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The Roles of the Endogenous Cannabinoid System in Cancer-Induced Bone Pain and Opioid-Induced Reward

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The Roles of the Endogenous Cannabinoid System in Cancer-Induced Bone Pain and Opioid-Induced Reward The Roles of the Endogenous Cannabinoid System in Cancer-Induced Bone Pain and Opioid-Induced Reward Item Type text; Electronic Dissertation Authors Zhang, Hong 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, presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 26/09/2021 08:58:43 Link to Item http://hdl.handle.net/10150/641370 THE ROLES OF THE ENDOGENOUS CANNABINOID SYSTEM IN CANCER- INDUCED BONE PAIN AND OPIOID-INDUCED REWARD by Hong Zhang __________________________ Copyright © Hong Zhang 2020 A Dissertation Submitted to the Faculty of the DEPARTMENT OF PHARMACOLOGY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY WITH A MAJOR IN MEDICAL PHARMACOLOGY In the Graduate College THE UNIVERSITY OF ARIZONA 2020 ACKNOWLEDGEMENTS “Time is like a running horse, who swiftly passes through a crevice.” This is a Chinese proverb describing how time flies so quickly in our life. Now, it is exactly described how I feel about my 5-year Ph.D. training. When looking back to this long journey, I am very pleased that I have achieved my initial goal when I just attended graduate school – becoming a qualified researcher who is able to make contribution to the scientific world. Undoubtedly, my goal would not have been possible without the support of many people. I am immensely grateful to my advisor Dr. Todd Vanderah for all the invaluable guidance and suggestions he provided to me for both my research and my life. His words have always inspired me and pushed me forward every time I thought I have reached my limits. I will always keep these words in my mind and try my best to be a greater scientist and a better person during my lifetime. I am truly thankful to my committee members Drs. Tally Largent-Milnes, John Streicher, Edward French, and Mohab Ibrahim. I deeply appreciate their selfless help on my experiments especially when I encountered difficulties, as well as their sincere encouragement when I made achievements. My deep appreciation also goes to all of the previous and current students and co-workers in the Vanderah and Largent-Milnes labs as well as the Department of Pharmacology - Dr. Lauren Slosky, Dr. Alexander Sandweiss, Dr. Shaness Grenald, Dr. Karissa Cottier, Dr. William Staatz, Austen Thompson, Austin Flohrschutz, Maha Sulaiman, Alysha Swanson, Kelly Karlage, Dr. Erika Liktor-Busa, Jared Wahl, Seph Palomino, Beth Wiese, Vani Verkhovsky, Dominique Lund, Haley Ciccone, Holly Ellingson, Dez Coleman, Ryan Vanderah, Angela Smith, Dr. Frank Porreca, Dr. Lusine Gomtsian, Nathan Eyde, Donna Lu, Dr. Wei Lei, Dr. Attila Keresztes, Justin Lavigne, Dr. Aubin Moutal, Dr. Razaz Felemban, and Dr. Wazir Abdullahi. Thank you for being with me all the way. It is your generous help and support that made this challenging journey a pleasant and fruitful one. I would like to specifically thank Dr. Lusine Gomtsian, an extremely kind and considerate colleague and friend, who provided the best possible help for me a foreigner to settle down and get used to the life in U.S. Lastly, I would like to acknowledge with gratitude to my family – my parents, Gaoyi Zhang and Lingli Yang, as well as my grandma Yuanxiu Tang, who constantly provide their support and love throughout my pursuit of this degree; to my girlfriend, Yanxia Chen, who always encourages me when I experienced failures and applauded for me when I made great progresses; to all the Chinese friends I have met at the University of Arizona – Dr. Xuezhen Ge, Dr. Kun Xiong, Dr. Mengdie Wang, Dr. Amy Wong, Xinyuan Liu and Nan Song, who bring me a feeling of home at this different side of the world. 3 This work was made possible with the financial support from the NIH National Cancer Institute grant R01CA142115 (Dr. Todd Vanderah) and UC Center for Accelerated Innovation grant U54HL119893 (Dr. Igor Spigelman). 4 TABLE OF CONTENTS LIST OF FIGURES ............................................................................................. 10 LIST OF TABLES ............................................................................................... 13 ABSTRACT ........................................................................................................ 14 LIST OF ABBREVIATIONS ................................................................................ 16 CHAPTER 1: INTRODUCTION .......................................................................... 19 1.1 Chronic pain .............................................................................................. 