DOCSLIB.ORG

Human Experimental Pain Models for Assessing the Therapeutic Efficacy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Human Experimental Pain Models for Assessing the Therapeutic Efficacy 1521-0081/12/6403-722–779$25.00 PHARMACOLOGICAL REVIEWS Vol. 64, No. 3 Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics 5447/3781330 Pharmacol Rev 64:722–779, 2012 ASSOCIATE EDITOR: ULF SIMONSEN Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs Anne Estrup Olesen, Trine Andresen, Camilla Staahl, and Asbjørn Mohr Drewes Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark (A.E.O., T.A., A.M.D.); Gru¨nenthal GmBH,R&D,Aachen, Germany (C.S.); and Center for Sensory-Motor Interaction, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark (A.M.D.) Abstract............................................................................... 724 Downloaded from I. Introduction ........................................................................... 725 II. The pain system ....................................................................... 725 A. Macro anatomy and mechanisms ..................................................... 725 1. Sensory nerves .................................................................. 725 a. Nociceptors in skin ............................................................ 725 b. Nociceptors in muscle and bone................................................. 726 pharmrev.aspetjournals.org c. Nociceptors in viscera ......................................................... 726 2. The spinal level.................................................................. 727 3. The supraspinal level ............................................................ 727 4. The sensitized pain system ....................................................... 729 B. Cellular and receptor level........................................................... 729 1. Pain physiology .................................................................. 729 2. Plasticity and sensitization ....................................................... 730 III. Animal versus human pain models ...................................................... 732 at Univ of Pittsburgh, HSLS on September 9, 2013 IV. Clinical studies versus experimental human pain models .................................. 733 V. Experimental human pain models ....................................................... 734 A. Skin ............................................................................... 734 1. Mechanical stimulation........................................................... 734 a. Touch ........................................................................ 735 b. Pinprick...................................................................... 735 c. Pressure ..................................................................... 735 2. Electrical stimulation ............................................................ 735 3. Thermal stimulation.............................................................. 735 a. Cold ......................................................................... 735 b. Contact heat.................................................................. 735 c. Laser ........................................................................ 736 4. Models evoking hyperalgesia ...................................................... 736 a. Capsaicin .................................................................... 736 b. Nerve growth factor ........................................................... 737 c. Glutamate.................................................................... 737 d. Burn injury................................................................... 737 e. Freeze lesion ................................................................. 737 f. Mustard oil................................................................... 737 g. Menthol ...................................................................... 738 h. Acid phosphate buffer ......................................................... 738 i. Sodium lauryl sulfate.......................................................... 738 j. Pinch ........................................................................ 738 k. Electrical stimulation.......................................................... 738 B. Muscle and bone.................................................................... 738 Address correspondence to: Dr. Anne Estrup Olesen, Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg Hospital, Mølleparkvej 4, 9000 Aalborg, Denmark. E-mail: [email protected] This article is available online at http://pharmrev.aspetjournals.org. http://dx.doi.org/10.1124/pr.111.005447. 722 PHARMACOLOGY OF HUMAN PAIN MODELS 723 1. Mechanical stimulation. .......................................................... 739 a. Muscle ....................................................................... 739 b. Bone ......................................................................... 739 2. Electrical stimulation ............................................................ 739 3. Thermal stimulation ............................................................. 739 4. Models evoking hyperalgesia. ..................................................... 740 a. Ischemic stimulation .......................................................... 740 b. Exercise-induced muscle pain .................................................. 