DOCSLIB.ORG

Human Visceral Afferent Recordings: a Pre-Clinical Human Model of Visceral Pain

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Human Visceral Afferent Recordings: a Pre-Clinical Human Model of Visceral Pain HUMAN VISCERAL AFFERENT RECORDINGS: A PRE-CLINICAL HUMAN MODEL OF VISCERAL PAIN by Cian McGuire Submitted in partial fulfilment of the requirements of the Degree of Doctor of Philosophy 1 I, Cian McGuire, confirm that the research included within this thesis is my own work or that where it has been carried out in collaboration with, or supported by others, that this is duly acknowledged below and my contribution indicated. Previously published material is also acknowledged below. I attest that I have exercised reasonable care to ensure that the work is original, and does not to the best of my knowledge break any UK law, infringe any third party’s copyright or other Intellectual Property Right, or contain any confidential material. I accept that the College has the right to use plagiarism detection software to check the electronic version of the thesis. I confirm that this thesis has not been previously submitted for the award of a degree by this or any other university. The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author. Signature: Cian McGuire Date: 13.11.14 2 PUBLICATIONS: Publications: HOCKLEY, J. R., BOUNDOUKI, G., CIBERT-GOTON, V., MCGUIRE, C., YIP, P. K., CHAN, C., TRANTER, M., WOOD, J. N., NASSAR, M. A., BLACKSHAW, L. A., AZIZ, Q., MICHAEL, G. J., BAKER, M. D., WINCHESTER, W. J., KNOWLES, C. H. & BULMER, D. C. 2014. Multiple roles for NaV1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease-derived stimuli. Pain, 155, 1962-75. (Hockley et al., 2014) Abstracts/Posters: British Pharmacology Society Conference, London, 2011. The effects of bradykinin and ATP on human visceral afferent fibre activity, a pilot study International Association for the Study of Pain, Milan, 2012. Mechanical and chemical stimulation of human visceral afferents Neurogastroenterology and Motility Conference, Bologna, 2012. Mechanical and chemical stimulation of human visceral afferents National Centre for the Replacement, Refinement, and Reduction of Animals in Research Conference, London, 2012. Mechanical and chemical stimulation of human visceral afferents Digestive Diseases Week, Orlando, 2013. Identification of a distinct population of human visceral nociceptors United European Gastroenterology Week, Berlin, 2013. Identification of a distinct population of human visceral nociceptors International Association for the Study of Pain, Buenos Aires, 2014 Human visceral afferents display mechanical hyposensitivity in tissue from patients with inflammatory bowel disease Talks: Digestive Disease Week, Orlando, 2013. Anatomical sensory nerve markers in human gut 3 ACKNOWLEDGEMENTS I am indebted to my supervisor Dr. David Bulmer for his input, encouragement, technical expertise and enthusiasm for my project. I would also like to thank Professor Charles Knowles and Professor Ashley Blackshaw for their advice throughout my PhD. I’d like to pay a special tribute to my parents for their continued encouragement and support over the last number of years. I would also like to thank my sisters Aoife and Nicola, and brother in law Paul for their support. I should also like to thank the following: Mr. George Boundouki for his commitment to human tissue collection, at the expense of his own time. Dr. Jim Hockley for his guidance when learning electrophysiology, and his answers to an uncountable number of questions. Dr. John Broad for his help with human tissue collection, data analysis, and the odd plastic pot. Mr. Victor Kung for his continuing endevor to collect every single piece of human tissue. The pathology team, especially Chris Evagora and Becky Carroll for their