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Microfilms International 300 N CENTRAL NERVOUS SYSTEM REGULATION OF INTESTINAL MOTILITY: ROLE OF ENDOGENOUS OPIOID PEPTIDES (ENDORPHINS, ENKEPHALINS) Item Type text; Dissertation-Reproduction (electronic) Authors GALLIGAN, JAMES JOSEPH. 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 25/09/2021 06:17:11 Link to Item http://hdl.handle.net/10150/187571 INFORMATION TO USERS This reproduction was made from a copy of a document sent to us for microfilming. While the most advanced technology has been used to photograph and reproduce this document, the quality of the reproduction is heavily dependent upon the quality of the material submitted. The following explanation of techniques is provided to help clarify markings or notations which may appear on this reproduction. I. The sign or "target" for pages apparently lacking from the document photographed is "Missing Page(s)". If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages. This may have necessitated cutting through an image and duplicating adjacent pages to :'<:3ure complete continuity. 2. When an image on the film is obliterated with a round black mark, it is an indication of either blurred copy because of movement during exposure, duplicate copy, or copyrighted materials that should not have been filmed. For blurred pages, a good image of the page can be found in the adjacent frame. If copyrighted materials were deleted, a target note will appear listing the pages in the adjacent frame. 3. 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Zeeb Road Ann Arbor, MI48106 8403228 Galligan, James Joseph CENTRAL NERVOUS SYSTEM REGULATION OF INTESTINAL MOTILITY: ROLE OF ENDOGENOUS OPIOID PEPTIDES The University of Arizona PH.D. 1983 University Microfilms International 300 N. Zeeb Road, Ann Arbor, MI48106 PLEASE NOTE: In all cases this material has been filmed in the best possible way from the available copy. Problems encountered with this document have been identified here with a check mark ..; 1. Glossy photographs or pages __ 2. Colored illustrations, paper or print_ 3. Photographs with dark background_ 4. Illustrations are poor copy __ 5. Pages with black marks, not original copy __ 6. Print shows through as there is text on both sides of page __ 7. Indistinct, broken or small print on several pages __ S. Print exceeds margin requirementS __ 9. Tightly bound copy with print lost in spine __ 10. Computer printout pages with indistinct print __ 11. Page(s) lacking when material received, and not available from school or author. 12. Page(s) seem to be missing in numbering only as text follows. 13. Two pages numbered . Text follows. 14. Curling and wrinkled pages __ 15. Other Dissertation contains pages with print at a slant, filmed as received. University Microfilms International CENTRAL NERVOUS SYSTEM REGULATION OF INTESTINAL MOTILITY: ROLE OF ENDOGENOUS OPIOID PEPTIDES by James J. Galligan A Dissertation Submitted to the Faculty of the PROGRAM IN PHARMACOLOGY AND TOXICOLOGY In Partial Fulfillment of the Requirements For the degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 1 983 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Final Examir,9.tion Committee, we certify that we have read the dissertation prepared by James J. Gallisan entitled _____C_en __ tr_a_1 __ N_e_r_v_o_u_s __ S~y_s_t_e_m __ R_e~g_u_l_a_ti_o_n __ o_f_·_I_n_t_e_s_t_i_n_a_l __ M_o~t_i~l~i~ty~: _____ Role of Endogenous Opioid Peptides. and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy ----------------.