The direct and modulatory antinociceptive actions of endogenous and exogenous opioid delta agonists Item Type text; Dissertation-Reproduction (electronic) Authors Vanderah, Todd William. 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 04/10/2021 00:14:57 Link to Item http://hdl.handle.net/10150/187190 INFORMATION TO USERS This ~uscript }las been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely. event that the author did not send UMI a complete mannscript and there are missing pages, these will be noted Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginnjng at the upper left-hand comer and contimJing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in. this copy for an additional charge. Contact UMI directly to order. UMI A Bell & Howell Information Company 300 North Zeeb Road. Ann Arbor. M148106· 1346 USA 313/761-4700 800:521·0600 THE DIRECT AND MODULATORY ANTINOCICEPTIVE ACTIONS OF ENDOGENOUS AND EXOGENOUS OPIOID DELTA AGONISTS by TODD WILLIAM VANDERAH A Dissertation Submitted to the Faculty of the COMMITTEE ON PHARMACOLOGY AND TOXICOLOGY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 1 995 UMI Number: 9534695 OMI Microform 9534695 Copyright 1995, by OMI Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United states Code. UMI 300 North Zeeb Road Ann Arbor, MI 48103 2 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Final Examination Committee, we certify that we have read the dissertation prepared by--------------------------------------- Todd W. Vanderah entitled The Direct and Modulatory Antinociceptive Actions of Endogenous and Exogenous Opioid Delta Agonists. and recommend that it be accepted as fulfilling the dissertation Doctor of Philosophy Date MMc,t-l 2.3 I (6j 1 '5 Date t?LJ ;2 7, 11<1;- Date I ~f!f-5.-ate 1/14$ 2tf, (1'15 nate ' Final approval and acceptance of this dissertation is contingent upon the candidate's submission of the final copy of the dissertation to the Graduate College. I have read this dissertation prepared under my that it be accepted as fulfilling the dissertation 3 STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of the 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 quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his or her judgement the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author. SIGNED:~~ 4 ACKNOWLEDGEMENTS I would like to first acknowledge my parents Jim and Linda Vanderah for their support throughout my college education and for teaching me how to be responsible in accomplishing my goals. I am grateful to my grandfather, Roger O'Toole, who has continually enlightened me and stimulated my desire to learn more about the world around us. I would also like to thank my brother, Tony and my sisters Kari and Nicole for encouraging me to continue my education. I would like to especially acknowledge Dr. Frank Porreca for his guidance and support. Dr. Porreca has been nothing less than a father to me, setting an example of what I can only hope to achieve in the future. His brilliance in science and teaching is something I will cherish throughout my career. I would like to extend my appreciation to both Dr. Porreca and his wife, Gabriella, who have been extremely kind and generous to me and my family. I would like·to thank Dr. Yamamura for his leadership and assistance in the field of molecular pharmacology, as well as for helping me receive my first National Institute of Health fellowship. Dr. Yamamura has given me continual and strong encouragement in my school and experimental studies. A sincere thanks is in order for my other committee members, including Dr. Roeske, Dr. Laird and Dr. Lai, for their input and assistance in helping me achieve my doctorate degree. Lastly, I would like to thank numerous friends and family for helping me in my studies, experiments and for support. First, I would like to thank Drs. Robert Horvath, Ken Wild, Antonia Mattia, Qi Jiang, as well as Pam Peterson, Kent Menkens, Rob Bernstein and Ed Bilsky for their help in my experiments for this dissertation. I would also like to thank several other friends that have helped make life during graduate school bearable including, Nick Perrotta, Mike Nichols, Carl Kovelowski, Wanda Hauglum, Russ Ingersoll, Steve Stratton, Tom Ziegler, Mike Ossipov, John McCormick, Chuck Bian, Kathy Dillon, Kim Mayfield, Tracy Crook, Peg Davis, Rebecca Craft, John Murphy, Roland Cooper, Pierre-Louis LIeu, Sue Maxwell, Kathy Lee, Vanna Santoro, Eva Varga, Ichiro Sora, Richard Knapp, Ewa Malatynska, Jeremy Richman, Irene De Leon, Elizabeth Babin, Terri Vorholzer, Anita Russell, Rita Wedell, Jane Ageton, Karla Hayes and Sandy Sledge. I would also like to thank the support relatives gave me including Dr. John Jansheski and his wife Andree, Gloria Felice, Randy Gingerelli and Mark Jansheski. A very special thanks is in order for those who have helped in preparing and proof-reading this dissertation including Dr. Porreca, Sue Waite, Gina Jansheski, Mike Nichols, Ed Bilsky and Dr. Ossipov. 5 DEDICATION I would like to dedicate this dissertation to my wonderful wife, Gina Jansheski, and my beautiful children, Jordan, Jared and Ryan. My wife and children have continually supported and encouraged me throughout my college career. Although there have been times were I have been extremely busy at work, my wife and family understood and never discouraged me from completing my degree. Over the past four years my family has done more for me than I can ask for in a lifetime. Therefore, it is only proper that I dedicate this dissertation to them. 6 TABLE OF CONTENTS Page LIST OF ILLUSTRATIONS ................................. 9 LIST OF TABLE ............•.......................... 16 ABSTRACT ..........•..•............................ 17 INTRODUCTION . • . • . • . 19 Background ...•....•.....•...................... 1 9 Nociception and Pain Pathways ........•........•. 20 Opiates .................................... 25 Pain and the Medicinal Use of Opiates . 26 Opioid Receptors and Endogenous Opioids . .. 28 Endogenous Opioids and Stress . 36 Cloning and Molecular Mechanisms of Opioid Receptors .. 38 Delta Opioid Receptors and Their Relationship to Pain .... 53 Evidence for Opioid Delta Receptor Subtypes . .. 60 Modulatory Effects on Mu Agonists . 67 Hypothesis of the Dissertation . 71 METHODS ........................................... 75 Animals ........................................ 75 Chemicals ....................................... 75 Antisera ........................................ 76 Injection Techniques ............................... 77 Intracerebroventricular Injections . 77 Spinal Injections . • • . 77 Subcutaneous and Intraperitoneal Injections . .. 77 7 Intraplantar Injections .......................... 78 Tail-Flick Assay . 78 Evaluation of Hyperalgesia ........................... 79 Cold-Water Swim-Stress ............................. 80 Cold-Water Swim-Stress Modulation .................... 80 Experimental Procedures ............................. 81 Agonist/Antagonist Studies ...................... 81 Administration of Oligodeoxynucleotides . .. 85 Tolerance and Cross-Tolerance Studies . 87 Body Temperature . 89 Statistics ....................................... 90 Cloning of an Orphan Receptor ........................ 90 Expression and Characterization of the Orphan Receptor . .. 93 Delta Receptor Subtype Studies Results ......................................... 95 Summary ...................................... 101 Cold-Water Swim-Stress Studies Results . 1 06 Summary ...................................... 1 33 Cold-Water Swim-Stress Modulation Studies Results . 141 Summary ... .. 1 50 8 Delta Receptor Modulation Studies in