740 c. Chemically induced muscle hyperalgesia ........................................ 740 C. Viscera ............................................................................ 741 1. Mechanical stimulation........................................................... 741 2. Electrical stimulation ............................................................ 742 3. Thermal stimulation ............................................................. 742 4. Models evoking hyperalgesia ...................................................... 742 VI. Experimental pain modulation .......................................................... 743 A. Conditioned pain modulation ........................................................ 743 B. Summation ........................................................................ 743 C. Thermal stimulation ................................................................ 743 D. Chemical stimulation ............................................................... 743 E. Long-term potentiation/depression.................................................... 744 VII. Pain assessment ....................................................................... 744 A. Psychophysical methods ............................................................. 744 1. One-dimensional pain assessment tools ............................................ 744 2. Multidimensional pain assessment tools............................................ 744 B. Neurophysiological methods ......................................................... 745 1. Magnetic resonance imaging ...................................................... 745 2. Single photon emission computed tomography and positron emission tomography ...... 745 3. Electroencephalography .......................................................... 745 4. Magnetoencephalography ......................................................... 746 C. The nociceptive withdrawal reflex .................................................... 746 D. Referred pain area .................................................................. 746 VIII. Analgesic assessment by experimental human pain models in healthy volunteers ............ 747 A. Nonopioids ......................................................................... 747 1. Nonsteroidal anti-inflammatory drugs and acetaminophen ........................... 747 a. Acetylsalicylic acid (aspirin) .................................................... 747 b. Ibuprofen .................................................................... 747 c. Ketorolac. .................................................................... 748 d. Acetaminophen (paracetamol)................................................... 748 2. N-Methyl-D-aspartate antagonists.................................................. 749 a. Ketamine .................................................................... 749 3. Adjuvant analgesics. ............................................................. 750 a. Gabapentin and pregabalin .................................................... 750 b. Lamotrigine .................................................................. 750 c. Imipramine................................................................... 751 B. Opioids ............................................................................ 751 1. Short-acting opioids .............................................................. 751 a. Alfentanil and remifentanil .................................................... 751 2. Longer acting opioids. ............................................................ 752 a. Traditional ␮-receptor agonists ................................................. 752 b. Opioids with weak affinity for the ␮-opioid receptor .............................. 755 c. ␬-Receptor agonists............................................................ 756 3. Opioids with mixed binding profile. ................................................ 756 a. Tramadol. .................................................................... 756 C. Other types of analgesics ............................................................ 756 1. Cannabinoids...................................................................
Load more

Recommended publications
  • Radiolabelled Molecules for Brain Imaging with PET and SPECT • Peter Brust Radiolabelled Molecules for Brain Imaging with PET and SPECT
    Radiolabelled Molecules for Brain Imaging with PET and SPECT Radiolabelled • Peter Brust Molecules for Brain Imaging with PET and SPECT Edited by Peter Brust Printed Edition of the Special Issue Published in Molecules www.mdpi.com/journal/molecules Radiolabelled Molecules for Brain Imaging with PET and SPECT Radiolabelled Molecules for Brain Imaging with PET and SPECT Editor Peter Brust MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade • Manchester • Tokyo • Cluj • Tianjin Editor Peter Brust Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf Germany Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Molecules (ISSN 1420-3049) (available at: https://www.mdpi.com/journal/molecules/special issues/PET SPECT). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03936-720-7 (Hbk) ISBN 978-3-03936-721-4 (PDF) c 2020 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Editor .............................................. vii Preface to ”Radiolabelled Molecules for Brain Imaging with PET and SPECT” ........
