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Aromatase Inhibitors Produce Hypersensitivity In AROMATASE INHIBITORS PRODUCE HYPERSENSITIVITY IN EXPERIMENTAL MODELS OF PAIN: STUDIES IN VIVO AND IN ISOLATED SENSORY NEURONS Jason Dennis Robarge Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Doctor of Philosophy in the Department of Pharmacology and Toxicology, Indiana University September 2014 Accepted by the Graduate Faculty, of Indiana University, in partial fulfillment of the requirements for the degree of Doctor of Philosophy. ___________________________________ David A. Flockhart, M.D., Ph.D., Chair ___________________________________ Jill C. Fehrenbacher, Ph.D. Doctoral Committee ___________________________________ Rajesh Khanna, Ph.D. ___________________________________ Todd C. Skaar, Ph.D. June 9, 2014 ___________________________________ Michael R. Vasko, Ph.D. ii DEDICATION For Dad iii ACKNOWLEDGEMENTS This scientific endeavor was possible with the support, guidance, and collaboration of many individuals at Indiana University. Foremost, I am grateful for the mentorship of two excellent scientists, Dr. David Flockhart and Dr. Michael Vasko, who encouraged me to pursue scientific questions with thoughtful ambition. For the rest of my scientific career, I will always ask two critical questions: “What’s the clinical impact?” and “What’s the question?”. I am also equally thankful for the friendship and mentorship of many members of the Vasko lab family. I enjoyed so many enlightening conversations about scientific and non-scientific matters alike with Dr. Djane Duarte, Dr. Ramy Habashy, Behzad Shariati, and others. I thank Dr. Todd Skaar, Dr. Rajesh Khanna, and Dr. Jill Fehrenbacher for their encouragement and fair critique as members of my committee. I would especially like to thank my family. To my parents, who provided me with every opportunity to pursue higher education and were unwavering in their support and confidence in me. Dad would be unquestionably proud and content with this accomplishment. To my wife, Tami, for her love, support, and patience, and her insistence in leading a balanced life. Somehow, in the middle of it all, we’ve started a wonderful family and I look forward to what lies ahead, as a scientist and as a dad. A special thanks to several agencies for continued financial support throughout my degree. This work was made possible, in part, by a Predoctoral Traineeship Award from the Indiana Clinical and Translational Sciences Institute and a Predoctoral Traineeship Award funded by the Department of Defense Breast Cancer Research Program (W81XWH-10-1-0349). iv Jason Dennis Robarge AROMATASE INHIBITORS PRODUCE HYPERSENSITIVITY IN EXPERIMENTAL MODELS OF PAIN: STUDIES IN VIVO AND IN ISOLATED SENSORY NEURONS Aromatase inhibitors (AIs) are the current standard of care for the treatment of hormone receptor positive breast cancer in postmenopausal women. Nearly one-half of patients receiving AI therapy develop musculoskeletal toxicity that is characterized by joint and/or muscle pain and approximately one-fourth of patients discontinue their therapy as a result of musculoskeletal pain. Since there are no effective strategies for prevention or treatment, insight into the mechanisms of AI-induced pain is critical to improve treatment. However, there are few studies of AI effects in animal models of nociception. To determine whether AIs produce hypersensitivity in animal models of pain, I examined the effects of AI administration on mechanical, thermal, and chemical sensitivity in rats. The results demonstrate that (1) repeated injection of 5 mg/kg letrozole in male rats produces mechanical, but not thermal, hypersensitivity that extinguishes when drug dosing is stopped; (2) administering a single dose of 1 or 5 mg/kg letrozole in ovariectomized (OVX) rats also induces mechanical hypersensitivity, without altering thermal sensitivity and (3) a single dose of 5 mg/kg letrozole or daily dosing of letrozole or exemestane in male rats augments flinching behavior induced by intraplantar ATP injection. To determine whether the effects of AIs on nociceptive behaviors are mediated by activation or sensitization of peptidergic sensory neurons, I determined whether letrozole exposure alters release of calcitonin gene-related peptide (CGRP) from isolated rat sensory neurons and from sensory nerve endings in rat spinal cord slices. No changes in basal, capsaicin-evoked or high extracellular potassium- evoked CGRP release were observed in sensory neuronal cultures acutely or chronically v exposed to letrozole. Furthermore, letrozole exposure did not alter the ability of ATP to augment CGRP release from sensory neurons in culture. Finally, chronic letrozole treatment did not augment neuropeptide release from spinal cord slices. Taken together, these results do not support altered release of this neuropeptide into the spinal cord as mediator of letrozole-induced mechanical hypersensitivity and suggest the involvement of other mechanisms. Results from this dissertation provide a new experimental model for AI-induced hypersensitivity that could be beneficial in delineating mechanisms mediating pain during AI therapy. David A. Flockhart, M.D., Ph.D., Chair vi TABLE OF CONTENTS LIST OF TABLES ....................................................................................................... xii LIST OF FIGURES ..................................................................................................... xiii LIST OF ABBREVIATIONS ........................................................................................ xv INTRODUCTION ........................................................................................................ 1 Aromatase ........................................................................................................... 2 Discovery and biochemistry of aromatase .................................................... 2 Contribution of aromatase activity to tissue estrogen concentrations ............ 7 Aromatase inhibitors ............................................................................................ 9 Rationalization, discovery, and development of AIs as breast cancer therapies ....................................................................................................... 9 Pharmacology of third-generation AIs: exemestane and letrozole................. 10 Aromatase inhibitor-induced musculoskeletal symptoms (AIMSS) ....................... 13 Detection and measurement of AIMSS ......................................................... 13 Common symptoms, their severity and frequency ........................................ 16 Objective evaluation of joints in patients receiving aromatase inhibitors ....... 17 AI-induced musculoskeletal symptoms reduce compliance........................... 20 Clinical predictors and factors associated with aromatase inhibitor- induced musculoskeletal symptoms .............................................................. 21 Demographic and other clinical factors that influence risk of musculoskeletal toxicity ......................................................................... 21 Germline genetic variation ..................................................................... 25 Inflammation .......................................................................................... 26 Reduced bone mineral density............................................................... 27 Estrogen depletion ................................................................................. 28 vii Summary ............................................................................................... 30 Estrogen deficiency and animal models of pain ................................................... 31 The ovariectomized (OVX) rat ...................................................................... 32 Aromatase inhibitor treatment ....................................................................... 36 Sensory neurons ................................................................................................. 38 General anatomy and physiology.................................................................. 38 Molecular classification ................................................................................. 40 Estrogen receptors ................................................................................ 40 Transient receptor potential cation channel subfamily V member 1 (TRPV1) ................................................................................................ 42 Calcitonin gene-related peptide (CGRP) ................................................ 43 Purinergic receptors ............................................................................... 45 Aromatase ............................................................................................. 48 Sensory neuron cultures from the dorsal root ganglia ................................... 50 Summary and Research Aims ............................................................................. 53 MATERIALS AND METHODS .................................................................................... 54 Animals ............................................................................................................... 54 Chemicals and other materials ............................................................................ 55 Drug administration ............................................................................................. 57 Behavioral testing ...............................................................................................
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