology of gastroesophageal reflux disease and the importance of esophageal hypersensitivity. This perspective can be supported by the fact that other functional gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia often overlap with RH. Although several possible pathophysiological mechanisms of esophageal hypersensitivity have been identified, there is still unmet medical needs in terms of treatment for this condition. This review summarizes the current knowledge regarding RH.
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Affiliation(s)
- Akinari Sawada
- Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Daniel Sifrim
- Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Yasuhiro Fujiwara
- Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
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10
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Gorgulu V, Ergun P, Kipcak S, Doganavsargil B, Sifrim D, Bor S. Revisiting the Role of Esophageal Mucosal Dilated Intercellular Spaces in the Diagnosis and Pathophysiology of Heartburn. J Neurogastroenterol Motil 2023; 29:436-445. [PMID: 37814434 PMCID: PMC10577464 DOI: 10.5056/jnm22142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 12/01/2022] [Accepted: 02/12/2023] [Indexed: 10/11/2023] Open
Abstract
Background/Aims Dilated intercellular spaces (DISs) facilitate the diffusion of noxious agents into the deep layers of the esophageal epithelium. The role of DIS in heartburn pathogenesis is still controversial. Therefore, we aim to reinvestigate DIS in an extensively evaluated group of patients and healthy controls (HCs). Methods We classified 149 subjects into the following groups: 15 HC, 58 mild erosive reflux disease (ERD), 17 severe ERD, 25 nonerosive reflux disease (NERD), 15 reflux hypersensitivity (RH), and 19 functional heartburn (FH). A total of 100 length measurements were performed for each patient's biopsy. Results The overall intercellular spaces (ISs) value of gastroesophageal reflux disease (GERD) patients was higher than that of HC (P = 0.020). In phenotypes, mild ERD (vs HC [P = 0.036], NERD [P = 0.004], RH [P = 0.014]) and severe ERD (vs HC [P = 0.002], NERD [P < 0.001], RH [P = 0.001], FH [P = 0.004]) showed significantly higher IS. There was no significant difference between the HC, NERD, RH, and FH groups. The 1.12 μm DIS cutoff value had 63.5% sensitivity and 66.7% specificity in the diagnosis of GERD. There was a weak correlation (r = 0.302) between the IS value and acid exposure time, and a weak correlation (r = -0.359) between the IS value and baseline impedance. A strong correlation was shown between acid exposure time and baseline impedance (r = -0.783). Conclusions Since the IS length measurement had better discrimination power only in erosive groups, it is not feasible to use in daily routine to discriminate other nonerosive phenotypes and FH. The role of DIS in heartburn in nonerosive patients should be reconsidered.
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Affiliation(s)
- Volkan Gorgulu
- Departments of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Pelin Ergun
- Departments of Medical Biochemistry, Faculty of Medicine, Ege University, Izmir, Turkey
- Division of Gastroenterology, Faculty of Medicine, Ege Reflux Study Group, Ege University, Izmir, Turkey
| | - Sezgi Kipcak
- Division of Gastroenterology, Faculty of Medicine, Ege Reflux Study Group, Ege University, Izmir, Turkey
- Departments of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Basak Doganavsargil
- Departments of Pathology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Daniel Sifrim
- Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Serhat Bor
- Division of Gastroenterology, Faculty of Medicine, Ege Reflux Study Group, Ege University, Izmir, Turkey
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11
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Hung CH, Chin Y, Fong YO, Lee CH, Han DS, Lin JH, Sun WH, Chen CC. Acidosis-related pain and its receptors as targets for chronic pain. Pharmacol Ther 2023; 247:108444. [PMID: 37210007 DOI: 10.1016/j.pharmthera.2023.108444] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/24/2023] [Accepted: 05/15/2023] [Indexed: 05/22/2023]
Abstract
Sensing acidosis is an important somatosensory function in responses to ischemia, inflammation, and metabolic alteration. Accumulating evidence has shown that acidosis is an effective factor for pain induction and that many intractable chronic pain diseases are associated with acidosis signaling. Various receptors have been known to detect extracellular acidosis and all express in the somatosensory neurons, such as acid sensing ion channels (ASIC), transient receptor potential (TRP) channels and proton-sensing G-protein coupled receptors. In addition to sense noxious acidic stimulation, these proton-sensing receptors also play a vital role in pain processing. For example, ASICs and TRPs are involved in not only nociceptive activation but also anti-nociceptive effects as well as some other non-nociceptive pathways. Herein, we review recent progress in probing the roles of proton-sensing receptors in preclinical pain research and their clinical relevance. We also propose a new concept of sngception to address the specific somatosensory function of acid sensation. This review aims to connect these acid-sensing receptors with basic pain research and clinical pain diseases, thus helping with better understanding the acid-related pain pathogenesis and their potential therapeutic roles via the mechanism of acid-mediated antinociception.
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Affiliation(s)
- Chih-Hsien Hung
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yin Chin
- Department of Life Science & Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-On Fong
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Cheng-Han Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Der-Shen Han
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan
| | - Jiann-Her Lin
- Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, Taipei Medical University Hospital, Taipei, Taiwan
| | - Wei-Hsin Sun
- Department of Life Science & Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Cheng Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan; Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan.
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12
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Ustaoglu A, Woodland P. Sensory Phenotype of the Oesophageal Mucosa in Gastro-Oesophageal Reflux Disease. Int J Mol Sci 2023; 24:ijms24032502. [PMID: 36768825 PMCID: PMC9917190 DOI: 10.3390/ijms24032502] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 01/14/2023] [Accepted: 01/18/2023] [Indexed: 02/03/2023] Open
Abstract
Gastroesophageal reflux disease (GORD) affects up to 20% of Western populations, yet sensory mechanisms underlying heartburn pathogenesis remain incompletely understood. While central mechanisms of heartburn perception have been established in earlier studies, recent studies have highlighted an important role of neurochemical, inflammatory, and cellular changes occurring in the oesophageal mucosa itself. The localization and neurochemical characterisation of sensory afferent nerve endings differ among GORD phenotypes, and could explain symptom heterogeneity among patients who are exposed to similar levels of reflux. Acid-induced stimulation of nociceptors on pain-sensing nerve endings can regulate afferent signal transmission. This review considers the role of peripheral mechanisms of sensitization in the amplification of oesophageal sensitivity in patients with GORD.
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13
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Yao Y, Liu ZJ, Zhang YK, Sun HJ. Mechanism and potential treatments for gastrointestinal dysfunction in patients with COVID-19. World J Gastroenterol 2022; 28:6811-6826. [PMID: 36632313 PMCID: PMC9827583 DOI: 10.3748/wjg.v28.i48.6811] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/01/2022] [Accepted: 12/07/2022] [Indexed: 12/26/2022] Open
Abstract
The global coronavirus disease 2019 (COVID-19) has become one of the biggest threats to the world since 2019. The respiratory and gastrointestinal tracts are the main targets for severe acute respiratory syndrome coronavirus 2 infection for they highly express angiotensin-converting enzyme-2 and transmembrane protease serine 2. In patients suffering from COVID-19, gastrointestinal symptoms have ranged from 12% to 61%. Anorexia, nausea and/or vomiting, diarrhea, and abdominal pain are considered to be the main gastrointestinal symptoms of COVID-19. It has been reported that the direct damage of intestinal mucosal epithelial cells, malnutrition, and intestinal flora disorders are involved in COVID-19. However, the underlying mechanisms remain unclear. Thus, in this study, we reviewed and discussed the correlated mechanisms that cause gastrointestinal symptoms in order to help to develop the treatment strategy and build an appropriate guideline for medical workers.
