Opioids and Glia: Investigating the Mechanisms through Which Ultra-low Dose Opioid Antagonists Modulate Opioid Tolerance and Hyperalgesia

........................................................................................................................................... ii Co-Authorship ................................................................................................................................ iv Acknowledgements .......................................................................................................................... v List of Figures...................................................................................................x List of Tables..................................................................................................xii List of Abbreviations........................................................................................xiii CHAPTER 1: INTRODUCTION .................................................................................................... 1 1.1.1 Social and Economic Impact of Chronic Pain ......................................................... 1 1.2 Opioid Analgesics ............................................................................................................ 2 1.3 Opioid Tolerance ............................................................................................................. 6 1.3.1 Mechanisms of Opioid Tolerance ............................................................................ 8 1.3.2 Bimodal Theory of Tolerance .................................................................................. 9 1.3.3 Involvement of Spinal Glia in Tolerance ............................................................... 11 1.3.3.1 Glial Activation .................................................................................................. 11 1.3.3.2 Opioid-Induced Glial Activation ....................................................................... 11 1.3.3.3 Gliosis and Opioid Tolerance ............................................................................ 12 1.3.3.4 Inhibition of Gliosis Augments Opioid Tolerance ............................................. 13 1.3.4 TLR4-Induced Gliosis............................................................................................ 14 1.3.4.1 TLR4 Structure & Signaling .............................................................................. 15 1.3.4.2 TLR4 and Opioids .............................................................................................. 17 1.4 ULD Antagonists Attenuate Opioid Tolerance & Hyperalgesia .................................... 18 1.4.1 ULD Antagonists and the Bimodal Theory ........................................................... 18 1.4.2 ULD Antagonists and Filamin A Hypothesis ........................................................ 18 1.4.3 ULD Antagonists and Gliosis ................................................................................ 19 1.5 Research Statement and Objectives ............................................................................... 20 CHAPTER 2: INTRATHECAL CATHETERIZATION INFLUENCES TOLERANCE TO CHRONIC MORPHINE IN RATS ............................................................................................... 22 2.