    [Show full text]
  • ID-75-77 If the United States Is to Develop an Effective International
    UN1TED STATES REPO@F !FfyT’?f?8T CONGRESSOfb7J+ JUL 3 I ?wl llillllllllllillll1lll1lll~llll~~l LM096967 “-...-. x-- If The Un’ited States Is To Develop An Effective International Narcotics Control Program, Much More Must Be Done In this Feport GAO examines U.S. diplomatic actions and other activities aimed at halting International production and trafficking of illicit narcotics and at stopping their flow into the United States. BY THE COMPTROLLER GENERAL OF THE UNITED STATES @ ID-75-77 COMPTROLLER GENERAL OF THE UNITED STATES WASHINGTON. D.C. X’S48 E-175425 To the President of the Senate and the br Speaker of the House of Representatives This report examines U.S. international narcotics control efforts and discusses improvements needed in opera- tions, activities, and related policies and objectives. We made our review pursuant to the Budget and Accounting Act, 1921 (31 U.S.C. 53), and the Accounting and Auditing Act of 1950 (31 U.S.C. 67). We are sending copies of this report to the Director, Office of Management and Budget; the Secretary of State; the Attorney General; and the Administrator, Agency for Inter- national Development. Comptroller General of the United States r- t Contents Page DIGEST i CHAPTER 1 INTRODUCTION AND BACKGROUND General overview Funding Cabinet Committee Scope of review 2 U.S. OPIUM POLICY 8 U.S. opium policy unclear 8 Evolution of an alleged opium shortage 10 Increasing medicinal opiate supplies 13 Agency comments and our evaluation 18 Conclusions 22 Recommendation 22 3 ILLICIT NARCOTICS PRODUCTION AND TRAFFICKING
    [Show full text]
  • Interactions Fonctionnelles Entre Récepteurs À Peptide RF-Amide Et Caractérisation De Ligands Bifonctionnels Des Récepteurs Mu Opioïde Et NPFF
    UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE des Sciences de la Vie et de la Santé UMR 7242 -Biotechnologie et signalisation cellulaire THÈSE En vue de l’obtention du DOCTORAT DE L’UNIVERSITE DE STRASBOURG Discipline : Pharmacologie Etude des interactions fonctionnelles entre les récepteurs à peptide RF-amide et caractérisation de ligands bifonctionnels des récepteurs mu opioïde et NPFF Présentée et soutenue par Armand DRIEU LA ROCHELLE Le 12 avril 2018 JURY Dr. SIMONIN Frédéric, Directeur de recherche, université de Strasbourg Directeur de Thèse Dr MORISSET-LOPEZ Séverine, Chargé de recherche, CBM, Orléans Rapporteur externe Dr. BELTRAMO Massimiliano, Directeur de recherche, Centre INRA Val de Loire Rapporteur externe Pr. GAVERIAUX-RUFF Claire, Professeur de l’université de Strasbourg Examinateur interne Remerciements Je souhaite tout d’abord adresser mes remerciements aux membres du jury pour avoir accepté d’évaluer mon travail, Dr. Séverine Morisser-Lopez, Pr. Claire Gavériaux-Ruff, Dr. Massimiliano Beltramo et Dr. Didier Rognan. Je voudrais également remercier Frédéric Simonin pour m’avoir accueilli dans son équipe, et pour son soutien dans la préparation du concours de l’école doctorale en Master 2. Merci pour le partage de tes connaissances, tant sur les mécanismes de l’hyperalgésie induite par les opiacés que sur les orchidées sauvages d’Alsace, merci pour ta disponibilité et pour l’autonomie que tu m’as accordée dans ces divers projets. Ma gratitude et ma reconnaissance vont à Brigitte Ilien, ton exigence et ta rigueur accompagnées de ta bonne humeur resteront un exemple pour moi. Merci à toi pour ces longues conversations de pharmacologie moléculaire, en particulier sur le FRET, qui m’ont tant appris et m’auront permis de construire un regard critique sur ce travail de thèse.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2014/0221277 A1 Menzaghi Et Al
    US 20140221277A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0221277 A1 Menzaghi et al. (43) Pub. Date: Aug. 7, 2014 (54) METHOD FOR ELEVATING PROLACTIN IN tion No. 12/300,595, filed on Apr. 22, 2009, now Pat. MAMMALS No. 8,217,000, filed as application No. PCT/US2007/ 012285 on May 22, 2007. (71)71) ApplicantsApplicants: MStFrederi Le.g.,M hi, RVe, S. SterNY E.(US) ); (60) Provisional application No. 60/808,677, filed on May (US); Derek T. Chalmers, Riverside, CT 26, 2006. (US) Publication Classification (72) Inventors: Frederique Menzaghi, Rye, NY (US); (51) Int. Cl. Michael E. Lewis, West Chester, PA A638/07 (2006.01) (US); Derek T. Chalmers, Riverside, CT A6II 45/06 (2006.01) (US) (52) U.S. Cl. CPC ................. A61 K38/07 (2013.01); A61K 45/06 (73) Assignee: CARATHERAPEUTICS, INC., (2013.01) SHELTON, CT (US) USPC ............................. 514/4.7: 514/7.3; 514/11.5 (21) Appl. No.: 14/087,142 (57) ABSTRACT Methods for elevating and stabilizing prolactin levels in a (22) Filed: Nov. 22, 2013 mammal including methods of treating disorders and condi tions associated with reduced serum levels of prolactin are O O provided. Also provided are methods of using certain Syn Related U.S. Application Data thetic tetrapeptide amides which are peripherally selective (63) Continuation of application No. 13/543,128, filed on kappa opioid receptor agonists to elevate or stabilize serum Jul. 6, 2012, now abandoned, Continuation of applica prolactin levels. Patent Application Publication Aug. 7, 2014 Sheet 1 of 7 US 2014/0221277 A1 Figure 1: Arithmetic Mean Changes from Baseline (Pre dose) in Serum Prolactin Concentrations Following a 1 hour IV Infusion in Male Subjects (Part A) O 2 A.
