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Brain CYP2D Metabolism of Opioids Impacts Brain Levels, Analgesia, and Tolerance Brain CYP2D Metabolism of Opioids Impacts Brain Levels, Analgesia, and Tolerance by Douglas McMillan A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Pharmacology and Toxicology University of Toronto © Copyright by Douglas McMillan 2018 Brain CYP2D Metabolism of Opioids Impacts Brain Levels, Analgesia, and Tolerance Douglas McMillan Doctor of Philosophy Graduate Department of Pharmacology and Toxicology University of Toronto 2018 Abstract Cytochrome P450 2D (CYP2D) is a subfamily of enzymes expressed in both liver and brain that metabolizes clinically used drugs, neurotoxins, and endogenous neurochemicals. Opioid analgesics are metabolized by CYP2D to more potent analgesic metabolites, and variation in this metabolism may alter opioid response. While human CYP2D expression in the liver is primarily regulated by genetics, brain CYP2D activity may be altered by genetics, environmental inducers, and hormonal regulation. Smokers have higher brain, but not liver, CYP2D and nicotine induces rat brain, but not liver, CYP2D. This thesis investigated the impact of altering rat brain CYP2D activity in vivo on the brain metabolism of opioids and resulting analgesia. Rats were administered opioids and analgesia was measured; drug levels were assessed in brain and plasma after sacrifice, or in brain in vivo by microdialysis. Rat brain CYP2D was inhibited by intracerebroventricular injection of a CYP2D mechanism-based inhibitor or induced by seven-day subcutaneous nicotine treatment. We found that rat brain CYP2D activation of codeine to morphine mediates acute codeine analgesia; inhibiting brain CYP2D decreased, and inducing brain CYP2D increased, brain morphine from codeine and resulting codeine analgesia. In a rat model of codeine analgesic tolerance, inducing brain CYP2D increased acute analgesia and the rate of analgesic tolerance, producing a greater absolute decrease in analgesia per codeine dose. Administering higher doses of codeine similarly increased acute analgesia and the rate of tolerance. The rate of tolerance correlated to acute analgesia indicating that brain CYP2D influenced codeine tolerance by altering acute analgesic-response. Lastly, we found that rat brain CYP2D metabolism of oxycodone to oxymorphone decreased acute oxycodone analgesia; inhibiting brain CYP2D increased brain oxycodone levels and resulting analgesia, while inducing brain CYP2D increased brain oxymorphone levels but decreased oxycodone analgesia. This thesis demonstrated an impact of rat ii brain CYP2D on acute codeine and oxycodone induced analgesia, as well as the rate of codeine analgesic tolerance. Variation in human brain CYP2D metabolism may be a clinically relevant source of variation in opioid response. Novel approaches to understanding interindividual differences in opioid analgesia and adverse effects remain critical for improving opioid efficacy and mitigating abuse. iii Acknowledgements First, I wanted to thank my supervisor Rachel Tyndale for her support throughout my research. Your mentorship has helped immeasurably in developing my skills in scientific writing, critical thinking, presenting, and independent research. The training and opportunities I have been given will be invaluable moving forward in my career and I am very grateful. I also wanted to thank my PhD supervisory committee members David Riddick and Jose Nobrega for sharing their scientific expertise by way of continued insight and helpful suggestions. I also wanted to extend many thanks to all past and present members of the Tyndale lab. Specifically, thanks to Sharon Miksys for her kindness and approachability in all matters scientific and otherwise, Bin Zhao for his resilience in running my thousands of samples, Fariba Baghai Wadji for her masterful surgical hands, Ewa Hoffman for providing welcomed distractions and an outlet for my hockey addiction, Meghan Chenoweth for ensuring I was always well-caffeinated, and JAT for leading the way and providing me with a graduate school blueprint which without, I would be nowhere near finishing this PhD. Lastly, beyond the Tyndale lab, I wanted to thank my friends and family. Thanks to Lauren, my better-half through the majority of this PhD. Your passion, work ethic, and avid curiosity continues to inspire me and you have provided me with an incredibly solid foundation throughout my studies. Thank you to my sister Katie, my brother-in-law Justyn, and my nephews Tyler and Jackson, for providing fun diversions from work whenever needed. And finally, to my parents, I’ll never be able to thank you enough for everything you’ve done for me. Your support through my decade of university has allowed my only source of stress to be academic, and you’ve provided me with endless encouragement, validation, love, clean Barrie air, and Leafs tickets. Without you this wouldn’t have been possible. iv Table of Contents Acknowledgements ........................................................................................................................ iii List of Publications ........................................................................................................................ ix List of Tables ................................................................................................................................. xi List of Figures ............................................................................................................................... xii List of Abbreviations .................................................................................................................... xv List of Appendices ...................................................................................................................... xvii Statement of Research Problem ................................................................................................. xviii Main Research Objectives ........................................................................................................... xxi 1. General Introduction ................................................................................................................... 1 1.1 – Opioid analgesics ............................................................................................................... 1 1.1.1 General introduction ....................................................................................................... 1 1.1.2 Current clinical use and treatment indications ............................................................... 1 1.1.3 Pharmacology ................................................................................................................. 2 1.1.3.1 Opioid receptors ....................................................................................................... 2 1.1.3.2 Opioid metabolism ................................................................................................... 4 1.1.4 Opioid neuropharmacology ............................................................................................ 5 1.1.4.1 Analgesia.................................................................................................................. 5 1.1.4.2 Tolerance.................................................................................................................. 7 1.1.4.3 Dependence .............................................................................................................. 9 1.1.5 Opioid epidemic; misuse and abuse ............................................................................. 10 1.2 – CYPs................................................................................................................................. 14 1.2.1 General introduction ..................................................................................................... 14 1.2.2 CYP2D6 enzyme .......................................................................................................... 15 1.2.2.1 Substrates and clinical drugs of interest ................................................................. 15 1.2.2.2 Variation in CYP2D6 ............................................................................................. 17 1.2.2.2.1 Genetic sources of variation ............................................................................ 17 1.2.2.2.1.1. Interethnic variability .............................................................................. 19 1.2.2.2.1.2 Functional impact of CYP2D6 polymorphism ......................................... 21 1.2.2.2.2 Non-genetic sources of variation and drug-drug interactions ......................... 22 1.2.2.3 Species differences in CYP2D6 enzyme ............................................................... 23 1.3 – CYP2D6 and opioids ........................................................................................................ 24 v 1.3.1 CYP2D6 metabolism of opioids ................................................................................... 24 1.3.2 Impact of CYP2D6 phenotype on opioid analgesia ..................................................... 25 1.3.3 Impact of CYP2D6 phenotype on opioid abuse liability .............................................. 28 1.3.4 Other sources of variability in opioid response ............................................................ 29 1.4 – Brain CYPs ....................................................................................................................... 30 1.4.1 Brain CYP
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