19 1.2 Cancer-induced bone pain ........................................................................ 20 1.2.1 Neuropathic mechanisms of cancer-induced bone pain ..................... 20 1.2.2 Inflammatory mechanisms of cancer-induced bone pain.................... 22 1.2.3 Bone-specific mechanisms of cancer-induced bone pain ................... 24 1.2.4 Treatment of chronic cancer pain & limitations ................................... 27 1.3 Opioid epidemic ........................................................................................ 28 1.3.1 Prevalence of opioid epidemic ............................................................ 28 1.3.2 Current treatment of opioid abuse and addiction ................................ 29 1.3.3 Mechanisms of opioid reward – Two-neuron model ........................... 30 1.4 Endogenous cannabinoid system ............................................................. 33 1.4.1 Cannabinoid receptors ....................................................................... 33 1.4.2 Endocannabinoids & their synthesis and metabolism......................... 37 1.4.3 Endogenous cannabinoid system in the treatment of pain ................. 39 1.4.4 Strategies to overcome the central side effects of cannabinoids ........ 41 1.4.5 Endogenous cannabinoid system in the modulation of opioid reward 44 5 1.5 Hypothesis and specific aims .................................................................... 45 CHAPTER 2: MATERIALS AND METHODS ...................................................... 48 2.1 In vitro ....................................................................................................... 48 2.1.1 Cell culture ......................................................................................... 48 2.1.2 C-terminal telopeptides of Type I collagen assay ............................... 48 2.1.3 XTT assay .......................................................................................... 48 2.1.4 Western blotting ................................................................................. 49 2.1.5 Quantitative real-time polymerase chain reaction ............................... 50 2.1.6 Measurement of monoacylglycerol lipase activity ............................... 51 2.1.7 Single guide RNA design for CB2 receptor (cnr2) gene editing .......... 52 2.1.8 Plasmid construction .......................................................................... 52 2.1.8.1 Cloning of sgRNA ........................................................................ 52 2.1.8.2 Construction of target plasmid expressing rat CB2R gene .......... 53 2.1.9 Culturing and transfection of catecholamine A differentiated (CAD) cells ............................................................................................................. 54 2.1.10 Tracking of indels by decomposition analysis ................................... 54 2.2 In vivo........................................................................................................ 55 2.2.1 Animals ............................................................................................... 55 2.2.2 Drug treatment ................................................................................... 56 2.2.3 Intramedullary implantation of 66.1 breast cancer cells ...................... 57 2.2.4 Behavioral testing protocols ............................................................... 57 2.2.4.1 Acute and chronic behavioral testing of spontaneous pain .......... 57 2.2.4.2 Open field testing ......................................................................... 58 6 2.2.4.3 Rotarod testing............................................................................. 59 2.2.4.4 Rectal temperature testing ........................................................... 59 2.2.4.5 Ring immobility testing ................................................................. 59 2.2.4.6 Conditioned place preference ...................................................... 60 2.2.5 Radiography ....................................................................................... 61 2.2.6 Measurement of body weight and body composition .......................... 61 2.2.7 Assessment of defecation .................................................................. 62 2.2.8 in vivo microdialysis for endocannabinoids ......................................... 62 2.2.9 Quantification of endocannabinoid contents in microdialysates ......... 63 2.2.10 Stereotaxic injection of CRISPR/Cas9 plasmids in VTA ................... 64 2.3 Ex vivo ...................................................................................................... 65 2.3.1 VTA tissue collection .......................................................................... 65 2.4 Statistical Analysis
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