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Affiliation(s)
- Yang Yao
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, College of Basic Medical, Chongqing 404120, China
- Department of Clinical Pharmacology, College of Pharmacy, Dalian 116044, Liaoning Province, China
- Ministry of Public Infrastructure, Chongqing Three Gorges Medical College, Chongqing 404120, China
| | - Zhu-Jun Liu
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, College of Basic Medical, Chongqing 404120, China
- Department of Basic Medicine, Chongqing Three Gorges Medical College, Chongqing 404120, China
- Department of Business Administration, Metropolitan College of Science and Technology, Chongqing 404120, China
| | - Yu-Kun Zhang
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, College of Basic Medical, Chongqing 404120, China
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, Peking University, Beijing 100191, China
| | - Hui-Jun Sun
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, College of Basic Medical, Chongqing 404120, China
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, Liaoning Province, China
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14
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Anand U, Pacchetti B, Anand P, Sodergren MH. The Endocannabinoid Analgesic Entourage Effect: Investigations in Cultured DRG Neurons. J Pain Res 2022; 15:3493-3507. [PMID: 36394060 PMCID: PMC9642605 DOI: 10.2147/jpr.s378876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/08/2022] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND The endocannabinoid 2-Arachidonyl glycerol (2-AG) exerts dose-related anti-nociceptive effects, which are potentiated by the related but inactive 2-palmitoyl glycerol (2-PG) and 2-linoleoyl glycerol (2-LG). This potentiation of analgesia and other in vivo measures was described as the "entourage effect". We investigated this effect on TRPV1 signalling in cultured dorsal root ganglion (DRG) nociceptors. METHODS Adult rat DRG neurons were cultured in medium containing NGF and GDNF at 37°C. 48 h later cultures were loaded with 2 µM Fura2AM for calcium imaging, and treated with 2-AG, 2-PG and 2-LG, individually or combined, for 5 min, followed by 1 µMol capsaicin. The amplitude and latency of capsaicin responses were measured (N=3-7 rats, controls N=16), and analysed. RESULTS In controls, 1 µMol capsaicin elicited immediate calcium influx in a subset of neurons, with average latency of 1.27 ± 0.2 s and amplitude of 0.15 ± 0.01 Units. 2-AG (10-100 µMol) elicited calcium influx in some neurons. In the presence of 2-AG (0.001-100 µMol), capsaicin responses were markedly delayed in 64% neurons by up to 320 s (P<0.001). 2-PG increased capsaicin response latency at 0.1 nMol-100 µMol (P<0.001), in 60% neurons, as did 2-LG at 0.1-100 µMol (P<0.001), in 76% neurons. Increased capsaicin response latency due to 2-AG and 2-PG was sensitive to the CB2 but not to the CB1 receptor antagonist. Combined application of 1 µMol 2-AG, 5 µMol 2-PG and 10 µMol 2-LG, also resulted in significantly increased capsaicin response latency up to 281.5 ± 41.5 s (P<0.001), in 96% neurons, that was partially restored by the CB2, but not the CB1 antagonist. CONCLUSION 2-AG, 2-LG and 2-PG significantly delayed TRPV1 signalling in the majority of capsaicin-sensitive DRG neurons, that was markedly increased following combined application. Further studies of these endocannabinoids are required to identify the underlying mechanisms.
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Affiliation(s)
- Uma Anand
- Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, London, W12 0HS, UK
| | | | - Praveen Anand
- Professor of Clinical Neurology, Department of Brain Sciences, Imperial College London, London, W12 0HS, UK
| | - Mikael Hans Sodergren
- Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, London, W12 0HS, UK
- Curaleaf International Limited, London, EC2A 2EW, UK
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15
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Zhang S, Shoda T, Aceves SS, Arva NC, Chehade M, Collins MH, Dellon ES, Falk GW, Gonsalves N, Gupta SK, Hirano I, Khoury P, Leung J, Spergel AKR, Spergel JM, Wechsler JB, Yang GY, Furuta GT, Rothenberg ME. Mast cell-pain connection in eosinophilic esophagitis. Allergy 2022; 77:1895-1899. [PMID: 35175645 PMCID: PMC9167217 DOI: 10.1111/all.15260] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/19/2022] [Accepted: 02/07/2022] [Indexed: 01/10/2023]
Affiliation(s)
- Simin Zhang
- Division of Allergy and Immunology, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Tetsuo Shoda
- Division of Allergy and Immunology, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Seema S Aceves
- Division of Allergy Immunology, Departments of Pediatrics and Medicine, University of California, San Diego, California, USA.,Rady Children's Hospital, San Diego, California, USA
| | - Nicoleta C Arva
- Department of Pathology, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois, USA
| | - Mirna Chehade
- Mount Sinai Center for Eosinophilic Disorders, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Margaret H Collins
- Division of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Evan S Dellon
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Gary W Falk
- Division of Gastroenterology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Nirmala Gonsalves
- Division of Gastroenterology & Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Sandeep K Gupta
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Riley Hospital for Children/Indiana University School of Medicine, and Community Health Network, Indianapolis, Indiana, USA
| | - Ikuo Hirano
- Division of Gastroenterology & Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Paneez Khoury
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - John Leung
- Division of Gastroenterology, Tufts Medical Center, Boston, Massachusetts, USA
| | | | - Jonathan M Spergel
- Division of Allergy and Immunology, University of Pennsylvania Perelman School of Medicine/Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Joshua B Wechsler
- Division of Gastroenterology, Hepatology & Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Guang-Yu Yang
- Department of Pathology, Northwestern University, Chicago, Illinois, USA
| | - Glenn T Furuta
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Marc E Rothenberg
- Division of Allergy and Immunology, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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16
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Boudaka A, Tominaga M. Physiological and Pathological Significance of Esophageal TRP Channels: Special Focus on TRPV4 in Esophageal Epithelial Cells. Int J Mol Sci 2022; 23:ijms23094550. [PMID: 35562940 PMCID: PMC9099744 DOI: 10.3390/ijms23094550] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/16/2022] [Accepted: 04/19/2022] [Indexed: 12/10/2022] Open
Abstract
Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel that is broadly expressed in different human tissues, including the digestive system, where it acts as a molecular sensor and a transducer that regulates a variety of functional activities. Despite the extensive research to determine the role of this channel in the physiology and pathophysiology of different organs, the unique morphological and functional features of TRPV4 in the esophagus remain largely unknown. Ten years ago, TRPV4 was shown to be highly expressed in esophageal epithelial cells where its activation induces Ca2+-dependent ATP release, which, in turn, mediates several functions, ranging from mechanosensation to wound healing. This review summarizes the research progress on TRPV4, and focuses on the functional expression of TRPV4 in esophageal epithelium and its possible role in different esophageal diseases that would support TRPV4 as a candidate target for future therapeutic approaches to treat patients with these conditions.
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Affiliation(s)
- Ammar Boudaka
- Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khoud, P.O. Box 35, Muscat 123, Oman
- Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki 444-8787, Aichi, Japan;
- Correspondence:
| | - Makoto Tominaga
- Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki 444-8787, Aichi, Japan;
- Department of Physiological Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki 444-8787, Aichi, Japan
- Exploratory Research Center on Life and Living Systems, Thermal Biology Group, Okazaki 444-8787, Aichi, Japan
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Nikaki K, Sifrim D. Pathophysiology of Pediatric Gastroesophageal Reflux Disease: Similarities and Differences With Adults. J Clin Gastroenterol 2022; 56:99-113. [PMID: 34560757 DOI: 10.1097/mcg.0000000000001604] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Gastroesophageal reflux (GOR) is defined as "the passage of gastric contents into the esophagus with or without regurgitation and vomiting" and gastroesophageal reflux disease (GORD) is defined "when GOR leads to troublesome symptoms affecting the daily functioning and/or complications." This definition was first developed in 2006 by the Montreal consensus group (1) and later on adopted by pediatric gastroenterology societies such as ESPGHAN and NASPGHAN in 2009 (2). The definition of gastroesophageal reflux reveals little about its pathophysiology and is focused on symptomatology. In this way, it acts as an umbrella term for the multifactorial causes of the disease and the various phenotypes encountered; from functional heartburn to hypersensitive esophagus and nonerosive reflux disease, to erosive esophagitis and Barrett's esophagus. This article is devoted to the pathophysiology of pediatric GORD in comparison to adult GORD and is divided in 2 parts. In the first part, we will systematically describe the different mechanisms for the generation and clearance of reflux events, while on the second part we will discuss the mechanisms involved in symptoms generation. Finally, we will discuss the similarities and differences between pediatric and adult GORD.
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Affiliation(s)
- Kornilia Nikaki
- Gastroenterology Department, Great Ormond Street Hospital for Children
| | - Daniel Sifrim
- Wingate Institute of Neurogastroenterology, The Blizard Institute, QMUL, London, UK
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18
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da Silva JF, Binda NS, Pereira EMR, de Lavor MSL, Vieira LB, de Souza AH, Rigo FK, Ferrer HT, de Castro CJ, Ferreira J, Gomez MV. Analgesic effects of Phα1β toxin: a review of mechanisms of action involving pain pathways. J Venom Anim Toxins Incl Trop Dis 2021; 27:e20210001. [PMID: 34868281 PMCID: PMC8610172 DOI: 10.1590/1678-9199-jvatitd-2021-0001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 03/26/2021] [Indexed: 01/01/2023] Open
Abstract
Phα1β is a neurotoxin purified from spider venom that acts as a high-voltage-activated (HVA) calcium channel blocker. This spider peptide has shown a high selectivity for N-type HVA calcium channels (NVACC) and an analgesic effect in several animal models of pain. Its activity was associated with a reduction in calcium transients, glutamate release, and reactive oxygen species production from the spinal cord tissue and dorsal ganglia root (DRG) in rats and mice. It has been reported that intrathecal (i.t.) administration of Phα1β to treat chronic pain reverted opioid tolerance with a safer profile than ω-conotoxin MVIIA, a highly selective NVACC blocker. Following a recent development of recombinant Phα1β (CTK 01512-2), a new molecular target, TRPA1, the structural arrangement of disulphide bridges, and an effect on glial plasticity have been identified. CTK 01512-2 reproduced the antinociceptive effects of the native toxin not only after the intrathecal but also after the intravenous administration. Herein, we review the Phα1β antinociceptive activity in the most relevant pain models and its mechanisms of action, highlighting the impact of CTK 01512-2 synthesis and its potential for multimodal analgesia.