----~~-------------------------------- Date Date Date Date Final approval and acceptance of this dissertation is contingent upon the candidate's submission of the final copy of the disser.tation to the Graduate College. I hereby certify that I have read this dissertation prepared under my dire~~tion and recommend tha,t it be accepted as fl1lfilling the dissertation Date J STA'rEMENT BY AUTHOR This dissertation has been submitted in partial fulfillemnt of the requirments for an advanced degree at the University of Arizona and is deposited in the University Library to be made available to borrowers under the rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment of the source is made. Rpquests for permission for extended quotation from of 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 wlllm in his judgement the proposed use of the material in in the interests of scholarship. In all other instances, however, per­ mission must be obtai ned from th(~ author. DEDICATION This dissertation and all the work involved in its completion is dedicated to my father. iii ACKNOWLEDGMENTS A special thanks to Dr. David L. Kreulen who provided expert assistance and advice on many of these experiments and also allowed the use of his laboratory during the ~n v~tro studies. iv TABLE OF CONTENTS Page LIST OF ILLUSTRATIONS •••••• CI ••••••••••••••••••••••••••••••• vii LIST OF TABLES ............................................. x ABSTRACT ................................................... xi INTRODUCTION •••••••••••••••• 0 •••••••••••••••••••••••••••••••••• 1 Hormonal Control of Intestinal Motility.................... 2 Intrinsic Neural Control of Intestinal Motlity ••••••••••••• 3 Extrinsic Neural Control of Intestinal Motility............ 5 Patterns of Intestinal Motility............................ 7 Opiates and Motility....................................... 11 Irritable Bowel Syndrome ••••••••••••••••••••••••••••••••••• 18 Statement of Problem •••••• ~................................ 22 METHODS ........................................................ 24 Surgical Preparation of Animals for Intestinal Transit Studies •••••••••••••••••••••••••••••••••••••••••••• 24 Intracerebroventricular Cannulas •••••••••••••••••••••• 26 Hypophys~ctomy •••••••••••••••••••••••••••••••••••••••• 27 Spinal Cord Section •••••••••••••••••••••••••••••••••• 27 Subdiaphramatic Vagotmy ••••••••••••••••••••••••••••••• 27 Evaluation of Intestinal Transit and Gastric Emptying •••••• 28 Gastric Emptying ••••••••••• ~.......................... 28 Small and Large Intestinal Transit •••••••••••••••••••• 29 Effects of Morphine on Small Intestinal Transit and Gastric Emptying ••••••••••••••••••••••••••••••••••••••• 31 Direct Measurement of Small Intestinal Motility............ 31 Effects of Opioid Peptides on Small Intestinal Transit in Castor Oil-Treated Rats ••••••••••••••••••••••••• 34 Effects of Electroconvulsive Shock on Gastrointestinal Motility and Analgesia ••••••••••••••••••••••••••••••••••••• 35 Effects of Inescapable Footshock on Gastrointestinal Motility and Analgesia ••••••••••••••••••••••••••••••••••••• 36 Kyotorphin Effects on Intestinal Transit and Analgesia ••••• 37 Determination of Opioid Receptor Selectivity of Agonists in Vitro ••••••••••••••••••••••••••••••••••••••• 38 Determination of the Opioid Receptors Mediating the Analgesic and Intestinal Motility Effects of Centrally-Administered Opioids ••••••••••••••••••••••••••••• 41 v TABLE OF CONTENTS continued Page RESULTS 43 Effects of Morphine on Gastric Emptying and Small Intestinal Transit and Motility............................ 43 Effects of Opioid Peptides on Intestinal Transit in Castor Oil-Treated Rats ••••••••••••••••••••••••• 52 Effects of ECS on Gastrointestinal Motility and Analges 1a .•..•••...•............••••.•....•...•.•...••. 64 Effects of IFS on Gastrointestinal Motility and Analgesia •••••••••••••••••••••••••••••••••••••••••••••• 67 Effects of Kyotorphin of Small Intestinal Transit a nd Analgesia •••••••••••.•••.••••.••••••••••••....•.••..•.• 67 In Vitro Determination of Receptor Selectivity............. 67 Effects of Receptor Selective Agonists on Small Intestinal Transit and AnalgeSia •••••••••••••••••••••••••••••••••••••• 75 Relative Potencies In Vivo ••••••••••••••••••••••••••••••••• 84 DISCUSSION 88 REFERENCES 110 vi LIST OF ILLUSTRATIONS Figure Page 1. Schematic drawing of the implant used in these studies to record intestinal motility from unanesthetized rats ••••••••••••••••••••••••••••••••• 33 2. Distribution of radiochromium in the small intestine of rats treated with intracerebro- ventricular morphine or saline ••••••••••••••••••••••• 44 3. Dose-response curves for morphine induced-inhibit-
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