help in processing the tissue. Dr. David Reed for his company while doing human afferent recordings, and his help with watching countless of sport on a laptop. Michael Tranter for his presence in the lab, and his company on conference trips. Dr. Harween Dogra for her chat, energy, and her suggestions that its pub time. Dr. Vincent Cibert-Goton for his collaboration in many ongoing projects. Ann Rakpraja for her support, encouragement, and friendship. All my friends from football, my friends I’ve met in London, and my friends back home. 4 ABSTRACT Aim: We have recently developed electrophysiological recordings of human visceral afferent (HVA) activity in isolated gastrointestinal tissues. The aim of the this study was 1) test the mechano- and chemosensitivity of HVAs, 2) characterise subpopulations of HVAs based on their response to mechanical stimuli, 3) test the effect of drugs that have/are in clinical trials on the mechanosensitivity (von Frey hair (VFH) probing and appendix distension) of HVAs. Methods: All experiments were performed in accordance with UK human ethics regulations [NREC09/H0704/2]. Surgically resected human ileum, colon, and appendix were obtained from consenting patients undergoing bowel resection. Tissues were pinned in a tissue bath, or cannulated (appendix), and superfused with carbongenated Krebs buffer, at 6ml/min, 32-34°C. Mesenteric nerve bundles were carefully dissected and afferent activity was recorded using suction electrodes. Tissues were tested for mechanosensitivity (VFHs, stretching, mucosal stroking, distension) and chemosensitivity (bradykinin (BK), ATP (adenosine trisphosphate), PGE2 (prostaglandin E2), serotonin (aka 5-hydroxytryptamine (5-HT)), histamine, adenosine). The receptors involved in the activation of HVAs by BK, or ATP were also investigated. The response of HVAs to VFH probing or distension was tested before and after the application of tegaserod, STa endotoxin, or a transient receptor potential vanilloid 4 (TRPV4) agonist (GSK1016790A) or antagonist (HC067047). Results and Conclusion: HVAs were characterised as mesenteric, serosal, muscular, or muscular-mucosal. HVAs were chemosensitive to all mediators. Bradykinin B2 receptors are the most important receptors involved in the activation of HVAs by BK. P2Y receptors may play an important role in the activation of HVAs by ATP. Application of tegaserod, HC067047 or STa endotoxin reduced the HVA response to mechanical stimuli. HVA recordings are feasible and practical and are suitable for both basic scientific mechanistic studies, and could potentially be used as a pre-clinical model, in conjunction with animal experiments, to help predict the efficacy of novel compounds before clinical trials. 5 TABLE OF CONTENTS Page No. Title 1 Statement of originality 2 Publications 3 Acknowledgements 4 Abstract 5 Table of contents 6 Figures 21 Tables 25 Abbreviations 26 CHAPTER 1: GENERAL INTRODUCTION 1.1 ABDOMINAL PAIN IN GASTROINTESTINAL DISEASES 28 1.2 OVERVIEW OF THE EXTRINSIC INNERVATION OF THE GASTROINTESTINAL TRACT 30 1.2.1 Overview 30 1.2.2 Vagal afferents 31 1.2.3 Spinal afferents 32 1.2.4 Subtypes of vagal and spinal afferents innervating the gut 37 1.2.4.1 Vascular afferents 37 1.2.4.1.1 Splanchnic and pelvic 37 1.2.4.2 Silent afferents 39 1.2.4.3 Muscular afferents 40 1.2.4.3.1 Vagal 40 1.2.4.3.2 Splanchnic and pelvic 41 1.2.4.3.2.1 rIGLEs 41 6 1.2.4.4 Mucosal afferents 42 1.2.4.4.1 Vagal 42 1.2.4.4.2 Splanchnic and pelvic 43 1.2.4.5 Muscular-mucosal 43 1.2.4.5.1 Vagal tension-mucosal and pelvic muscular-mucosal afferents 43 1.3 OVERVIEW OF THE ENTERIC NERVOUS SYSTEM 48 1.3.1 Overview 48 1.4 NERVE FUNCTION 54 1.4.1 Ionotropic and metabotropic signalling 54 1.4.2 Membrane potential 55 1.4.3 Generation of action potentials in sensory nerves 56 1.5 VISCERAL PAIN 57 1.5.1 Mechanisms