    [Show full text]
  • The Effect of Harvest Date and Pre-Storage Drying Methods On
    AN ABSTRACT OF THE THESIS OF Majid Seddigh for the degree of Master of Science in Crop Science presented on April 4, 1980 Title: The Effect of Harvest Date and Pre Storage Drying_ Methods on Capsule Thebaine Yield, Seed Oil Yield and Seed Germination of Two Accessions of Papaver Vacteatum Andl. Abstract approved: Redacted for privacy r Gary 00. Jollf A field study was conducted in 1978 and 1979 at the Hyslop Crop Science Field Laboratory near Corvallis, Oregon, to determine the opti- mum capsule harvest date of Papaver bracteatum Lind. for thebaine yield and oil yield, while maintaining an acceptable percentage of seed ger- mination. Accessions PI 383309 and PI 381607 were chosen for this study because of their superior yield characteristics. The effects of pre-storage drying of harvested plant materials on the yields and seed germination were studied in the second year of the experiment. Both accessions responded similarly to all treatments. The effects of harvest dates on the yield components and seed germination were com- parable in the two years of the study except for the seed yield.The difference for the seed yield was due to earlier capsule maturity in 1979 that resulted in earlier seed shattering in that year. Drying of the harvested plant materials in a dryer immediately after harvest did not significantly affect the oil and thebaine yields or the percentage of seed germination. Although the data for the thebaine concentration of the capsules in 1978 were of questionable accuracy, capsule thebaine yield was not significantly different for the harvest dates later than four weeks after petal opening.
    [Show full text]
  • PET Radiochemistry for the Investigation of the Biology of Pain and Inflammation
    PET Radiochemistry for the Investigation of the biology of pain and inflammation A thesis submitted to the University of Manchester for the degree of PhD in the Faculty of Medical and Human Sciences 2015 Michael Fairclough School of Medicine Institute of Population Health, Imaging Sciences Contents Abbreviations ............................................................................................................. 9 List of Figures ........................................................................................................... 14 List of Tables ............................................................................................................ 19 List of Equations ...................................................................................................... 21 Abstract ..................................................................................................................... 22 Declaration ................................................................................................................ 23 Copyright Statement ................................................................................................ 23 Dedication ................................................................................................................. 24 CHAPTER 1: Introduction (Part 1) – The endogenous opiate system ............... 25 Pain in Rheumatoid Arthritis ................................................................................. 25 The Pain Matrix.....................................................................................................
    [Show full text]
  • Synthesis and Diels-Alder Reactions of Novel Morphinandienes
    SYNTHESIS AND DIELS-ALDER REACTIONS OF NOVEL MORPHINANDIENES r TR diss 1737 J.T.M. LINDERS SYNTHESIS AND DIELS-ALDER REACTIONS OF NOVEL MORPHINANDIENES PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Technische Universiteit Delft op gezag van de Rector Magnificus, prof.drs. P.A. Schenck, in het openbaar te verdedigen ten overstaan van een commissie aangewezen door het College van Dekanen op maandag 12 juni 1989 te 16.00 uur door Joannes Theodorus Maria Linders geboren te Roosendaal en Nispen scheikundig ingenieur Dit proefschrift is goedgekeurd door de promotor Prof.dr.ir. A.P.G. Kieboom Toegevoegd promotor Dr.ir. L. Maat The author gratefully acknowledges Diosynth B.V., Apeldoorn, The Netherlands, for financial support of the investigations described in this thesis. "Niemand wird als Meister geboren. Der Weg zur Meisterschaft führt über lange Jahre des Lernens, des Kampfens, über Freude und Enttauschungen der errungenen Resultate hinweg." Paul Keres, "Ausgewahlte Partien 1931-1956, zugleich ein Lehrbuch des praktischen Schachs." X^H'MIS~C<V>- O. An experiment is in progress, but it is uncertain if we are in control or just observers R. Hoffmann, "The Metamict State" On the front cover: Two of the four possible Diels-Alder adducts of thebaine and maleic anhydride. Taken from C. Schöpf, K. von Gottberg and W. Petri, Lieb. Ann. Chem. 536, 216 (1938). On the back cover: X-ray structures of 7a-acetyl-6a,14a-ethenisomorphinan and 70-acetyl-60,140-ethenomorphinan. CHAPTER 1 INTRODUCTION 1 1.1. Diels-Alder reactions of thebaine, a historical overview 2 1.2. Nomenclature 7 1.3.