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Affiliation(s)
- Juliana Figueira da Silva
- Laboratory of Pharmacology, Department of Pharmacy, Federal
University of Ouro Preto, Ouro Preto, MG, Brazil
| | - Nancy Scardua Binda
- Laboratory of Pharmacology, Department of Pharmacy, Federal
University of Ouro Preto, Ouro Preto, MG, Brazil
| | - Elizete Maria Rita Pereira
- Graduate Program in Health Sciences, Institute of Education and
Research, Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
| | | | - Luciene Bruno Vieira
- Department of Pharmacology, Institute of Biological Sciences (ICB),
Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Alessandra Hubner de Souza
- Graduate Program in Health Sciences, Institute of Education and
Research, Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
| | - Flávia Karine Rigo
- Graduate Program in Health Sciences, University of the Extreme South
of Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Hèlia Tenza Ferrer
- Center of Technology in Molecular Medicine, School of Medicine,
Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Célio José de Castro
- Graduate Program in Health Sciences, Institute of Education and
Research, Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
| | - Juliano Ferreira
- Department of Pharmacology, Federal University of Santa Catarina,
Florianópolis, SC, Brazil
| | - Marcus Vinicius Gomez
- Graduate Program in Health Sciences, Institute of Education and
Research, Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
- Center of Technology in Molecular Medicine, School of Medicine,
Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
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19
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Pérez de Arce E, Quera R, Quigley EMM. The Dilemma of Persistent Irritable Bowel Syndrome Symptoms in Patients with Quiescent Inflammatory Bowel Disease. Gastroenterol Clin North Am 2021; 50:689-711. [PMID: 34304795 DOI: 10.1016/j.gtc.2021.03.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Irritable bowel syndrome and inflammatory bowel disease differ in their natural evolution, etiopathogenesis, diagnostic criteria, and therapeutic approach. However, recent evidence has suggested some similarities in mechanisms underlying symptom development and progression. There is a relevant role for alterations in the microbiome-brain-gut axis in both diseases. The presence of irritable bowel syndrome symptoms in patients with quiescent inflammatory bowel disease is common in clinical practice. To determine the cause of irritable bowel syndrome symptoms in patients with quiescent inflammatory bowel disease is a clinical challenge. This review aims to illustrate possible causes and solutions for these patients.
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Affiliation(s)
- Edith Pérez de Arce
- Department of Medicine, Division of Gastroenterology, Hospital Clínico Universidad de Chile, Dr. Carlos Lorca Tobar 999, Independencia, Región Metropolitana, Santiago, Chile
| | - Rodrigo Quera
- Division of Gastroenterology, Inflammatory Bowel Disease Program, Clínica Universidad de los Andes, Estoril 450, Las Condes, Región Metropolitana, Santiago, Chile
| | - Eamonn M M Quigley
- Division of Gastroenterology and Hepatology, Lynda K and David M Underwood Center for Digestive Disorders, Houston Methodist Hospital, Weill Cornell Medical College, Houston, TX, USA.
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20
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Esophageal Mucosa Innervation in Children With Nonerosive Reflux Disease. Am J Gastroenterol 2021; 116:1727-1729. [PMID: 33927127 DOI: 10.14309/ajg.0000000000001286] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 03/26/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Esophageal mucosa innervation in adults with nonerosive reflux disease (NERD) is more superficial compared with healthy volunteers. We delineated the esophageal mucosal innervation in pediatric NERD and controls. METHODS Distal and proximal pediatric esophageal biopsies were immunohistochemically stained with calcitonin gene-related peptide and transient receptor potential cation channel subfamily V member 1. RESULTS Mucosal innervation was assessed in 18 controls (9M:9F, median age: 9 years) and 11 NERD patients (6M:5F, median age: 5 years). Calcitonin gene-related peptide positive nerve fibers were lying deep in the mucosa in both groups, P > 0.05 and did not coexpress transient receptor potential cation channel subfamily V member 1. DISCUSSION The pediatric esophageal mucosa in NERD displays deep lying nerve fibers, in contrast to adults.
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21
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Abstract
PURPOSE OF REVIEW Despite the wide prevalence of gastro-esophageal reflux disease (GERD), the neurophysiological mechanisms underlying heartburn perception in the esophagus of patients with GERD remains incompletely understood. Recent studies have highlighted the potential influence sensory afferent nerves innervating the oesophageal epithelium may have on heartburn pathogenesis. The purpose of this review is to consider the current understanding of esophageal afferent neuronal innervation, including the nociceptive role of acid-sensing receptors expressed on these sensory nerves, in relation to pain perception in the esophagus of GERD patients. RECENT FINDINGS Central and peripheral pathways of sensitization following noxious stimulation of nociceptive receptors expressed on afferent nerves can regulate the strength of sensory nerve activation in the esophagus, which can result in the amplification or suppression of afferent signal transmission. The localization and characterization of mucosal sensory afferent nerves vary between GERD phenotypes and may explain the heterogeneity of symptom perception in patients with apparently similar levels of reflux. SUMMARY In this review, we discuss the relevance of afferent esophageal innervation in heartburn perception, with a particular focus on the pathways of reflux-induced activation of nociceptive nerves.
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22
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Yu M, Chang C, Undem BJ, Yu S. Capsaicin-Sensitive Vagal Afferent Nerve-Mediated Interoceptive Signals in the Esophagus. Molecules 2021; 26:3929. [PMID: 34203134 PMCID: PMC8271978 DOI: 10.3390/molecules26133929] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 01/14/2023] Open
Abstract
Heartburn and non-cardiac chest pain are the predominant symptoms in many esophageal disorders, such as gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), functional heartburn and chest pain, and eosinophilic esophagitis (EoE). At present, neuronal mechanisms underlying the process of interoceptive signals in the esophagus are still less clear. Noxious stimuli can activate a subpopulation of primary afferent neurons at their nerve terminals in the esophagus. The evoked action potentials are transmitted through both the spinal and vagal pathways to their central terminals, which synapse with the neurons in the central nervous system to induce esophageal nociception. Over the last few decades, progress has been made in our understanding on the peripheral and central neuronal mechanisms of esophageal nociception. In this review, we focus on the roles of capsaicin-sensitive vagal primary afferent nodose and jugular C-fiber neurons in processing nociceptive signals in the esophagus. We briefly compare their distinctive phenotypic features and functional responses to mechanical and chemical stimulations in the esophagus. Then, we summarize activation and/or sensitization effects of acid, inflammatory cells (eosinophils and mast cells), and mediators (ATP, 5-HT, bradykinin, adenosine, S1P) on these two nociceptive C-fiber subtypes. Lastly, we discuss the potential roles of capsaicin-sensitive esophageal afferent nerves in processing esophageal sensation and nociception. A better knowledge of the mechanism of nociceptive signal processes in primary afferent nerves in the esophagus will help to develop novel treatment approaches to relieve esophageal nociceptive symptoms, especially those that are refractory to proton pump inhibitors.
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Affiliation(s)
| | | | | | - Shaoyong Yu
- Department of Medicine, Johns Hopkins University School of Medicine, Ross Research Building, 720 Rutland Ave, Baltimore, MD 21205, USA; (M.Y.); (C.C.); (B.J.U.)
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23
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Jaffal SM, Abbas MA. TRP channels in COVID-19 disease: Potential targets for prevention and treatment. Chem Biol Interact 2021; 345:109567. [PMID: 34166652 PMCID: PMC8217345 DOI: 10.1016/j.cbi.2021.109567] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/15/2021] [Accepted: 06/21/2021] [Indexed: 01/05/2023]
Abstract
Coronavirus disease 2019 [COVID-19] is a global health threat caused by severe acute respiratory syndrome coronavirus 2 [SARS-CoV2] that requires two proteins for entry: angiotensin-converting enzyme 2 [ACE2] and -membrane protease serine 2 [TMPRSS2]. Many patients complain from pneumonia, cough, fever, and gastrointestinal (GI) problems. Notably, different TRP channels are expressed in various tissues infected by SARS-CoV-2. TRP channels are cation channels that show a common architecture with high permeability to calcium [Ca2+] in most sub-families. Literature review shed light on the possible role of TRP channels in COVID-19 disease. TRP channels may take part in inflammation, pain, fever, anosmia, ageusia, respiratory, cardiovascular, GI and neurological complications related to COVID-19. Also, TRP channels could be the targets for many active compounds that showed effectiveness against SARS-CoV-2. Desensitization or blocking TRP channels by antibodies, aptamers, small molecules or venoms can be an option for COVID-19 prevention and future treatment. This review provides insights into the involvement of TRP channels in different symptoms and mechanisms of SARS-CoV-2 , potential treatments targeting these channels and highlights missing gaps in literature.
