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Bradykinin Receptors Mediate Dynorphin Pronociceptive Action to Produce Persistent Pain

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Bradykinin Receptors Mediate Dynorphin Pronociceptive Action to Produce Persistent Pain Bradykinin Receptors Mediate Dynorphin Pronociceptive Action To Produce Persistent Pain Item Type text; Electronic Dissertation Authors Chen, Qingmin Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 24/09/2021 14:59:24 Link to Item http://hdl.handle.net/10150/195460 BRADYKININ RECEPTORS MEDIATE DYNORPHIN PRONOCICEPTIVE ACTION TO PRODUCE PERSISTENT PAIN By Qingmin Chen Copyright © Qingmin Chen 2007 A Dissertation Submitted to the Faculty of the DEPARTMENT OF MEDICAL PHARMACOLOGY In Partial Fulfillment of the Requirement For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 2007 2 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Qingmin Chen entitled “BRADYKININ RECEPTORS MEDIATE DYNORPHIN PRONOCICEPTIVE ACTION TO PRODUCE PERSISTENT PAIN” and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy Frank Porreca, Ph.D. Date: 10/10/2007 Josephine Lai, Ph.D. Date: 10/10/2007 Todd Vanderah, Ph.D. Date: 10/10/2007 Edward French, Ph.D. Date: 10/10/2007 Robert Sloviter, Ph.D. Date: 10/10/2007 Final approval and acceptance of this dissertation is contingent upon the candidate’s submission of the final copies of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. Frank Porreca, Ph.D. Date: 10/10/2007 Dissertation Director: Frank Porreca, Ph. D. 3 STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at the University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotations from or reproduction of this manuscript in whole or in part may be granted by the copyright holder. Signed: Qingmin Chen 4 ACKNOWLEDGEMENTS Over the course of my graduate studies at the University of Arizona, I have had the support and help of a great number of people. I would like to thank first and foremost my advisor, Dr. Frank Porreca, not only for sharing with me his vast knowledge of science, but also for his inspiring stamina, competent and foreseeing guidance, and constant support throughout the years leading up to the preparation and completion of this work. His educational advice and moral encouragement throughout all the phases of the process are extremely valuable. His brilliance in science is something I will enjoy throughout my career. I would also like to express my deepest gratitude to the members of my committee, Dr. Josephine Lai, Dr. Todd Vanderah, Dr. Edward French and Dr. Robert Sloviter for their valuable comments, suggestions and support throughout my entire educational and research experience at the University of Arizona and helping me achieve my doctoral degree here. In addition, very special thanks go to Dr. Michael Ossipov and Dr. Tamara King, who are always there to help on any kind of problems I encountered. I would also like to thank Dr. Miaw-Chyi Luo and Cinzia Cantu for helping with RT-PCR data; Dr. Louis Vera-Portocarrero and Marina Vardanyan for helping with pancreatitis model; Peg Davis for helping me with the American culture, language and proofreading my manuscripts and dissertation; also Lisa Majuta for being such an excellent lab manager and information center. I sincerely thank all of my lab-mates for all their help including: Dongqin Zhang, Wenhong Guo, Shouwu Ma, Hamid Badghisi, Juliana Chichorro, Milena DeFelice, Becky Edelmayer, Beatriz Fioravanti, Stephanie Hartz, Shannon Holt, Mohab Ibrahim, Justin Kowal, Kiran Kumar, Dr. Phil Malan, Tim Marshall, Eddie Mata, Ohannes Melemedjian, Ramon Mercado, Tally Largent-Milnes, Miki Ota, Janice Somoza-Oyarzo, Jiyang Ren, Jill Roberts, Nicole Schechter, Nicola Stagg, Lauren Tabis, Anna Vardanyan, Laura Vogel, Ruizhong Wang, Yanhua Xie (Jennifer) and En-Tan Zhang. In addition, appreciation is also extended to all the other faculty and students of the department of Pharmacology at the University of Arizona. 