of visceral pain 58 1.5.1.1 Peripheral sensitisation 59 1.5.1.1.1 Neurogenic inflammation and sensitisation 60 1.5.1.1.2 Potential causes of peripheral sensitisation in bowel diseases 61 1.5.1.1.3 “Silent nociceptors in peripheral sensitisation 62 1.5.1.2 Central sensitisation 65 1.6 TRANSLATION 69 1.6.1 A pre-clinical model of visceral pain 71 1.7 AIMS 73 CHAPTER 2 PART 1: CHARACTERISATION OF SUBTYPES OF AFFERENTS INNERVATING THE HUMAN INTESTINE 7 2.1.1 INTRODUCTION 74 2.1.1.1 OVERVIEW OF THE EXTRINSIC INNERVATION OF THE GUT 74 2.1.1.2 GRADED RESPONSES TO VFH PROBING 76 2.1.1.3 SPONTANEOUS ACTIVITY 77 2.1.1.4 TRP CHANNELS 79 2.1.1.4.1 TRPV channels 80 2.1.1.4.1.1 TRPV4 channels 81 2.1.1.4.1.1.1 TRPV4 channels in visceral pain 82 2.1.1.5 AIMS 86 2.1.2 METHODS 87 2.1.2.1 PATIENTS 87 2.1.2.2 ELECTROPHYSIOLOGY RECORDINGS 89 2.1.2.3 MECHANOSENSITIVITY 91 2.1.2.3.1 VFH probing, circumferential and longitudinal stretch, and mucosal stroking 91 2.1.2.3.2 VFH time matched controls 92 2.1.2.4 MECHANOSENSITIVITY PROTOCOLS 95 2.1.2.4.1 VFH probing protocol 95 2.1.2.5 OFFLINE WAVEFORM ANALYSIS 97 2.1.2.6 DRUGS 97 2.1.3 RESULTS 99 2.1.3.1 OVERALL TISSUE COLLECTION – FLAT SHEET 99 2.1.3.2 TISSUE – FLAT SHEET CHARACTERISATION 101 2.1.3.3 TISSUE – TRPV4 VFH PROBING EXPERIMENTS 101 2.1.3.4 BASIC MECHANOSENSORY PROPERTIES OF HUMAN VISCERAL AFFERENTS 104 2.1.3.5 GRADED RESPONSES TO VFH PROBING IN SEROSAL/MESENTERIC AND 8 MUSCULAR AFFERENTS 109 2.1.3.6 SPONTANEOUS ACTIVITY 112 2.1.3.7 VFH TIME MATCHED CONTROLS 116 2.1.3.8 TRPV4 VFH PROBING PROTOCOL 118 2.1.3.9 SUMMARY OF RESULTS 124 2.1.4 DISCUSSION 125 2.1.4.1 MECHANOSENSITIVITY AND HVA CHARACTERISATION 125 2.1.4.2 SEROSAL AND MESENTERIC AFFERENTS 125 2.1.4.3 MUSCULAR, MUSCULAR-MUCOSAL AND MUCOSAL AFFERENTS 127 2.1.4.4 “SILENT” AFFERENTS 129 2.1.4.5 GRADED RESPONSES TO VFH PROBING 131 2.1.4.6 SPONTANEOUS ACTIVITY 133 2.1.4.7 TRPV4 135 2.1.5 CONCLUSION 138 CHAPTER 2 PART 2: CHARACTERISATION OF SUBTYPES OF AFFERENTS
Load more

Recommended publications
  • 1 TRP About Online
    a TR P to Spain International Workshop on Transient Receptor Potential Channels 12th – 14th September 2012 Valencia, Spain www.trp2012.com SCHEDULE and ABSTRACTS BOOK September 2012 Dear participants, Travelling to faraway places in search of spiritual or cultural enlightenment is a millennium old human activity. In their travels, pilgrims brought with them news, foods, music and traditions from distant lands. This friendly exchange led to the cultural enrichment of visitors and the economic flourishing of places, now iconic, such as Rome, Santiago, Jerusalem, Mecca, Varanasi or Angkor Thom. The dissemination of science and technology also benefited greatly from these travels to remote locations. The new pilgrims of the Transient Receptor Potential (TRP) community are also very fond of travelling. In the past years they have gathered at various locations around the globe: Breckenridge (USA), Eilat (Israel), Stockholm (Sweden) and Leuven (Belgium) come to mind. These meetings, each different and exciting, have been very important for the dissemination of TRP research. We are happy to welcome you in Valencia (Spain) for TRP2012. The response to our call has been extraordinary, surpassing all our expectations. The speakers, the modern bards, readily attended our request to communicate their new results. At last count we were already more than 170 participants, many of them students, and most presenting their recent work in the form of posters or short oral presentations. At least 25 countries are sending TRP ambassadors to Valencia, making this a truly international meeting. We like to thank the staff of the Cátedra Santiago Grisolía, Fundación Ciudad de las Artes y las Ciencias for their dedication and excellence in handling the administrative details of the workshop.
