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Investigating Interactions Between Mu and Delta Opioid Receptors Using Bifunctional Peptides

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Investigating Interactions Between Mu and Delta Opioid Receptors Using Bifunctional Peptides INVESTIGATING INTERACTIONS BETWEEN MU AND DELTA OPIOID RECEPTORS USING BIFUNCTIONAL PEPTIDES by Lauren C. S. Purington A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Pharmacology) in The University of Michigan 2011 Doctoral Committee: Professor John R. Traynor, Chair Professor Stephen K. Fisher Professor Henry I. Mosberg Professor James H.Woods © Lauren C. S. Purington 2011 Dedication For Bompa ii Acknowledgements First, I would like to thank my mentor Dr. John Traynor for his direction and help in training me as a pharmacologist. He has patiently assisted me in learning to develop hypotheses, write manuscripts, and present results to the department and other scientists. I would also like to thank my co-mentor Dr. Hank Mosberg. I have enjoyed our semi-weekly meetings and appreciate his guidance and unwavering support in my project. I thank him for providing insightful comments and ideas for peptide synthesis. I also acknowledge the other members of my thesis committee: Dr. Steve Fisher and Dr. Jim Woods, who have given invaluable advice, comments, and suggestions in developing my project. I thank all the members of the Traynor and Mosberg labs, both past and present, for their scientific help and creating a positive work environment. Specifically, I acknowledge Jessica Anand, Dr. Emily Jutkiewicz, Dr. Kate Kojiro, Dr. Ira Pogozheva, Jasmine Schimmel, and Hui-fang Song for technical assistance and collaborative efforts on many experiments. I gratefully acknowledge undergraduate students Christopher Dolan, Joanna Gross, and Aleksandra Syrkina, all of whom contributed to projects for this thesis and other work. I give special thanks to Erica Levitt and Jennifer Lamberts, who have been fantastic friends. I would also like to acknowledge the support and training I have received, including training grants from the Department of Neuroscience and the University of Michigan Substance Abuse Research Center, as well as funding from National Institutes of Health grants to both the Traynor and Mosberg labs. Finally, I would like to thank my husband Jacob who has given unwavering support and encouragement throughout this period. I am forever indebted to him. I am also extremely grateful to my family and friends, without whom I could not have completed my graduate studies. iii Table of Contents Dedication ....................................................................................................................... ii Acknowledgements ........................................................................................................ iii List of Figures ................................................................................................................ vi List of Tables ............................................................................................................... viii List of Abbreviations ..................................................................................................... ix Abstract ........................................................................................................................... x Chapter I.......................................................................................................................... 1 Introduction ..................................................................................................................... 1 Opioids and Opioid Receptors .................................................................................... 1 Theories of tolerance development ............................................................................. 3 Role for the δ opioid receptor in modulating μ receptor-induced tolerance and dependence development ............................................................................................ 6 Development of multi-functional ligands as tools to investigate interactions between opioid receptors ......................................................................................................... 10 Hypothesis and Objectives ........................................................................................ 13 Chapter II ...................................................................................................................... 18 Inhibition of acute morphine tolerance and dependence by the delta antagonist naltrindole ..................................................................................................................... 18 Summary ................................................................................................................... 18 Introduction ............................................................................................................... 19 Results ....................................................................................................................... 21 Discussion ................................................................................................................. 25 iv Materials and Methods .............................................................................................. 27 Chapter III ..................................................................................................................... 37 Pentapeptides displaying mu opioid receptor agonist and delta opioid receptor partial agonist/antagonist properties ........................................................................................ 37 Summary ................................................................................................................... 37 Introduction ............................................................................................................... 37 Results ....................................................................................................................... 40 Discussion ................................................................................................................. 44 Materials and Methods .............................................................................................. 46 Chapter IV ..................................................................................................................... 57 Development and in vitro characterization of a novel bifunctional mu agonist/delta antagonist opioid tetrapeptide ....................................................................................... 57 Summary ................................................................................................................... 57 Introduction ............................................................................................................... 57 Results ....................................................................................................................... 60 Discussion ................................................................................................................. 63 Materials and Methods .............................................................................................. 65 Chapter V ...................................................................................................................... 77 Discussion and Future Directions ................................................................................. 77 Overview ................................................................................................................... 77 Role for the δ receptor in modulating μ receptor-induced tolerance: Interactions between receptors ...................................................................................................... 78 Structural Components of Efficacy: Development of multi-functional ligands as tools to investigate interactions between opioid receptors ....................................... 84 Overall summary and significance ............................................................................ 89 References ..................................................................................................................... 94 v List of Figures Figure 1.1 Long-term exposure of mice to the μ agonist morphine produces a significant increase in EC50 for the drug over saline-treated control animals. ................................... 15 Figure 1.2 Potential mechanisms whereby heterodimerization can prevent μ agonist- induced tolerance. ............................................................................................................. 16 Figure 1.3 Schematic representation of different bifunctional ligands. ............................ 17 Figure 2.1: Morphine antinociception in the hot plate assay. ........................................... 33 Figure 2.2. Withdrawal precipitated with 10 mg/kg naltrexone (s.c.) 4 h after morphine exposure. ........................................................................................................................... 34 Figure 2.3. [35S]GTPγS binding in mouse brainstem membranes ex vivo is decreased when measured in brainstem homogenates harvested 4 h after a single in vivo injection of 32 mg/kg morphine (i.p.) .................................................................................................. 35 Figure 2.4. Loss in high-affinity μ receptor expression (labeled with [3H]DAMGO) in brainstem membranes prepared 4 h after in vivo treatment of mice with a single injection of 32 mg/kg morphine (i.p.). ............................................................................................. 36 Figure 3.1: Modeling
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