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Affiliation(s)
- Sahar M Jaffal
- Department of Biological Sciences, Faculty of Science, The University of Jordan, 11942, Amman, Jordan.
| | - Manal A Abbas
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, 19328, Amman, Jordan; Pharmacological and Diagnostic Research Center, Al-Ahliyya Amman University, 19328, Amman, Jordan
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Pérez de Arce E, Quera R, Beltrán CJ, Madrid AM, Nos P. Irritable Bowel Syndrome in Inflammatory Bowel Disease. Synergy in alterations of the gut-brain axis? GASTROENTEROLOGIA Y HEPATOLOGIA 2021; 45:66-76. [PMID: 34023477 DOI: 10.1016/j.gastrohep.2021.02.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 02/02/2021] [Accepted: 02/15/2021] [Indexed: 10/21/2022]
Abstract
The presence of digestive symptoms associated with irritable bowel syndrome (IBS) in patients with inflammatory bowel disease (IBD) in remission is a topic of growing interest. Although there is heterogeneity in clinical studies regarding the use of IBD remission criteria and the diagnosis of IBS, the available data indicate that the IBD-IBS overlap would affect up to one third of patients in remission, and they agree on the finding of a negative impact on the mental health and quality of life of the individuals who suffer from it. The pathophysiological bases that would explain this potential overlap are not completely elucidated; however, an alteration in the gut-brain axis associated with an increase in intestinal permeability, neuroimmune activation and dysbiosis would be common to both conditions. The hypothesis of a new clinical entity or syndrome of "Irritable Inflammatory Bowel Disease" or "Post-inflammatory IBS" is the subject of intense investigation. The clinical approach is based on certifying the remission of IBD activity and ruling out other non-inflammatory causes of potentially treatable persistent functional digestive symptoms. In the case of symptoms associated with IBS and in the absence of sufficient evidence, comprehensive and personalized management of the clinical picture (dietary, pharmacological and psychotherapeutic measures) should be carried out, similar to a genuine IBS.
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Affiliation(s)
- Edith Pérez de Arce
- Departamento de Medicina Interna, Servicio de Gastroenterología, Hospital Clínico Universidad de Chile, Santiago, Chile.
| | - Rodrigo Quera
- Programa Enfermedad Inflamatoria Intestinal, Departamento de Gastroenterología, Clínica Universidad de los Andes, Santiago, Chile
| | - Caroll J Beltrán
- Laboratorio de Inmuno-gastroenterología, Servicio de Gastroenterología, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - Ana María Madrid
- Departamento de Medicina Interna, Servicio de Gastroenterología, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - Pilar Nos
- Unidad de Enfermedad Inflamatoria Intestinal, Servicio de Medicina Digestiva, Hospital Universitari i Politècnic La Fe, Valencia, España
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25
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Ustaoglu A, Sawada A, Lee C, Lei WY, Chen CL, Hackett R, Sifrim D, Peiris M, Woodland P. Heartburn sensation in nonerosive reflux disease: pattern of superficial sensory nerves expressing TRPV1 and epithelial cells expressing ASIC3 receptors. Am J Physiol Gastrointest Liver Physiol 2021; 320:G804-G815. [PMID: 33655767 DOI: 10.1152/ajpgi.00013.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The underlying causes of heartburn, characteristic symptom of gastroesophageal reflux disease (GERD), remain incompletely understood. Superficial afferent innervation of the esophageal mucosa in nonerosive reflux disease (NERD) may drive nociceptive reflux perception, but its acid-sensing role has not yet been established. Transient receptor potential vanilloid subfamily member-1 (TRPV1), transient receptor potential melastatin 8 (TRPM8), and acid-sensing ion channel 3 (ASIC3) are regulators of sensory nerve activity and could be important reflux-sensing receptors within the esophageal mucosa. We characterized TRPV1, TRPM8, and ASIC3 expression in esophageal mucosa of patients with GERD. We studied 10 patients with NERD, 10 with erosive reflux disease (ERD), 7 with functional heartburn (FH), and 8 with Barrett's esophagus (BE). Biopsies obtained from the distal esophageal mucosa were costained with TRPV1, TRPM8, or ASIC3, and CGRP, CD45, or E-cadherin. RNA expression of TRPV1, TRPM8, and ASIC3 was assessed using qPCR. Patients with NERD had significantly increased expression of TRPV1 on superficial sensory nerves compared with ERD (P = 0.028) or BE (P = 0.017). Deep intrapapillary nerve endings did not express TRPV1 in all phenotypes studied. ASIC3 was exclusively expressed on epithelial cells most significantly in patients with NERD and ERD (P ≤0.0001). TRPM8 was expressed on submucosal CD45+ leukocytes. Superficial localization of TRPV1-immunoreactive nerves in NERD, and increased ASIC3 coexpression on epithelial cells in NERD and ERD, suggests a mechanism for heartburn sensation. Esophageal epithelial cells may play a sensory role in acid reflux perception and act interdependently with TRPV1-expressing mucosal nerves to augment hypersensitivity in patients with NERD, raising the enticing possibility of topical antagonists for these ion channels as a therapeutic option.NEW & NOTEWORTHY We demonstrate for the first time that increased pain perception in patients with nonerosive reflux disease likely results from expression of acid-sensitive channels on superficial mucosal afferents and esophageal epithelial cells, raising the potential for topical therapy.
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Affiliation(s)
- Ahsen Ustaoglu
- Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Akinari Sawada
- Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Chung Lee
- Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Wei-Yi Lei
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Chien-Lin Chen
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Richard Hackett
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Daniel Sifrim
- Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Madusha Peiris
- Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Philip Woodland
- Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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26
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Spekker E, Laborc KF, Bohár Z, Nagy-Grócz G, Fejes-Szabó A, Szűcs M, Vécsei L, Párdutz Á. Effect of dural inflammatory soup application on activation and sensitization markers in the caudal trigeminal nucleus of the rat and the modulatory effects of sumatriptan and kynurenic acid. J Headache Pain 2021; 22:17. [PMID: 33789568 PMCID: PMC8011387 DOI: 10.1186/s10194-021-01229-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 03/15/2021] [Indexed: 01/12/2023] Open
Abstract
Background The topical inflammatory soup can model the inflammation of the dura mater causing hypersensitivity and activation of the trigeminal system, a phenomenon present in migraineurs. Calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase are important in the sensitization process there. 5-HT1B/1D receptor agonists, triptans are used as a treatment of migraine. Kynurenic acid an NMDA antagonist can act on structures involved in trigeminal activation. Aim We investigated the effect of inflammatory soup induced dural inflammation on the calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase levels in the caudal trigeminal nucleus. We also tested whether pretreatment with a well-known antimigraine drug, such as sumatriptan and kynurenic acid, a compound with a different mechanism of action, can affect these changes and if their modulatory effects are comparable. Material and methods After subcutaneous sumatriptan or intraperitoneal kynurenic acid the dura mater of adult male Sprague-Dawley rats (n = 72) was treated with inflammatory soup or its vehicle (synthetic interstitial fluid). Two and a half or four hours later perfusion was performed and the caudal trigeminal nucleus was removed for immunohistochemistry. Results and conclusion Inflammatory soup increased calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase in the caudal trigeminal nucleus compared to placebo, which was attenuated by sumatriptan and kynurenic acid. This suggests the involvement of 5-HT1B/1D and NMDA receptors in neurogenic inflammation development of the dura and thus in migraine attacks.
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Affiliation(s)
- Eleonóra Spekker
- Department of Neurology, Interdisciplinary Excellence Center, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis utca 6, Szeged, H-6725, Hungary
| | - Klaudia Flóra Laborc
- Department of Neurology, Interdisciplinary Excellence Center, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis utca 6, Szeged, H-6725, Hungary
| | - Zsuzsanna Bohár
- Department of Neurology, Interdisciplinary Excellence Center, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis utca 6, Szeged, H-6725, Hungary.,MTA-SZTE Neuroscience Research Group, Szeged, Hungary
| | - Gábor Nagy-Grócz
- Department of Neurology, Interdisciplinary Excellence Center, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis utca 6, Szeged, H-6725, Hungary.,Faculty of Health Sciences and Social Studies, University of Szeged, Szeged, Hungary
| | | | - Mónika Szűcs
- Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary
| | - László Vécsei
- Department of Neurology, Interdisciplinary Excellence Center, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis utca 6, Szeged, H-6725, Hungary. .,MTA-SZTE Neuroscience Research Group, Szeged, Hungary.
| | - Árpád Párdutz
- Department of Neurology, Interdisciplinary Excellence Center, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis utca 6, Szeged, H-6725, Hungary
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27
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Capsaicin 8% patch Qutenza and other current treatments for neuropathic pain in chemotherapy-induced peripheral neuropathy (CIPN). Curr Opin Support Palliat Care 2021; 15:125-131. [PMID: 33905384 DOI: 10.1097/spc.0000000000000545] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
PURPOSE OF REVIEW Current oral treatments for neuropathic pain associated with chemotherapy-induced peripheral neuropathy (CIPN) have limited clinical efficacy, and undesirable side-effects. Topically delivered treatments have the advantage of avoiding CNS side-effects, while relieving pain. We have reviewed treatments of neuropathic pain associated with CIPN, focusing on the Capsaicin 8% patch, which can provide pain relief for up to 3 months or longer after a single 30-60-min application. RECENT FINDINGS Capsaicin 8% patch is a licensed treatment in the EU/UK for neuropathic pain and shown to be safe and effective in providing pain relief for patients with CIPN. Repeated daily oral or topical administrations are not required, as with other current treatments. The side-effects are transient and restricted to the time around patch application. New evidence suggests the Capsaicin 8% patch can promote the regeneration and restoration of skin nerve fibres in CIPN, in addition to the pain relief. SUMMARY The Capsaicin 8% patch is now often a preferred a treatment option for localised neuropathic pain conditions, including the feet and hands in patients with CIPN. Capsaicin 8% patch can be repeated three-monthly, if needed, for a year. In addition to pain relief, it may have a disease-modifying effect.