    [Show full text]
  • Therapeutic Targets for the Treatment of Chronic Cough
    Therapeutic Targets for the Treatment of Chronic Cough Roe, N., Lundy, F., Litherland, G. J., & McGarvey, L. (2019). Therapeutic Targets for the Treatment of Chronic Cough. Current Otorhinolaryngology Reports. https://doi.org/10.1007/s40136-019-00239-9 Published in: Current Otorhinolaryngology Reports Document Version: Publisher's PDF, also known as Version of record Queen's University Belfast - Research Portal: Link to publication record in Queen's University Belfast Research Portal Publisher rights Copyright 2019 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. General rights Copyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The Research Portal is Queen's institutional repository that provides access to Queen's research output. Every effort has been made to ensure that content in the Research Portal does not infringe any person's rights, or applicable UK laws. If you discover content in the Research Portal that you believe breaches copyright or violates any law, please contact [email protected]. Download date:25. Sep. 2021 Current Otorhinolaryngology Reports https://doi.org/10.1007/s40136-019-00239-9 CHRONIC COUGH (K ALTMAN, SECTION EDITOR) Therapeutic Targets for the Treatment of Chronic Cough N.
    [Show full text]
  • Therapeutic Targets for the Treatment of Chronic Cough
    Current Otorhinolaryngology Reports https://doi.org/10.1007/s40136-019-00239-9 CHRONIC COUGH (K ALTMAN, SECTION EDITOR) Therapeutic Targets for the Treatment of Chronic Cough N. A. Roe1 & F. T. Lundy1 & G. J. Litherland2 & L. P. A. McGarvey1 # The Author(s) 2019 Abstract Purpose of Review Chronic cough, defined in adults as one lasting longer than 8 weeks, is among the commonest clinical problems encountered by doctors both in general practice and in hospital. It can exist as a distinct clinical problem or as a prominent and troublesome symptom for patients with common pulmonary conditions including asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Recent Findings Chronic cough impacts considerably on patients’ daily-life activities and many patients are left frustrated by what they see as a complete lack of awareness among their doctors as how to treat their condition. Some of this arises from limited levels of physician knowledge about managing cough as a clinical problem but also because there are no very effective treatments that specifically target cough. Summary In this article, we review the current clinical thinking regarding cough and the treatments that are currently used and those undergoing clinical development. Keywords Cough . Cough receptor . Pharmacological targets . Novel . Ion channel Introduction and is likely due to a slowly resolving post-viral cough. In adult patients, a cough persisting for more than 8 weeks is Under normal physiological circumstances, coughing occurs termed ‘chronic’ and can occur as an isolated clinical problem with the primary purpose of protecting the lung from inhaled or associated with common respiratory and non-respiratory irritants and clearing unwanted airway secretions.
    [Show full text]
  • The TRPV4 Agonist GSK1016790A Regulates the Membrane Expression of TRPV4 Channels
    ORIGINAL RESEARCH published: 23 January 2019 doi: 10.3389/fphar.2019.00006 The TRPV4 Agonist GSK1016790A Regulates the Membrane Expression of TRPV4 Channels Sara Baratchi 1*, Peter Keov 1,2,3, William G. Darby 1, Austin Lai 1, Khashayar Khoshmanesh 4, Peter Thurgood 4, Parisa Vahidi 1, Karin Ejendal 5 and Peter McIntyre 1 1 School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia, 2 Molecular Pharmacology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia, 3 St Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW, Australia, 4 School of Engineering, RMIT University, Melbourne, VIC, Australia, 5 Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, United States TRPV4 is a non-selective cation channel that tunes the function of different tissues including the vascular endothelium, lung, chondrocytes, and neurons. GSK1016790A is the selective and potent agonist of TRPV4 and a pharmacological tool that is used to study the TRPV4 physiological function in vitro and in vivo. It remains unknown how the sensitivity of TRPV4 to this agonist is regulated. The spatial and temporal dynamics of receptors are the major determinants of cellular responses to stimuli. Membrane Edited by: Hugues Abriel, translocation has been shown to control the response of several members of the transient University of Bern, Switzerland receptor potential (TRP) family of ion channels to different stimuli. Here, we show that 2+ Reviewed by: TRPV4 stimulation with GSK1016790A caused an increase in [Ca ]i that is stable for Osama F. Harraz, a few minutes. Single molecule analysis of TRPV4 channels showed that the density University of Vermont, United States Irene Frischauf, of TRPV4 at the plasma membrane is controlled through two modes of membrane Johannes Kepler University of Linz, trafficking, complete, and partial vesicular fusion.