    [Show full text]
  • Molecules Active Key a Diary
    molecules Review A Survey of Molecular Imaging of Opioid Receptors Paul Cumming 1,2,* ,János Marton 3, Tuomas O. Lilius 4 , Dag Erlend Olberg 5 and Axel Rominger 1,* 1 Department of Nuclear Medicine, University of Bern, Inselspital, Freiburgstraße 18, 3010 Bern, Switzerland 2 School of Psychology and Counselling and IHBI, Queensland University of Technology, QLD 4059, Brisbane, Australia 3 ABX Advanced Biochemical Compounds, Biomedizinische Forschungsreagenzien GmbH, Heinrich-Glaeser-Strasse 10-14, D-1454 Radeberg, Germany; [email protected] 4 Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark; [email protected] 5 School of Pharmacy, University of Oslo, Norwegian Medical Cyclotron Centre, N-0372 Oslo, Norway and Norwegian Medical Cyclotron Centre Ltd., Sognsvannsveien 20, N-0372 Oslo, Norway; [email protected] * Correspondence: [email protected] (P.C.); [email protected] (A.R.); Tel.: +41-31-664-04-98 (P.C.); +41-31-632-26-10 (A.R.) Academic Editor: Peter Brust Received: 21 October 2019; Accepted: 13 November 2019; Published: 19 November 2019 Abstract: The discovery of endogenous peptide ligands for morphine binding sites occurred in parallel with the identification of three subclasses of opioid receptor (OR), traditionally designated as µ, δ, and κ, along with the more recently defined opioid-receptor-like (ORL1) receptor. Early efforts in opioid receptor radiochemistry focused on the structure of the prototype agonist ligand, morphine, although N-[methyl-11C]morphine, -codeine and -heroin did not show significant binding in vivo. [11C]Diprenorphine ([11C]DPN), an orvinol type, non-selective OR antagonist ligand, was among the first successful PET tracers for molecular brain imaging, but has been largely supplanted in research studies by the µ-preferring agonist [11C]carfentanil ([11C]Caf).
    [Show full text]
  • Truncated Mu Opioid Receptor Splice Variants As Targets for Powerful Pain Relief with Reduced Side Effects
    TRUNCATED MU OPIOID RECEPTOR SPLICE VARIANTS AS TARGETS FOR POWERFUL PAIN RELIEF WITH REDUCED SIDE EFFECTS A Dissertation Presented to the Faculty of the Weill Cornell Graduate School of Medical Sciences in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Steven G. Grinnell August 2015 © 2015 Steven G. Grinnell TRUNCATED MU OPIOID RECEPTOR SPLICE VARIANTS AS TARGETS FOR POWERFUL PAIN RELIEF WITH REDUCED SIDE EFFECTS Steven G. Grinnell, Ph.D. Cornell University, 2015 Relief from pain is a major goal of all branches of medicine, and poorly controlled pain is associated with substantial economic and human burden. Mu opioid receptors are targets for strong pain relief, mediating the analgesia of widely used analgesic drugs like morphine, hydrocodone, oxycodone, methadone, and fentanyl. Unfortunately, these drugs are associated with numerous side effects such as constipation, respiratory depression, physical dependence, abuse, and addiction. The mu opioid receptor gene undergoes extensive alternative splicing, although the physiological relevance of many of these splice variants is only now becoming clear. In particular, some of these splice variants produce truncated receptors possessing only 6 transmembrane domains, short of the canonical 7 transmembrane domain structure conserved across the G-protein coupled receptor superfamily. Initial studies suggested that these receptors were expressed in low levels relative to full length variants, and could not bind mu agonist drugs when they were transiently expressed in cell lines, calling into question their importance in opioid receptor pharmacology. Here, we show that these truncated receptors are in fact targets for a new pain reliever, IBNtxA, which is a potent pain reliever in mice and rats, yet exhibits a dramatically improved side effect profile over current clinically-used mu analgesics.
