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Positive Allosteric Modulators (Pams) in Mouse Models of Overt Cannabimimetic Activity, Subjective Drug Effects, and Neuropathic Pain

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Positive Allosteric Modulators (Pams) in Mouse Models of Overt Cannabimimetic Activity, Subjective Drug Effects, and Neuropathic Pain Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2021 Investigating Cannabinoid Type-1 Receptor (CB1R) Positive Allosteric Modulators (PAMs) in Mouse Models of Overt Cannabimimetic Activity, Subjective Drug Effects, and Neuropathic Pain Jayden Elmer Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Behavioral Neurobiology Commons, Behavior and Behavior Mechanisms Commons, Medicinal and Pharmaceutical Chemistry Commons, Nervous System Diseases Commons, and the Pharmacology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/6777 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. 2021 Investigating Cannabinoid Type-1 Receptor (CB1R) Positive Allosteric Modulators (PAMs) in Mouse Models of Overt Cannabimimetic Activity, Subjective Drug Effects and Neuropathic Pain Jayden A. Elmer Investigating Cannabinoid Type-1 Receptor (CB1R) Positive Allosteric Modulators (PAMs) in Mouse Models of Overt Cannabimimetic Activity, Subjective Drug Effects and Neuropathic Pain A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University By Jayden Aric Elmer Bachelor of Science, University of Virginia, 2018 Director: Dr. Aron Lichtman, Professor, Department of Pharmacology & Toxicology; Associate Dean of Research and Graduate Studies, School of Pharmacy Virginia Commonwealth University Richmond, Virginia July 2021 Acknowledgements I would first like to extend my gratitude towards the CERT program at VCU. The CERT program opened the doors for me to get involved in graduate research. I want to thank Dr. Damaj for writing my letter of recommendation when I applied to the MS program in Pharmacology & Toxicology. Since I started the MS program, I have developed a keener perspective on research in pharmacology and medicine. Next, I would like to thank my advisor Dr. Aron Lichtman. He gladly accepted me into his lab when I came to him interested in learning more about his research in early 2019. Through his guidance I’ve come to better understand scientific practice research principles. I want to thank Mohammed Mustafa for his help training me in the lab and always being willing to answer whatever questions I had. I am grateful to my family for the love and support they’ve provided over the years. I am also grateful to my friends and colleagues in the Lichtman lab and on the 3rd floor of Kontos Medical Sciences Building. Their company and enthusiastic support have made my time at VCU all the more enjoyable. I am very proud of my achievements and I am forever grateful to those who made a difference in my life, whether small or significant. Table of Contents Title page ...................................................................................................................................................................... 4 Acknowledgements ...................................................................................................................................................... 5 Table of Contents ......................................................................................................................................................... 6 List of Tables and Figures ........................................................................................................................................... 8 List of Abbreviations ................................................................................................................................................... 9 Abstract ...................................................................................................................................................................... 11 Chapter 1. General Introduction .............................................................................................................................. 13 Endogenous Cannabinoid System ........................................................................................................................... 13 Endogenous Cannabinoid Receptors .................................................................................................................. 13 Anatomic Distribution of Cannabinoid Receptors ............................................................................................. 14 Endocannabinoids .............................................................................................................................................. 15 Cannabinoid Pharmacology ................................................................................................................................... 16 Cannabinoid Receptor Structure and Binding Sites ........................................................................................... 16 Cannabinoid Receptor Signaling Pathways ....................................................................................................... 17 Allosteric Modulation of Cannabinoid Type I Receptors ........................................................................................ 17 Allosteric Modulation and Biased Signaling ...................................................................................................... 17 CB1 Negative Allosteric Modulators ................................................................................................................. 19 CB1 Positive Allosteric Modulators .................................................................................................................. 20 The Endogenous Cannabinoid System in Acute and Chronic Pain ........................................................................ 21 Ascending and Descending Pain Pathways ........................................................................................................ 21 Chronic Constriction Injury Model of Neuropathic Pain ................................................................................... 24 Investigating the Properties of Cannabinoids in vitro & in vivo ............................................................................ 24 Binding and Functional Assays In Vitro ............................................................................................................ 24 Behavioral Paradigms for Cannabimimetic Activity ......................................................................................... 25 Overview of 2-phenyl indoles Represented by ZCZ011 .......................................................................................... 25 Pharmacological Effects In Vitro ....................................................................................................................... 27 Pharmacological Effects In Vivo ....................................................................................................................... 28 Chapter 2: Cannabinoid Drug Discrimination - From Agonism to Allosteric Modulation ................................ 29 Historical Origins ................................................................................................................................................... 29 Core Concepts and Principles of Drug Discrimination .......................................................................................... 47 Subjective Effects of Drugs ............................................................................................................................... 47 Receptor Mechanisms of Discriminative Stimulus Effects ................................................................................ 49 Tolerance and Cross-Tolerance .......................................................................................................................... 51 Drug Discrimination in Drug Development ....................................................................................................... 52 Discriminative Stimulus Properties Cannabinoid Agonists .................................................................................... 53 Phytocannabinoids ............................................................................................................................................. 53 Synthetic Cannabinoids ...................................................................................................................................... 55 Endocannabinoids .............................................................................................................................................. 58 Discriminative Stimulus Properties of Endocannabinoid Degradative Enzyme Inhibitors .................................... 61 Monoacylglycerol Lipase (MAGL) Inhibitors ................................................................................................... 62 Fatty Acid Amide Hydrolase (FAAH) Inhibitors ............................................................................................... 63 Dual MAGL & FAAH Inhibitors ....................................................................................................................... 63 Discriminative Stimulus Properties of Cannabinoid Antagonists ........................................................................... 65 Discriminative Stimulus Properties
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