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Neurons Coexpressing Cholecystokinin-2 and Μ Pain Facilitatory Cells in Rostral Ventromedial Medulla: Neurons Coexpressing Cholecystokinin-2 and Mu-Opioid Receptors Item Type text; Electronic Dissertation Authors Zhang, Wenjun 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 18:17:21 Link to Item http://hdl.handle.net/10150/195291 1 PAIN FACILITATORY CELLS IN ROSTRAL VENTROMEDIAL MEDULLA: NEURONS COEXPRESSING CHOLECYSTOKININ-2 AND μ-OPIOID RECEPTORS By Wenjun Zhang A Dissertation Submitted to the Faculty of the COMMITTEE ON PHARMACOLOGY AND TOXICOLOGY (GRADUATE) In Partial Fulfillment of the Requirement For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 2005 2 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Wenjun Zhang entitled “Pain facilitatory cells in rostral ventromedial medulla: neurons coexpressing cholecystokinin-2 and mu-opioid receptors” and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy Josephine Lai, Ph.D __________________________________________________Date: Nov. 28, 2005 Edward French, Ph.D _________________________________________________Date: Nov. 28, 2005 Frank Porreca, Ph.D___________________________________________________ Date: Nov. 28, 2005 Naomi Rance, M.D, Ph.D_____________________________________________Date: Nov. 28, 2005 Todd Vanderah, Ph.D__________________________________________________Date: Nov. 28, 2005 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. Josephine Lai, Ph.D____________________________________ Date: Nov. 28, 2005 Dissertation Director: 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 head of the major department or the Dean of the Graduate College when in his or her judgment 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: Wenjun Zhang 4 ACKNOWLEDGEMENTS I must acknowledge, foremost, my primary advisor, Dr. Josephine Lai, not only for sharing with me her vast knowledge of science, but also for her inspiring stamina, competent and foreseeing guidance, and constant support throughout the years leading up to the preparation and completion of this work. Her brilliance in science is something I will enjoy throughout my career. Without her support, I might never have achieved this milestone in my career. She has always been a tremendous help in my sometimes overwhelmingly difficult effort to transform from paratrooper to scientist. She played significant roles that resulted in my succeeding, and sometimes, my survival. I can never forget how she encouraged me and support me while I had a visa problem. My gratitude is greater than my memory, so I leave them all in my heart. I also greatly appreciate my committee members. I am indebted to Dr. Frank Porreca, an exceptional role model of being a great scientist. He has done his utmost to help with every concern that his advises have. I would like to thank Dr. Todd Vanderah, who always take time and give me valuable advice. Dr. Naomi Rance deserves thanks for a lot of help troubleshooting in situ hybridization techniques and allowing me to use her laboratory whenever needed. I am extremely honored to have Dr. Edward French in my committee, whose incisive comments were a great help in my research projects. Special thanks go to Dr. Tamara King. She is willing to tackle all the headaches that no one else would touch, from computer to microscopy. I thank Dr. Michael Ossipov for his help on any kind of problems I may encounter. I would express my special appreciation to a scientist outside the university, Dr. Sergio Ojada in Oregon Health Sciences University. His working protocol directly contributes to my research. I would also like to thank Dongqin Zhang, for being extremely helpful with surgeries and behavioral studies; my predecessor Dr. Shannon Burgess and Jennifer Xie, whose work provided a foundation for my studies; Members in Dr. Rance's lab, Sally Krajewski, Michelle Burke and Adona, Rometo, for their generous help on the techniques of in situ hybridization and autoradiography; Lynne Richter in the Department of Pathology, for helping me on the use of microscopy; postdoctoral fellow Dr. Miaw-chyi Luo, my favorite labmate, whose molecular biology expertises are a great source of knowledge; Dr. Shouwu Ma and Hamid Badghisi, for helping me handle radioactive chemicals; Ohannes Melemedjian, my fellow student, and a participant in a large variety of conversation, for sharing his intelligence and happiness with me; Nicole Schechter, our lab manager, for her professional assistance on everyday's lab activities; Tammi Morrissy, for her kind help when I first arrived the lab; Dr. En-Tan Zhang and Ruizhong Wang, for sharing me their invaluable hand-on experience on immunohistochemistry; Milena DeFelice and Justin Kowal, for their help on tissue collection; Almet Dogrul, Qingmin Chen and Wenhong Guo, for teaching me survival surgeries; Dr. Louis Vera- Portocarrero, for his willingness to help me out whenever I asked for; Lisa Majuta and Peg Davis, for being an excellent information center and helping me with English; Mohab Ibrahim, for his kind help on my oral examination; Karla Hayes, for helping me using WordPerfect; Patrisha Stanley, Terri Vorholzer, Cheryl Anderson, Jane Ageton, for protecting me from any of the administrative nightmares. 5 DEDICATION I would like to dedicate this dissertation and degree to my wonderful wife, Dr. Xiaobo Chen, whose influence is significantly related to my academic gains. Her unconditional support throughout the whole period of time leads to finishing my doctoral degree. I also dedicate this work to my elder daughter April and the newest member Hannah. Although they contributed greatly to many sleepless nights and hazy days during this endeavor, they have been the greatest source of stress relief that I have had. The simplicity that only a small child can bring has provided a safe haven from the complexities of life. I dedicate this study and degree to my parents. They have taught me a lot during my maturation - of courage and hard work, believing and achieving, patience and perseverance, inner strength and gentle hope. I also dedicate this whole work to my dearest advisor, Dr. Josephine Lai, a person that definitely changed my life forever. 6 TABLE OF CONTENTS LIST OF FIGURES ............................................................................................................12 ABBREVIATIONS ............................................................................................................14 ABSTRACT........................................................................................................................15 INTRODUCTION ..............................................................................................................17 Pain and pain transmission pathway.......................................................................17 Peripheral neuropathy and its animal models-spinal nerve ligation .......................19 Pain modulation systems - descending facilitatory pathway ..................................21 Descending facilitatory pathway in neuropathic pain.............................................23 Role of rostral ventral medulla on descending facilitation ....................................24 Neuroanatomy.............................................................................................24 Functional characterizations of RVM cells.................................................25 Role in descending facilitation....................................................................26 Cholecystokinin-receptor-system and the role in descending facilitation ..............27 Cholecystokinin: neuropeptides in CNS.....................................................27 Cholecystokinin receptors: gene structures and localization......................30 Cholecystokinin-receptor system: signal transduction pathways ...............31 Roles in pain facilitation .............................................................................32 Saporin conjugates as a targeted tool to selectively destroy receptor-expressing cells .............................................................................................................33 Figures and legends.................................................................................................36 7 TABLE OF
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