    [Show full text]
  • Core Outcome Measures in Preclinical Assessment of Candidate Analgesics
    1521-0081/71/2/225–266$35.00 https://doi.org/10.1124/pr.118.017210 PHARMACOLOGICAL REVIEWS Pharmacol Rev 71:225–266, April 2019 Copyright © 2019 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: MICHAEL A. NADER Core Outcome Measures in Preclinical Assessment of Candidate Analgesics S. Stevens Negus Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia Abstract. ....................................................................................225 I. Introduction. ..............................................................................226 II. Behavioral Outcome Measures in Analgesic Drug Discovery . ...............................228 A. Unconditioned Behavior .................................................................228 1. Definition ............................................................................228 2. Pain Stimulus as an Unconditioned Stimulus .........................................229 3. Pain Stimulus as a Contextual Stimulus ..............................................231 4. Summary ............................................................................233 B. Classical Conditioning . ..................................................................233 1. Definition ............................................................................233 Downloaded from 2. Pain Stimulus as the Unconditioned Stimulus . .....................................234 3. Pain Stimulus as a Contextual
    [Show full text]
  • Bladon, Christine Mary (1982) Studies in Morphinan Chemistry. Phd Thesis
    Bladon, Christine Mary (1982) Studies in morphinan chemistry. PhD thesis http://theses.gla.ac.uk/5534/ Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] STUDIES IN MORPHINAN CHEMISTRY A thesis presented in part fulfilment of the requirements for the degree of Doctor of Philosophy by CHRISTINE MARY BLADON Department of Chemistry September 1982 University of Glasgow IMAGING SERVICES NORTH Boston Spa, Wetherby West Yorkshire, LS23 7BQ www.bl.uk BEST COpy AVAILABLE. TEXT IN ORIGINAL IS CLOSE TO THE EDGE OF THE PAGE To my paren ts ACKNOWLEDGEMENTS First and foremost I would like to thank my supervisor Professor G. W. Kirby for his guidance and encouragement throughout this project. I also wi sh to thank my 1abora tory colleagues and the techni ca 1 staff of the Chemistry Department for their help over the past three years, Reckitt and Colman Ltd. for the pharmacological testing, and the Science and Engineering Research Council for financial support. I am grateful to Dr. P. Bladon for the high resolution mass spectra and the 250 MHz IH n .m.r.
    [Show full text]
  • Synthesis, Biochemical, Pharmacological Characterization and in Silico Profile Modelling of Highly Potent Opioid Orvinol and Thevinol Derivatives
    Comparative biochemical and pharmacological investigations of various newly developed opioid receptor ligands Ph.D. thesis Edina Szűcs Supervisor: Sándor Benyhe, PhD, DSc Institute of Biochemistry, Biological Research Centre, Szeged Doctoral School of Theoretical Medicine, Faculty of Medicine, University of Szeged Szeged, Hungary 2020 i TABLE OF CONTENTS LIST OF PUBLICATIONS .......................................................................................... iii ACKNOWLEDGEMENTS ......................................................................................... vii LIST OF ABBREVIATIONS ....................................................................................... ix 1 INTRODUCTION ............................................................................................... 1 1.1 G-protein coupled receptors (GPCRs) .......................................................... 1 1.1.1 About GPCRs in general ...................................................................... 1 1.1.2 The structure of GPCRs ....................................................................... 1 1.1.3 GPCR signalling ................................................................................... 2 1.1.3.1 Gα signalling ................................................................................. 3 1.1.3.2 G signalling ................................................................................. 4 βγ 1.2 The opioid system ....................................................................................... 4 1.2.1 Poppy
    [Show full text]