    [Show full text]
  • Note: the Letters 'F' and 'T' Following the Locators Refers to Figures and Tables
    Index Note: The letters ‘f’ and ‘t’ following the locators refers to figures and tables cited in the text. A Acyl-lipid desaturas, 455 AA, see Arachidonic acid (AA) Adenophostin A, 71, 72t aa, see Amino acid (aa) Adenosine 5-diphosphoribose, 65, 789 AACOCF3, see Arachidonyl trifluoromethyl Adlea, 651 ketone (AACOCF3) ADP, 4t, 10, 155, 597, 598f, 599, 602, 669, α1A-adrenoceptor antagonist prazosin, 711t, 814–815, 890 553 ADPKD, see Autosomal dominant polycystic aa 723–928 fragment, 19 kidney disease (ADPKD) aa 839–873 fragment, 17, 19 ADPKD-causing mutations Aβ, see Amyloid β-peptide (Aβ) PKD1 ABC protein, see ATP-binding cassette protein L4224P, 17 (ABC transporter) R4227X, 17 Abeele, F. V., 715 TRPP2 Abbott Laboratories, 645 E837X, 17 ACA, see N-(p-amylcinnamoyl)anthranilic R742X, 17 acid (ACA) R807X, 17 Acetaldehyde, 68t, 69 R872X, 17 Acetic acid-induced nociceptive response, ADPR, see ADP-ribose (ADPR) 50 ADP-ribose (ADPR), 99, 112–113, 113f, Acetylcholine-secreting sympathetic neuron, 380–382, 464, 534–536, 535f, 179 537f, 538, 711t, 712–713, Acetylsalicylic acid, 49t, 55 717, 770, 784, 789, 816–820, Acrolein, 67t, 69, 867, 971–972 885 Acrosome reaction, 125, 130, 301, 325, β-Adrenergic agonists, 740 578, 881–882, 885, 888–889, α2 Adrenoreceptor, 49t, 55, 188 891–895 Adult polycystic kidney disease (ADPKD), Actinopterigy, 223 1023 Activation gate, 485–486 Aframomum daniellii (aframodial), 46t, 52 Leu681, amino acid residue, 485–486 Aframomum melegueta (Melegueta pepper), Tyr671, ion pathway, 486 45t, 51, 70 Acute myeloid leukaemia and myelodysplastic Agelenopsis aperta (American funnel web syndrome (AML/MDS), 949 spider), 48t, 54 Acylated phloroglucinol hyperforin, 71 Agonist-dependent vasorelaxation, 378 Acylation, 96 Ahern, G.
    [Show full text]
  • Transient Receptor Potential Vanilloid 4 Channel Deficiency Aggravates Tubular Damage After Acute Renal Ischaemia Reperfusion
    www.nature.com/scientificreports OPEN Transient Receptor Potential Vanilloid 4 Channel Defciency Aggravates Tubular Damage after Received: 29 March 2017 Accepted: 5 March 2018 Acute Renal Ischaemia Reperfusion Published: xx xx xxxx Marwan Mannaa1, Lajos Markó2, András Balogh2,3,4, Emilia Vigolo5, Gabriele N’diaye2, Mario Kaßmann1, Laura Michalick6, Ulrike Weichelt6, Kai M. Schmidt–Ott5, Wolfgang B. Liedtke7, Yu Huang8,9, Dominik N. Müller 2,5, Wolfgang M. Kuebler6 & Maik Gollasch1,2 Transient receptor potential vanilloid 4 (TRPV4) cation channels are functional in all renal vascular segments and mediate endothelium-dependent vasorelaxation. Moreover, they are expressed in distinct parts of the tubular system and activated by cell swelling. Ischaemia/reperfusion injury (IRI) is characterized by tubular injury and endothelial dysfunction. Therefore, we hypothesised a putative organ protective role of TRPV4 in acute renal IRI. IRI was induced in TRPV4 defcient (Trpv4 KO) and wild–type (WT) control mice by clipping the left renal pedicle after right–sided nephrectomy. Serum creatinine level was higher in Trpv4 KO mice 6 and 24 hours after ischaemia compared to WT mice. Detailed histological analysis revealed that IRI caused aggravated renal tubular damage in Trpv4 KO mice, especially in the renal cortex. Immunohistological and functional assessment confrmed TRPV4 expression in proximal tubular cells. Furthermore, the tubular damage could be attributed to enhanced necrosis rather than apoptosis. Surprisingly, the percentage of infltrating granulocytes and macrophages were comparable in IRI–damaged kidneys of Trpv4 KO and WT mice. The present results suggest a renoprotective role of TRPV4 during acute renal IRI. Further studies using cell–specifc TRPV4 defcient mice are needed to clarify cellular mechanisms of TRPV4 in IRI.