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28
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Duo L, Wu T, Ke Z, Hu L, Wang C, Teng G, Zhang W, Wang W, Ge Q, Yang Y, Dai Y. Gain of Function of Ion Channel TRPV1 Exacerbates Experimental Colitis by Promoting Dendritic Cell Activation. MOLECULAR THERAPY-NUCLEIC ACIDS 2020; 22:924-936. [PMID: 33251043 PMCID: PMC7666365 DOI: 10.1016/j.omtn.2020.10.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 10/09/2020] [Indexed: 01/07/2023]
Abstract
Dysregulated mucosal immunity plays an essential role in the pathophysiology of inflammatory bowel disease (IBD). Transient receptor potential vanilloid 1 (TRPV1) is a Ca2+-permeable ion channel that is implicated in modulating immune responses. However, its role in the pathogenesis of intestinal inflammation remains elusive. Here, we found that TRPV1 gain of function significantly increased the susceptibility of mice to experimental colitis, and that was associated with excessive recruitment of dendritic cells and enhanced Th17 immune responses in the lamina propria of colon. TRPV1 gain of function promoted dendritic cell activation and cytokine production upon inflammatory stimuli, and consequently enhanced dendritic cell-mediated Th17 cell differentiation. Further mechanistic studies showed that TRPV1 gain of function in dendritic cells enhanced activation of calcineurin/nuclear factor of activated T cells (NFATc2) signaling induced by inflammatory stimuli. Moreover, in patients with IBD, TRPV1 expression was increased in lamina propria cells of inflamed colon compared with healthy controls. Our findings identify an important role for TRPV1 in modulating dendritic cell activation and sustaining Th17 responses to inflammatory stimuli, which suggest that TRPV1 might be a potential therapeutic target in controlling mucosal immunity and IBD.
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Affiliation(s)
- Lina Duo
- Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.,Department of Dermatology, Chengdu Integrated TCM & Western Medicine Hospital, Chengdu, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China.,Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Ting Wu
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Ziliang Ke
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Linghan Hu
- Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China.,Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Chaohui Wang
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Guigen Teng
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Wei Zhang
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Weihong Wang
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Qing Ge
- Department of Immunology, Peking University Health Science Center, Beijing, China
| | - Yong Yang
- Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China.,Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China
| | - Yun Dai
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
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29
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Abstract
The gut-brain axis is a coordinated communication system that not only maintains homeostasis, but significantly influences higher cognitive functions and emotions, as well as neurological and behavioral disorders. Among the large populations of sensory and motor neurons that innervate the gut, insights into the function of primary afferent nociceptors, whose cell bodies reside in the dorsal root ganglia and nodose ganglia, have revealed their multiple crosstalk with several cell types within the gut wall, including epithelial, vascular, and immune cells. These bidirectional communications have immunoregulatory functions, control host response to pathogens, and modulate sensations associated with gastrointestinal disorders, through activation of immune cells and glia in the peripheral and central nervous system, respectively. Here, we will review the cellular and neurochemical basis of these interactions at the periphery, in dorsal root ganglia, and in the spinal cord. We will discuss the research gaps that should be addressed to get a better understanding of the multifunctional role of sensory neurons in maintaining gut homeostasis and regulating visceral sensitivity.
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Affiliation(s)
- Nasser Abdullah
- Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Manon Defaye
- Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Christophe Altier
- Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
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30
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Ustaoglu A, Nguyen A, Spechler S, Sifrim D, Souza R, Woodland P. Mucosal pathogenesis in gastro-esophageal reflux disease. Neurogastroenterol Motil 2020; 32:e14022. [PMID: 33118247 DOI: 10.1111/nmo.14022] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/02/2020] [Accepted: 10/05/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Despite gastro-esophageal reflux disease affecting up to 20% of Western populations, relatively little is known about the molecular mechanisms underlying its most troublesome symptom: heartburn. Recent findings have unveiled the role of components of the esophageal mucosa in the pathogenesis of GERD including sensory nociceptive nerves and inflammatory mediators. Erosive esophagitis was long believed to develop as a result of acid injury at the esophageal lumen, but novel concepts suggest the generation of reflux-induced esophageal injury as a result of cytokine-mediated inflammation. Moreover, the localization and characterization of mucosal afferent nerves vary between GERD phenotypes and could explain the heterogeneity of symptom perception between patients who experience similar levels of acid reflux. PURPOSE The purpose of this review is to consider the crosstalk of different factors of the esophageal mucosa in the pathogenesis of GERD, with a particular focus on mucosal innervation and molecular basis of acid-induced cytokine response. We discuss the current understanding of the mucosal response to acid injury, the nociceptive role of acid-sensitive receptors expressed in the esophageal mucosa, and the role of esophageal epithelial cells in initiating the onset of erosive esophagitis.
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Affiliation(s)
- Ahsen Ustaoglu
- Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Anh Nguyen
- Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, TX, USA
| | - Stuart Spechler
- Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, TX, USA
| | - Daniel Sifrim
- Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Rhonda Souza
- Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, TX, USA
| | - Philip Woodland
- Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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31
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Silverman HA, Chen A, Kravatz NL, Chavan SS, Chang EH. Involvement of Neural Transient Receptor Potential Channels in Peripheral Inflammation. Front Immunol 2020; 11:590261. [PMID: 33193423 PMCID: PMC7645044 DOI: 10.3389/fimmu.2020.590261] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 09/30/2020] [Indexed: 12/11/2022] Open
Abstract
Transient receptor potential (TRP) channels are a superfamily of non-selective cation channels that act as polymodal sensors in many tissues throughout mammalian organisms. In the context of ion channels, they are unique for their broad diversity of activation mechanisms and their cation selectivity. TRP channels are involved in a diverse range of physiological processes including chemical sensing, nociception, and mediating cytokine release. They also play an important role in the regulation of inflammation through sensory function and the release of neuropeptides. In this review, we discuss the functional contribution of a subset of TRP channels (TRPV1, TRPV4, TRPM3, TRPM8, and TRPA1) that are involved in the body’s immune responses, particularly in relation to inflammation. We focus on these five TRP channels because, in addition to being expressed in many somatic cell types, these channels are also expressed on peripheral ganglia and nerves that innervate visceral organs and tissues throughout the body. Activation of these neural TRP channels enables crosstalk between neurons, immune cells, and epithelial cells to regulate a wide range of inflammatory actions. TRP channels act either through direct effects on cation levels or through indirect modulation of intracellular pathways to trigger pro- or anti-inflammatory mechanisms, depending on the inflammatory disease context. The expression of TRP channels on both neural and immune cells has made them an attractive drug target in diseases involving inflammation. Future work in this domain will likely yield important new pathways and therapies for the treatment of a broad range of disorders including colitis, dermatitis, sepsis, asthma, and pain.
