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Ong Edmund W 201703 Phd.Pdf (5.844Mb) INVESTIGATING THE EFFECTS OF PROLONGED MU OPIOID RECEPTOR ACTIVATION UPON OPIOID RECEPTOR HETEROMERIZATION by Edmund Wing Ong A thesis submitted to the Graduate Program in Pharmacology & Toxicology in the Department of Biomedical and Molecular Sciences In conformity with the requirements for the degree of Doctor of Philosophy Queen’s University Kingston, Ontario, Canada March, 2017 Copyright © Edmund Wing Ong, 2017 Abstract Opioid receptors are the sites of action for morphine and most other clinically-used opioid drugs. Abundant evidence now demonstrates that different opioid receptor types can physically associate to form heteromers. Owing to their constituent monomers’ involvement in analgesia, mu/delta opioid receptor (M/DOR) heteromers have been a particular focus of attention. Understandings of the physiological relevance of M/DOR formation remain limited in large part due to the reliance of existing M/DOR findings upon contrived heterologous systems. This thesis investigated the physiological relevance of M/DOR generation following prolonged MOR activation. To address M/DOR in endogenous tissues, suitable model systems and experimental tools were established. This included a viable dorsal root ganglion (DRG) neuron primary culture model, antisera specifically directed against M/DOR, a quantitative immunofluorescence colocalizational analysis method, and a floxed-Stop, FLAG-tagged DOR conditional knock-in mouse model. The development and implementation of such techniques make it possible to conduct experiments addressing the nature of M/DOR heteromers in systems with compelling physiological relevance. Seeking to both reinforce and extend existing findings from heterologous systems, it was first necessary to demonstrate the existence of M/DOR heteromers. Using antibodies directed against M/DOR itself as well as constituent monomers, M/DOR heteromers were identified in endogenous tissues and demonstrated to increase in abundance following prolonged mu opioid receptor (MOR) activation by morphine. The next experiments addressed an aspect of the functional consequences of M/DOR formation in endogenous tissues by investigating the post-internalization trafficking of delta opioid receptor (DOR) in conditions of augmented M/DOR formation. These experiments identified perturbations to DOR trafficking consistent with incorporation into a M/DOR species ii with probabilistic post-internalisation trafficking behaviour intermediate to that of either constituent and responsive to both MOR and DOR agonists in a manner subject to blockade by DOR antagonist. These studies provide concurrent evidence of the existence and functionality of physiologically-relevant M/DOR heteromers in endogenous tissues. iii Co-Authorship The research upon which this thesis is based was conducted by Edmund W. Ong under the supervision of Dr. Catherine M. Cahill and Dr. Mary Cella Olmstead. In Chapter 2, Edmund W. Ong examined the effect of morphine on heteromer abundance in DRG cultures with the assistance of Mats Junek; Achla Gupta generated heteromer-selective monoclonal antibodies and carried out ELISA and binding assays; Jan Mulder carried out immunohistochemistry studies with animal tissue; Ivone Gomes carried out Western blot analysis and signalling assays with the assistance of Raphael Rozenfeld and Emeline Maillet; Ittai Bushlin carried out ELISA assays with MNTB and RVM membranes; Maribel Lim carried out reverse transcription polymerase chain reaction studies; Dr. Catherine M. Cahill, Dr. Tibor Harkany, and Dr. Lakshmi A. Devi prepared the final manuscript based on data in this chapter. Lihua Xue assisted with DRG neuronal cultures in Chapter 3. Maggie Li, Linsey Wilson, Priscilla Orellana, and Nancy Tang assisted with the behavioural experiments in Chapter 5. iv Acknowledgements Thank you so much to everyone, especially Cathy. Now turn the page and let’s talk science. v Table of Contents Abstract ............................................................................................................................................ ii Co-Authorship ................................................................................................................................ iv Acknowledgements .......................................................................................................................... v List of Figures .................................................................................................................................. x List of Tables ................................................................................................................................. xii List of Abbreviations .................................................................................................................... xiii Chapter 1 Introduction: Molecular Perspectives for mu/delta Opioid Receptor Heteromers as Distinct, Functional Receptors .................................................................................................... 1 1.1 Introduction and Historical Perspective ................................................................................. 1 1.2 Formation ............................................................................................................................... 5 1.2.1 Molecular Nature of Mu-Delta Interaction ..................................................................... 5 1.2.1.1 Computational .......................................................................................................... 5 1.2.1.2 Experimental Disruption .......................................................................................... 7 1.2.2 Coexpression of MOR and DOR .................................................................................... 9 1.2.3 Induction of M/DOR Formation ................................................................................... 11 1.2.4 Subcellular Location of Formation ............................................................................... 12 1.3 Outwards Trafficking ........................................................................................................... 13 1.3.1 Protein Chaperone ......................................................................................................... 13 1.3.2 Perspective from DOR Results ..................................................................................... 14 1.4 Function ............................................................................................................................... 16 1.4.1 Surface Expression ........................................................................................................ 17 1.4.2 Ligand Binding ............................................................................................................. 18 1.4.2.1 M/DOR-Active Ligands ......................................................................................... 20 1.4.2.2 M/DOR Specific/Selective Ligands ....................................................................... 20 1.4.2.3 Ligand Combinations ............................................................................................. 25 1.4.2.4 Bivalent Ligands .................................................................................................... 27 1.4.3 Downstream Coupling .................................................................................................. 29 1.5 Inwards Trafficking ............................................................................................................. 32 1.6 Conclusions and Outlooks ................................................................................................... 38 1.7 Research Statement and Objectives ..................................................................................... 40 Chapter 2 Increased Abundance of Opioid Receptor Heteromers After Chronic Morphine Administration .......................................................................................................................... 43 vi 2.1 Introduction .......................................................................................................................... 43 2.2 Materials and Methods ......................................................................................................... 45 2.2.1 Cell culture and transfection ......................................................................................... 45 2.2.2 Subtractive immunization ............................................................................................. 45 2.2.3 Generation of polyclonal antibodies ............................................................................. 46 2.2.4 Membrane preparation .................................................................................................. 46 2.2.5 ELISAs .......................................................................................................................... 46 2.2.6 Binding assays .............................................................................................................. 47 2.2.7 GTP-γ-S binding assays ................................................................................................ 47 2.2.8 Adenylyl cyclase assays ................................................................................................ 47 2.2.9 Gαi16-facilitated Ca2+ release ..................................................................................... 47 2.2.10 Immunoprecipitation and Western blotting
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