    [Show full text]
  • TRP CHANNELS AS THERAPEUTIC TARGETS TRP CHANNELS AS THERAPEUTIC TARGETS from Basic Science to Clinical Use
    TRP CHANNELS AS THERAPEUTIC TARGETS TRP CHANNELS AS THERAPEUTIC TARGETS From Basic Science to Clinical Use Edited by ARPAD SZALLASI MD, PHD Department of Pathology, Monmouth Medical Center, Long Branch, NJ, USA AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London, EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK First published 2015 Copyright © 2015 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangement with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein.
    [Show full text]
  • Application Note Activation and Inhibition of TRPV4 Using Different
    Channel: hTRPV4 Application Note Cells: CHO Tools: Port-a-Patch Activation and inhibition of TRPV4 using different stimuli on the Port-a-Patch The electrophysiology team at Nanion Technologies GmbH, Munich. Summary Results TRPV4 is a member of the transient receptor potential TRPV4 can be activated by a number of stimuli, includ- channel (TRP) family. Transient receptor potential vanilloid ing warm temperature >27°C6,7. We activated hTRPV4 type 4 (TRPV4) shares approximately 40% identity with expressed in CHO cells using heated solution at 45°C. TRPV1 and TRPV21 and is a Ca2+-permeable non-selective There was some basal activity of TRPV4 at room tempera- cation channel1-3 expressed in a wide range of tissues ture but the current amplitude increased to 5.7 ± 0.8 nA including neurons of the central and peripheral nervous (n = 6) from control current of 2.7 ± 0.6 nM (n = 6; p<0.01, systems, and in non-neuronal tissue including human T Student’s t test). Figure 1 shows the activation of TRPV4 by cells, corneal and retinal epithelial cells, endothelial cells warm solution from an example cell and the timecourse of the eye, liver, heart, kidney, synoviocytes, epithelial of the experiment. lining of trachea and lung airways, stellate cells of the A RT pancreas, and many more2. TRPV4 is activated by a 45°C number of stimuli including endogenous ligands such as lipid arachidonic acid and its metabolites4, synthetic ligands such as GSK1016790A5, warm temperature >27- 35°C6,7, hypotonic extracellular solution (cell swelling)1,8, and mechanical stress2. Given its widespread distribution in many organs, this suggests that TRPV4 plays a major role in many physiological processes2,9.
    [Show full text]
  • Ion Channels
    UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties.
    [Show full text]
  • GSK1016790A, a Novel and Potent TRPV4 Channel Agonist Induces Urinary Bladder Contraction and Hyperactivity
    JPET Fast Forward. Published on May 22, 2008 as DOI: 10.1124/jpet.108.139295 JPETThis Fast article Forward. has not been Published copyedited andon formatted. May 22, The 2008 final asversion DOI:10.1124/jpet.108.139295 may differ from this version. JPET #139295 Title Page GSK1016790A, a Novel and Potent TRPV4 Channel Agonist Induces Urinary Bladder Contraction and Hyperactivity: Part I Downloaded from Kevin S. Thorneloe, Anthony C. Sulpizio, Zuojun Lin, David J. Figueroa, Angela K. Clouse, Gerald P. McCafferty, Tim P. Chendrimada, Erin S.R. Lashinger, Earl jpet.aspetjournals.org A. Gordon, Louise Evans, Blake A. Misajet, Douglas J. DeMarini, Josephine H. Nation, Linda N. Casillas, Robert W. Marquis, Bartholomew J. Votta, Steven A. at ASPET Journals on September 27, 2021 Sheardown, Xiaoping Xu, David P. Brooks, Nicholas J. Laping, and Timothy D. Westfall Cardiovascular and Urogenital Centre of Excellence in Drug Discovery (KST, ACS, ZL, DJF, AKC, GPM, TM, ESRL, EAG, LE, BAM, XX, CPB, NJL, TDW) GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA, USA, 19406; Oncology Centre of Excellence in Drug Discovery (DJD, LNC, RWM, BJV) GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, Collegeville, PA, USA, 19426; Transgenics, Genotyping and Viral Vectors (JHN, SAS), GlaxoSmithKline Pharmaceuticals, Harlow, UK CM19 5AD 1 Copyright 2008 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on May 22, 2008 as DOI: 10.1124/jpet.108.139295 This article has not been copyedited and formatted. The final version may differ from this version. JPET #139295 Running Title Page Running Title: TRPV4 activator GSK1016790A induces bladder overactivity Correspondence: Kevin S.