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Affiliation(s)
- Harold A Silverman
- Laboratory of Biomedical Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Adrian Chen
- Laboratory of Biomedical Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Nigel L Kravatz
- Laboratory of Biomedical Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Sangeeta S Chavan
- Laboratory of Biomedical Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, NY, United States
| | - Eric H Chang
- Laboratory of Biomedical Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, NY, United States
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32
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Harsanyiova J, Ru F, Zatko T, Kollarik M, Hennel M. Vagus Nerves Provide a Robust Afferent Innervation of the Mucosa Throughout the Body of the Esophagus in the Mouse. Dysphagia 2020; 35:471-478. [PMID: 31468191 PMCID: PMC10688604 DOI: 10.1007/s00455-019-10051-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 08/12/2019] [Indexed: 12/12/2022]
Abstract
The vagal afferent nerves regulate swallowing and esophageal motor reflexes. However, there are still gaps in the understanding of vagal afferent innervation of the esophageal mucosa. Anatomical studies found that the vagal afferent mucosal innervation is dense in the upper esophageal sphincter area but rare in more distal segments of the esophagus. In contrast, electrophysiological studies concluded that the vagal afferent nerve fibers also densely innervate mucosa in more distal esophagus. We hypothesized that the transfection of vagal afferent neurons with adeno-associated virus vector encoding green fluorescent protein (AAV-GFP) allows to visualize vagal afferent nerve fibers in the esophageal mucosa in the mouse. AAV-GFP was injected into the vagal jugular/nodose ganglia in vivo to sparsely label vagal afferent nerve fibers. The esophageal tissue was harvested 4-6 weeks later, the GFP signal was amplified by immunostaining, and confocal optical sections of the entire esophagi were obtained. We found numerous GFP-labeled fibers in the mucosa throughout the whole body of the esophagus. The GFP-labeled mucosal fibers were located just beneath the epithelium, branched repeatedly, had mostly longitudinal orientation, and terminated abruptly without forming terminal structures. The GFP-labeled mucosal fibers were concentrated in random areas of various sizes in which many fibers could be traced to a single parental axon. We conclude that the vagus nerves provide a robust afferent innervation of the mucosa throughout the whole body of the esophagus in the mouse. Vagal mucosal fibers may contribute to the sensing of intraluminal content and regulation of swallowing and other reflexes.
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Affiliation(s)
- J Harsanyiova
- Department of Pathophysiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Mala Hora 4C, 036 01, Martin, Slovakia
- Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC 8, Tampa, FL, 33612, USA
| | - F Ru
- Department of Medicine, Allergy and Asthma Center, The Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD, 21224, USA
| | - T Zatko
- Department of Pathophysiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Mala Hora 4C, 036 01, Martin, Slovakia
| | - M Kollarik
- Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC 8, Tampa, FL, 33612, USA
| | - M Hennel
- Division of Neuroscience, Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Malá Hora 4C, 036 01, Martin, Slovakia.
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33
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Zachariah RA, Goo T, Lee RH. Mechanism and Pathophysiology of Gastroesophageal Reflux Disease. Gastrointest Endosc Clin N Am 2020; 30:209-226. [PMID: 32146942 DOI: 10.1016/j.giec.2019.12.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Gastroesophageal reflux (GER) describes a process in which gastric contents travel retrograde into the esophagus. GER can be either a physiologic phenomenon that occurs in asymptomatic individuals or can potentially cause symptoms. When the latter occurs, this represents GER disease (GERD). The process by which GER transforms into GERD begins at the esophagogastric junction. Impaired clearance of the refluxate also contributes to GERD. Reflux causes degradation of esophageal mucosal defense. The refluxate triggers sensory afferents leading to symptom generation.
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Affiliation(s)
- Robin A Zachariah
- H.H. Chao Comprehensive Digestive Disease Center, 333 City Boulevard West, Suite 400, Room 459, Orange, CA 92868, USA
| | - Tyralee Goo
- Tibor Rubin Veterans' Affairs Medical Center, 5901 E. Seventh Street, Long Beach, CA 90822, USA
| | - Robert H Lee
- H.H. Chao Comprehensive Digestive Disease Center, 333 City Boulevard West, Suite 400, Room 459, Orange, CA 92868, USA; Tibor Rubin Veterans' Affairs Medical Center, 5901 E. Seventh Street, Long Beach, CA 90822, USA.
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34
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Shibli F, Kitayama Y, Fass R. Novel Therapies for Gastroesophageal Reflux Disease: Beyond Proton Pump Inhibitors. Curr Gastroenterol Rep 2020; 22:16. [PMID: 32185589 DOI: 10.1007/s11894-020-0753-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
PURPOSE OF REVIEW Despite the many areas of unmet needs in gastroesophageal reflux disease (GERD), proton pump inhibitors (PPIs) remain the cornerstone of medical therapy. However, since their introduction, the therapeutic limitations of PPIs in GERD management have been increasingly recognized. RECENT FINDINGS In this review we discuss the new medical, endoscopic, and surgical therapeutic modalities that have been developed over the last decade. They include the potassium-competitive acid blockers (P-CABs) which provide a rapid onset, prolonged, and profound acid suppression, mucosal protectants which promote the physiological protective barrier of the esophageal mucosa, new prokinetics and neuromodulators. There are growing numbers of novel therapeutic endoscopic techniques that are under investigation or were recently introduced into the market, further expanding our therapeutic armamentarium for GERD. The development of diverse therapeutic modalities for GERD, despite the availability of PPIs, suggests that there are many areas of unmet need in GERD that will continue and drive future exploration for novel therapies.
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Affiliation(s)
- Fahmi Shibli
- The Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH, 44109, USA
| | - Yoshitaka Kitayama
- The Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH, 44109, USA
| | - Ronnie Fass
- The Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH, 44109, USA.
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Banovcin P, Duricek M, Zatko T, Liptak P, Hyrdel R, Kollarik M. The infusion of menthol into the esophagus evokes cold sensations in healthy subjects but induces heartburn in patients with gastroesophageal reflux disease (GERD). Dis Esophagus 2019; 32:5480065. [PMID: 31022726 DOI: 10.1093/dote/doz038] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 03/01/2019] [Indexed: 12/11/2022]
Abstract
Recent studies in animal models have reported that some afferent fibers innervating the esophagus express the cold receptor TRPM8. In the somatosensory system the stimulation of TRPM8 leads to cold sensations and in certain circumstances alleviates pain. It is therefore hypothesized in this paper that the esophageal infusion of the TRPM8 activator menthol evokes cold sensations from the esophagus and alleviates heartburn in humans. The esophageal infusion of menthol (3 mM, 20 min) evoked cold sensations in 11 of 12 healthy subjects. In striking contrast, the esophageal infusion of menthol evoked heartburn in 10 of 10 patients with gastroesophageal reflux disease (GERD). In healthy subjects the cold sensation evoked by menthol was perceived only as a minor discomfort as evaluated by the visual analog scale (VAS score 1.9 ± 0.3 on the scale 1-10). However, in patients with GERD the menthol-induced heartburn was perceived as painful (VAS score 5.6 ± 0.6, P < 0.01 compared to healthy subjects). It is concluded that the sensations evoked by esophageal infusion of menthol change from relatively nonpainful cold sensations in healthy subjects to painful heartburn sensations in patients with GERD. These qualitative and quantitative changes indicate substantial alterations in afferent signaling mediating sensations from the esophagus in patients with GERD.
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Affiliation(s)
| | | | - Tomas Zatko
- Department of Pathophysiology, Jessenius Faculty of Medicine in Martin (JFM CU), Comenius University in Bratislava, Martin, Slovakia
| | | | | | - Marian Kollarik
- Department of Pathophysiology, Jessenius Faculty of Medicine in Martin (JFM CU), Comenius University in Bratislava, Martin, Slovakia.,Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
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Marine Toxins and Nociception: Potential Therapeutic Use in the Treatment of Visceral Pain Associated with Gastrointestinal Disorders. Toxins (Basel) 2019; 11:toxins11080449. [PMID: 31370176 PMCID: PMC6723473 DOI: 10.3390/toxins11080449] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 07/24/2019] [Accepted: 07/26/2019] [Indexed: 12/12/2022] Open
Abstract
Visceral pain, of which the pathogenic basis is currently largely unknown, is a hallmark symptom of both functional disorders, such as irritable bowel syndrome, and inflammatory bowel disease. Intrinsic sensory neurons in the enteric nervous system and afferent sensory neurons of the dorsal root ganglia, connecting with the central nervous system, represent the primary neuronal pathways transducing gut visceral pain. Current pharmacological therapies have several limitations, owing to their partial efficacy and the generation of severe adverse effects. Numerous cellular targets of visceral nociception have been recognized, including, among others, channels (i.e., voltage-gated sodium channels, VGSCs, voltage-gated calcium channels, VGCCs, Transient Receptor Potential, TRP, and Acid-sensing ion channels, ASICs) and neurotransmitter pathways (i.e., GABAergic pathways), which represent attractive targets for the discovery of novel drugs. Natural biologically active compounds, such as marine toxins, able to bind with high affinity and selectivity to different visceral pain molecular mediators, may represent a useful tool (1) to improve our knowledge of the physiological and pathological relevance of each nociceptive target, and (2) to discover therapeutically valuable molecules. In this review we report the most recent literature describing the effects of marine toxin on gastrointestinal visceral pain pathways and the possible clinical implications in the treatment of chronic pain associated with gut diseases.