5 TABLE OF CONTENTS LIST OF FIGURES 9 LIST OF TABLES 12 ABBREVIATIONS 13 ABSTRACT 14 PART ONE ─ BRADYKININ RECEPTORS MEDIATE THE PRONOCICEPTIVE ACTION OF DYNORPHIN TO PRODUCE PERSISTENT PAIN IN THE NEUROPATHIC PAIN STATE 16 ABSTRACT 17 CHAPTER ONE: INTRODUCTION 19 1.1 Neuropathic pain 19 1.2 Animal models of neuropathic pain 21 1.3 Possible mechanisms of neuropathic pain 23 1.3.1 Ectopic discharge 23 1.3.2 Anatomical reorganization in the spinal cord 25 1.3.3 Sensitization in the spinal cord 26 1.3.4 Decreased inhibition in the spinal cord 26 1.3.5 Activation of decending facilitation from the RVM 27 1.3.6 Up-regulation of spinal dynorphin 28 1.3.6.1 The paradox of dynorphin 28 1.3.6.2 Non-opioid actions of dynorphin may maintain the persistent pain in neuropathic pain 30 1.3.6.3 Bradykinin receptor mediated excitatory effect of dynorphin in vitro 31 1.3.6.4 Dynorphin A raises intracellular calcium by activating voltage sensitive calcium channels 31 1.3.6.5 Dynorphin A (2-13) directly interacts with bradykinin receptors 33 1.4 Summary of research goals 35 CHAPTER TWO: MATERIALS AND METHODS 44 2.1 Animals 44 2.2 Drugs and doses 44 2.3 Surgical preparations 45 2.3.1 Subcutaneous osmotic pump implantation 45 2.3.2 Spinal nerve ligation (SNL) and sham surgery 45 2.3.3 Intrathecal catheterization 46 2.4 Behavioral testing 47 2.4.1 Von Frey test for tactile hypersensitivity 47 2.4.2 Radiant heat and hot plate test for thermal hypersensitivity 47 6 TABLE OF CONTENTS – Continued 2.5 Quantitative RT-PCR 48 2.6 Data analysis 49 CHAPTER THREE: RESULTS 50 3.1 Intrathecal administration of bradykinin to rats 50 3.2 Intrathecal administration of dynorphin A (2-13) to rats 50 3.3 Dynorphin-induced tactile and thermal hypersensitivities with bradykinin B2 receptor antagonist 51 3.4 Dynorphin-induced tactile and thermal hypersensitivities with bradykinin B1 receptor antagonist 52 3.5 Intrathecal dynorphin A (2-13) administered to bradykinin B2 receptor knock-out mice 52 3.6 Intrathecal injection of bradykinin B2 receptor antagonist in rats with nerve injury 53 3.7 Intrathecal injection of bradykinin B1 receptor antagonist in rats with nerve injury 54 3.8 Intrathecal co-administration of bradykinin B1 and B2 antagonist in rats with nerve injury 54 3.9 Intrathecal infusion of bradykinin B1 and B2 antagonists in rats with nerve injury 55 3.10 Systemic infusion of bradykinin B1 and B2 antagonists in rats with nerve injury 57 3.11 Local administration of bradykinin B1 and B2 antagonists in rats with nerve injury 58 3.12 Bradykinin B1 and B2 receptors’ mRNA expression in dorsal root ganglia and spinal cord after spinal nerve injury 58 3.13 Increased prodynorphin, but not kininogen, mRNA in the lumbar spinal cord after spinal nerve injury 59 3.14 Intrathecal administration of bradykinin anti-serum in rats with nerve injury 60 CHAPTER FOUR: DISCUSSION 79 PART TWO ─ ATTENUATION OF EXPERIMENTAL PANCREATITIS PAIN BY A BRADYKININ B2 RECEPTOR ANTAGONIST 88 ABSTRACT 89 CHAPTER ONE: INTRODUCTION 91 1.1 Visceral pain 91 1.2 Transmission of visceral pain 91 7 TABLE OF CONTENTS – Continued 1.3 Pancreatitis 93 1.4 Pancreatitis pain 93 1.5 Pathogenesis of pain in chronic pancreatitis 94 1.6 DBTC-induced persistent pancreatitis model 96 1.7 Role of kinin-kallikerin system in pancreatitis 96 1.8 Role of spinal dynorphin in pancreatitis pain 98 1.9 Summary of research goals 100 CHAPTER TWO: MATERIALS AND METHODS 104 2.1 Animals 104 2.2 Induction of pancreatitis 104 2.3 Intrathecal catheter implantation 104 2.4 Drugs and injection 105 2.5 Quantitative RT-PCR 105 2.6 Visceral pain behavioral measurements 107 2.7 Pancreatic histology 108 2.8 Data analysis 108 CHAPTER THREE: RESULTS 109 3.1 Pancreatic morphology analysis 109 3.2 Systemic B2 but not B1 receptor antagonist reverses the abdominal hypersensitivity induced by DBTC 109 3.3 mRNA expression of B1 and B2 receptor in pancreas after DBTC injection 110 3.4 Spinal B2 but not B1 receptor antagonist reverses abdominal hypersensitivity induced by DBTC 110 3.5 Spinal dynorphin anti-serum reverses the abdominal hypersensitivity induced by DBTC 111 3.6 Bradykinin B1 and B2 mRNA expression in the dorsal root ganglia and spinal cord after DBTC injection 111 CHAPTER FOUR: DISCUSSION 119 PART THREE ─ DYNORPHIN MAINTAINS CFA-INDUCED INFLAMMATORY PAIN VIA BRADYKININ RECEPTORS 124 ABSTRACT 125 CHAPTER ONE: INTRODUCTION 126 CHAPTER TWO: MATERIALS AND METHODS 128 2.1 Animals 128 8 TABLE OF CONTENTS – Continued 2.2 Intrathecal catherization and drug administration 128 2.3 Behavioral testing 129 2.4 Quantitative RT-PCR 129 CHAPTER THREE: RESULTS 132 3.1 Intraplantar CFA induces tactile and thermal hypersensitivities in rats 132 3.2 Intrathecal dynorphin anti-serum reverses CFA-induced tactile and thermal hypersensitivies at 72 but not 6 hours post-CFA 132 3.3 Intrathecal bradykinin antagonists reverse CFA-induced tactile and thermal hypersensitivies
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