    [Show full text]
  • (TRPM8) by Calcium-Rich Particulate Materials and Effects on Human
    Molecular Pharmacology Fast Forward. Published on October 16, 2017 as DOI: 10.1124/mol.117.109959 This article has not been copyedited and formatted. The final version may differ from this version. MOL #109959 Title: Activation of Human Transient Receptor Potential Melastatin-8 (TRPM8) by Calcium- Rich Particulate Materials and Effects on Human Lung Cells Authors: John G. Lamb, Erin G. Romero, Zhenyu Lu, Seychelle K. Marcus, Hannah C. Peterson, John M. Veranth, Cassandra E. Deering-Rice, and Christopher A. Reilly Affiliations: (J.G.L., E.G.R., Z.L., S.K.M., H.C.P., J.M.V., C.E.D-R., and C.A.R.) Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, 30 S. 2000 E., Room 201 Skaggs Hall, Salt Lake City, UT 84112, USA. Downloaded from molpharm.aspetjournals.org at ASPET Journals on September 27, 2021 1 Molecular Pharmacology Fast Forward. Published on October 16, 2017 as DOI: 10.1124/mol.117.109959 This article has not been copyedited and formatted. The final version may differ from this version. MOL #109959 Running Title: Activation of TRPM8 by Particles *Corresponding author: Dr. Christopher A. Reilly, Ph.D. University of Utah Department of Pharmacology and Toxicology 30 South 2000 East, 201 Skaggs Hall Salt Lake City, UT 84112 Phone: (801) 581-5236; FAX: (801) 585-5111 Email: [email protected] Number of text pages: 41 Downloaded from Number of Tables: 2 Number of Figures: 7 References: 40 Number of words in Abstract: 245 Number of words in Introduction: 704 molpharm.aspetjournals.org Number
    [Show full text]
  • The Combined Effect of Branching and Elongation on the Bioactivity Profile of Phytocannabinoids
    biomedicines Article The Combined Effect of Branching and Elongation on the Bioactivity Profile of Phytocannabinoids. Part I: Thermo-TRPs Daiana Mattoteia 1,†, Aniello Schiano Moriello 2,3,†, Orazio Taglialatela-Scafati 4 , Pietro Amodeo 2 , Luciano De Petrocellis 2 , Giovanni Appendino 1, Rosa Maria Vitale 2,* and Diego Caprioglio 1,* 1 Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy; [email protected] (D.M.); [email protected] (G.A.) 2 Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli, Italy; [email protected] (A.S.M.); [email protected] (P.A.); [email protected] (L.D.P.) 3 Epitech Group SpA, Saccolongo, 35100 Padova, Italy 4 Dipartimento di Farmacia, Università di Napoli Federico II, Via Montesano 49, 80131 Napoli, Italy; [email protected] * Correspondence: [email protected] (R.M.V.); [email protected] (D.C.); Tel.: +39-081-8675316 (R.M.V.); +39-0321-375843 (D.C.) † These authors contributed equally to this work. Abstract: The affinity of cannabinoids for their CB1 and CB2 metabotropic receptors is dramatically affected by a combination of α-branching and elongation of their alkyl substituent, a maneuver exemplified by the n-pentyl -> α,α-dimethylheptyl (DMH) swap. The effect of this change on other Citation: Mattoteia, D.; Schiano cannabinoid end-points is still unknown, an observation surprising since thermo-TRPs are targeted Moriello, A.; Taglialatela-Scafati, O.; by phytocannabinoids with often sub-micromolar affinity. To fill this gap, the α,α-dimethylheptyl Amodeo, P.; De Petrocellis, L.; analogues of the five major phytocannabinoids [CBD (1a), D8-THC (6a), CBG (7a), CBC (8a) and Appendino, G.; Vitale, R.M.; CBN (9a)] were prepared by total synthesis, and their activity on thermo-TRPs (TRPV1-4, TRPM8, Caprioglio, D.
    [Show full text]