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Wulamu W, Yisireyili M, Aili A, Takeshita K, Alimujiang A, Aipire A, Li Y, Jiang Y, Aizezi M, Li Z, Abudureyimu K. Chronic stress augments esophageal inflammation, and alters the expression of transient receptor potential vanilloid 1 and protease‑activated receptor 2 in a murine model. Mol Med Rep 2019; 19:5386-5396. [PMID: 31059059 DOI: 10.3892/mmr.2019.10192] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 03/07/2019] [Indexed: 11/06/2022] Open
Abstract
Stress is a pivotal factor for inflammation, reactive oxygen species (ROS) production and formation of visceral hypersensitivity (VH) in the process of gastroesophageal reflux disease (GERD). In the present study, the effects of stress on esophageal inflammation, oxidative stress and VH were investigated in a chronic restraint stress mouse model. C57BL/6J male mice were subjected to 2 weeks of intermittent restraint stress, and histopathological analysis revealed that stress induced esophageal inflammation and fibrosis, while no distinct changes were detected in non‑stressed control mice. In addition, increased NADPH oxidase 4 expression was observed in the plasma and esophagus of stressed mice, indicating accumulation of ROS. The expression levels of antioxidants, including Mn‑superoxide dismutase (MnSOD), Cu/Zn‑SOD, catalase and glutathione peroxidase, were also analyzed using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). In addition, transient receptor potential vanilloid 1 (TRPV‑1) and protease‑activated receptor 2 (PAR‑2), which are crucial receptors for VH, were measured by immunohistochemistry and RT‑qPCR. The results demonstrated that stress markedly reduced antioxidant expression, while it significantly upregulated TRPV‑1 and PAR‑2 expression levels in the mouse esophagus. Finally, 2 weeks of restraint stress significantly increased the esophageal and plasma levels of inflammatory cytokines, including interleukin (IL)‑6, IL‑8, interferon‑γ and tumor necrosis factor‑α. Taken together, the present study results indicated that stress‑induced esophageal inflammation and ROS generation involves VH.
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Affiliation(s)
- Wubulikasimu Wulamu
- Research Institute of General and Minimally Invasive Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830001, P.R. China
| | - Maimaiti Yisireyili
- Research Institute of General and Minimally Invasive Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830001, P.R. China
| | - Aikebaier Aili
- Research Institute of General and Minimally Invasive Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830001, P.R. China
| | - Kyosuke Takeshita
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 460‑8550, Japan
| | - Aziguli Alimujiang
- Department of Obstetrics and Gynecology Clinic, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830001, P.R. China
| | - Aliyeguli Aipire
- Research Institute of General and Minimally Invasive Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830001, P.R. China
| | - Yiliang Li
- Department of Minimally Invasive Surgery, Hernia and Abdominal Wall Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830001, P.R. China
| | - Yuan Jiang
- Department of Minimally Invasive Surgery, Hernia and Abdominal Wall Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830001, P.R. China
| | - Maimaitiaili Aizezi
- Department of Cardiac Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830001, P.R. China
| | - Zanlin Li
- Department of Minimally Invasive Surgery, Hernia and Abdominal Wall Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830001, P.R. China
| | - Kelimu Abudureyimu
- Research Institute of General and Minimally Invasive Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830001, P.R. China
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Hu Y, Yu X, Yu S. QX-314 inhibits acid-induced activation of esophageal nociceptive C fiber neurons. Neurogastroenterol Motil 2019; 31:e13543. [PMID: 30663188 PMCID: PMC6452878 DOI: 10.1111/nmo.13543] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 12/10/2018] [Accepted: 12/14/2018] [Indexed: 01/16/2023]
Abstract
INTRODUCTION Acid reflux in the esophagus can induce painful sensations such as heartburn and non-cardiac chest pain. These nociceptive symptoms are initiated by activation of TRPV1-positive afferent C fibers in the esophagus. The present study aimed to explore a novel C fiber inhibition approach. We hypothesized that activation of TRPV1 by acid enabled QX-314, a membrane impermeable sodium channel blocker, to inhibit acid-induced activation of esophageal nociceptive C fiber neurons. METHOD We determined the inhibitory effect of QX-314 in the presence of acid in guinea pig esophageal nociceptive vagal jugular C fiber neurons by both patch clamp recording in neuron soma and by extra-cellular recording at nerve terminals. KEY RESULTS Our data demonstrated QX-314 alone did not inhibit sodium currents. However, when applied along with capsaicin to activate TRPV1, QX-314 was able to block sodium currents in esophageal-specific jugular C fiber neurons. We then showed that in the presence of acid, QX-314 significantly blocked acid-evoked activation of jugular C fiber neurons. This effect was attenuated by TRPV1 antagonist AMG9810, suggesting acid-mediated inhibitory effect of QX-314 was TRPV1-dependent. Finally, we provided evidence at nerve endings that acid-evoked action potential discharges in esophageal jugular C fibers were inhibited by QX-314 when applied in the presence of acid. CONCLUSION AND INFERENCES Our data demonstrated that activation of TRPV1 by acid enabled membrane impermeable sodium channel blocker QX-314 to inhibit acid-induced activation in esophageal nociceptive C fibers. This supports a localized application of QX-314 in the esophagus to block esophageal nociception in acid reflux disorders.
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Affiliation(s)
| | | | - Shaoyong Yu
- Corresponding: Shaoyong Yu, MD, MPH., Johns Hopkins University School of Medicine, Ross Research Building, Room 945, 720 Rutland Ave, Baltimore 21205, Phone: (410) 502-2455,
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Iovino P, Santonicola A, Trudgill NJ. Pathophysiology of Gastroesophageal Reflux Disease and Natural History of Barrett’s Esophagus. REVISITING BARRETT'S ESOPHAGUS 2019:27-38. [DOI: 10.1007/978-3-319-92093-1_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Tack J, Pandolfino JE. Pathophysiology of Gastroesophageal Reflux Disease. Gastroenterology 2018; 154:277-288. [PMID: 29037470 DOI: 10.1053/j.gastro.2017.09.047] [Citation(s) in RCA: 209] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 09/07/2017] [Accepted: 09/08/2017] [Indexed: 12/13/2022]
Abstract
The pathogenesis of gastroesophageal reflux disease (GERD) is complex and involves changes in reflux exposure, epithelial resistance, and visceral sensitivity. The gastric refluxate is a noxious material that injures the esophagus and elicits symptoms. Esophageal exposure to gastric refluxate is the primary determinant of disease severity. This exposure arises via compromise of the anti-reflux barrier and reduced ability of the esophagus to clear and buffer the refluxate, leading to reflux disease. However, complications and symptoms also occur in the context of normal reflux burden, when there is either poor epithelial resistance or increased visceral sensitivity. Reflux therefore develops via alterations in the balance of aggressive and defensive forces.
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Affiliation(s)
- Jan Tack
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Belgium.
| | - John E Pandolfino
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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Manitpisitkul P, Shalayda K, Russell L, Sanga P, Solanki B, Caruso J, Iwaki Y, Moyer JA. Pharmacokinetics and Safety of Mavatrep (JNJ-39439335), a TRPV1 Antagonist in Healthy Japanese and Caucasian Men: A Double-Blind, Randomized, Placebo-Controlled, Sequential-Group Phase 1 Study. Clin Pharmacol Drug Dev 2017; 7:712-726. [PMID: 29125703 DOI: 10.1002/cpdd.413] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 09/25/2017] [Indexed: 01/05/2023]
Abstract
This single-center, double-blind, placebo-controlled, sequential-group phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of mavatrep (JNJ-39439335), a transient receptor potential vanilloid 1 antagonist, in healthy Japanese and caucasian subjects. In part 1, a single-ascending-dose study, 50 subjects (25 each healthy Japanese and caucasians) were enrolled and received a single oral dose of 10, 25, or 50 mg mavatrep. Caucasian subjects were matched to Japanese subjects with respect to age (±5 years) and body mass index (±5 kg/m2 ). In part 2, a multiple-ascending-dose study, 36 Japanese subjects were enrolled and received once-daily oral doses of 10, 25, or 50 mg of mavatrep for 21 days. The single-dose PK of mavatrep and its metabolites was similar in the Japanese and caucasian subjects after adjustment of body weight. Following multiple dosing in Japanese subjects, a steady-state condition was reached in approximately 14 days. M2 and M3 are major circulating metabolites with mean exposure > 10% of mavatrep. Nonrenal clearance was the major route of elimination for mavatrep, M2, and M3. Mavatrep exhibited a long half-life, ranging from 68 to 101 and 82-130 hours for Japanese and caucasian subjects, respectively. After single and multiple dosing, mavatrep was well tolerated. The most common adverse events observed were thermohypoesthesia, feeling cold, chills, and feeling hot. Mavatrep and its metabolites exhibited similar PK profiles after single ascending doses in healthy Japanese and caucasian men.
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Affiliation(s)
| | | | | | - Panna Sanga
- Janssen Research & Development, LLC, Raritan, NJ, USA
| | | | - Joseph Caruso
- Janssen Research & Development, LLC, Raritan, NJ, USA
| | - Yuki Iwaki
- Janssen Research & Development, LLC, Raritan, NJ, USA
| | - John A Moyer
- Janssen Research & Development, LLC, Raritan, NJ, USA
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Influence of GABA-B Agonist Baclofen on Capsaicin-Induced Excitation of Secondary Peristalsis in Humans. Clin Transl Gastroenterol 2017; 8:e120. [PMID: 28981081 PMCID: PMC5666117 DOI: 10.1038/ctg.2017.46] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 08/15/2017] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVES Esophageal instillation of capsaicin enhances secondary peristalsis, but the γ-aminobutyric acid receptor type B (GABA-B) agonist baclofen inhibits secondary peristalsis. This study aimed to investigate whether baclofen could influence heartburn perception and secondary peristalsis subsequent to capsaicin infusion in healthy adults. METHODS Secondary peristalsis was performed by slow and rapid mid-esophagus air injections in 15 healthy subjects. Two different sessions including esophageal infusion of capsaicin-containing red pepper sauce (0.84 mg) following pre-treatment with placebo or baclofen were randomly performed to test the effects on heartburn perception and secondary peristalsis. RESULTS The intensity of heartburn symptom subsequent to capsaicin infusion was significantly greater after pre-treatment of baclofen as compared with the placebo (P=0.03). Baclofen significantly increased the threshold volume of secondary peristalsis to slow air injections subsequent to esophageal capsaicin infusion (P<0.001). Baclofen significantly increased the threshold volume of secondary peristalsis to rapid air injections subsequent to esophageal capsaicin infusion (P<0.01). The frequency of secondary peristalsis subsequent to capsaicin infusion was significantly decreased with baclofen as compared with the placebo (P<0.002). Baclofen had no effect on any of the peristaltic parameters of secondary peristalsis subsequent to capsaicin infusion. CONCLUSIONS The GABA-B agonist baclofen appears to attenuate the esophagus to capsaicin-induced excitation of secondary peristalsis in healthy adults. Our study suggests the inhibitory modulation for GABA-B receptors on capsaicin-sensitive afferents mediating secondary peristalsis in human esophagus.
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Abstract
Functional heartburn (FH) is defined as a functional esophageal disorder characterized by symptoms of chronic heartburn with no apparent correlation to acid or nonacid reflux. In addition, its symptoms persist despite the lack of organic abnormalities or inflammation, esophageal motility disorders, or metabolic disorders. Although conditions presenting with esophageal symptoms without endoscopic abnormalities were previously categorized as nonerosive reflux disease, such conditions are now classified into 3 categories under Rome IV criteria: nonerosive reflux disease, reflux hypersensitivity, and FH. Although many aspects of FH remain unclear, its onset mechanism is considered to be strongly associated with peripheral or central sensitization, given the fact that its symptoms seem to be unrelated to gastroesophageal reflux. In addition, the cause of such hypersensitivity is an interesting topic in itself, and psychological factors, such as stress followed by increasing esophageal permeability are gaining attention as factors that can potentially influence this condition. There is a great unmet clinical need for therapeutic drugs that can be used to treat FH, and the development of novel drugs, diagnostic tests and biomarkers is eagerly awaited.
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Exploration of the Esophageal Mucosal Barrier in Non-Erosive Reflux Disease. Int J Mol Sci 2017; 18:ijms18051091. [PMID: 28534850 PMCID: PMC5455000 DOI: 10.3390/ijms18051091] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 05/05/2017] [Accepted: 05/13/2017] [Indexed: 12/17/2022] Open
Abstract
In the absence of visible mucosal damage, it is hypothesized that the esophageal mucosal barrier is functionally impaired in patients with non-erosive reflux disease (NERD). The aim of the present study was to perform an exploratory analysis of the mucosal barrier in NERD compared to erosive esophagitis (EE) and controls. A second aim was to explore TRPV1 gene transcription in relation to the mucosal barrier function and heartburn symptoms. In this prospective study, 10 NERD patients, 11 patients with active erosive esophagitis and 10 healthy volunteers were included. Biopsies from non-eroded mucosa were obtained for (1) ex vivo analyses (Ussing chamber) of transepithelial electrical resistance (TEER) and permeability (2) gene transcription of tight-junction proteins and transient receptor potential vanilloid subfamily member 1 (TRPV1). No differences in TEER or permeability were found between NERD and healthy volunteers, whereas TEER was lower in patients with erosive esophagitis. TRPV1 gene transcription was not significantly different between EE, NERD and controls. Conclusions: esophageal mucosal barrier function and TRPV1 transcription is not significantly altered in NERD patients. Future research is needed to explore other potential mechanisms that may account for the high symptom burden in these patients.
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Souza R. Diagnosing eosinophilic esophagitis: cytokine sizzle and fizzle - Mexican style. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2017. [DOI: 10.1016/j.rgmxen.2016.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Omari SA, Adams MJ, Geraghty DP. TRPV1 Channels in Immune Cells and Hematological Malignancies. ADVANCES IN PHARMACOLOGY 2017; 79:173-198. [DOI: 10.1016/bs.apha.2017.01.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Souza RF. Diagnosing eosinophilic esophagitis: cytokine sizzle and fizzle - Mexican style. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2016; 82:1-4. [PMID: 28034570 DOI: 10.1016/j.rgmx.2016.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 10/11/2016] [Indexed: 12/12/2022]
Affiliation(s)
- R F Souza
- Centro de Enfermedades Esofágicas, Departamento de Medicina, Sistema de Salud VA North Texas, Dallas, Texas, Estados Unidos; Centro Médico del Suroeste, Universidad de Texas, Dallas, Texas, Estados Unidos.
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Yi CH, Lei WY, Hung JS, Liu TT, Orr WC, Chen CL. Sleep disturbance and enhanced esophageal capsaicin sensitivity in patients with gastroesophageal reflux disease. J Gastroenterol Hepatol 2016; 31:1940-1945. [PMID: 27131333 DOI: 10.1111/jgh.13428] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/26/2016] [Indexed: 01/11/2023]
Abstract
BACKGROUND AND AIM Esophageal infusion of capsaicin-containing red pepper sauce induced heartburn symptoms in patients with gastroesophageal reflux disease (GERD). We aimed to test the hypothesis whether sleep disturbance modulates esophageal sensitivity to capsaicin infusion in patients with GERD. METHODS We enrolled 40 patients with their sleep quality measured by the Pittsburg Sleep Quality Index with > 5 indicating sleep disturbance. Esophageal sensation to capsaicin infusion was documented via measures of lag time to initial heartburn perception, heartburn intensity rating, and sensitivity score by esophageal infusion of capsaicin-containing red pepper sauce. Objective sleep measures were assessed by ambulatory actigraphy. RESULTS We found 22 patients with sleep disturbance. The patients with sleep disturbance had shorter lag time to initial heartburn perception (P = 0.03) and greater sensory intensity rating (P = 0.02). The sensitivity score for capsaicin infusion was greater in patients with sleep disturbance when compared with those without sleep disturbance (P = 0.04). Actigraphy measures revealed that patients with sleep disturbance also had poor sleep efficiency (P = 0.04), longer average awakening time (P = 0.03), and greater total activity account (P = 0.04). The lag time for perceiving capsaicin infusion was positively correlated with total sleep time (r = 0.43, P = 0.03). CONCLUSIONS We have shown that GERD patients with sleep disturbance have significantly enhanced heartburn perception to capsaicin infusion as compared with those with normal sleep. Our findings suggest that sleep disturbance is associated with esophageal hypersensitivity to capsaicin infusion in patients with GERD.
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Affiliation(s)
- Chih-Hsun Yi
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Wei-Yi Lei
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Jui-Sheng Hung
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Tso-Tsai Liu
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - William C Orr
- Lynn Institute for Healthcare Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Chien-Lin Chen
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
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TRP channels: potential drug target for neuropathic pain. Inflammopharmacology 2016; 24:305-317. [PMID: 27757589 DOI: 10.1007/s10787-016-0288-x] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 10/05/2016] [Indexed: 01/06/2023]
Abstract
Neuropathic pain is a debilitating disease which affects central as well as peripheral nervous system. Transient receptor potential (TRP) channels are ligand-gated ion channels that detect physical and chemical stimuli and promote painful sensations via nociceptor activation. TRP channels have physiological role in the mechanisms controlling several physiological responses like temperature and mechanical sensations, response to painful stimuli, taste, and pheromones. TRP channel family involves six different TRPs (TRPV1, TRPV2, TRPV3, TRPV4, TRPM8, and TRPA1) which are expressed in pain sensing neurons and primary afferent nociceptors. They function as transducers for mechanical, chemical, and thermal stimuli into inward currents, an essential first step for provoking pain sensations. TRP ion channels activated by temperature (thermo TRPs) are important molecular players in acute, inflammatory, and chronic pain states. Different degree of heat activates four TRP channels (TRPV1-4), while cold temperature ranging from affable to painful activate two indistinctly related thermo TRP channels (TRPM8 and TRPA1). Targeting primary afferent nociceptive neurons containing TRP channels that play pivotal role in revealing physical stimuli may be an effective target for the development of successful pharmacotherapeutics for clinical pain syndromes. In this review, we highlighted the potential role of various TRP channels in different types of neuropathic pain. We also discussed the pharmacological activity of naturally and synthetically originated TRP channel modulators for pharmacotherapeutics of nociception and neuropathic pain.
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