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Exploring the Glial Mechanisms Underlying Central Neuropathic Pain in a Novel Rat Model of Spinal Cord Injury

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Exploring the Glial Mechanisms Underlying Central Neuropathic Pain in a Novel Rat Model of Spinal Cord Injury i Exploring the Glial Mechanisms Underlying Central Neuropathic Pain in a Novel Rat Model of Spinal Cord Injury by Amanda Lynne Ellis B.A., University of Colorado, 2006 M.A., University of Colorado, 2011 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirement of the degree of Doctor of Philosophy Department of Psychology and Neuroscience 2014 ii This thesis entitled: Exploring the Glial Mechanisms Underlying Central Neuropathic Pain in a Novel Rat Model of Spinal Cord Injury written by Amanda Lynne Ellis has been approved for the Department of Psychology and Neuroscience ___________________________________ Dr. Linda Watkins ______________________________________________ Dr. Steven Maier ___________________________________________ Dr. Serge Campeau _______________________________________________ Dr. Benjamin Greenwood _______________________________________________ Dr. Michael Stallings Date____________ The final copy of this thesis has been examined by the signatories, and we Find that both the content and the form meet acceptable presentation standards Of scholarly work in the above mentioned discipline iii Abstract Ellis, Amanda Lynne (Ph.D., Psychology and Neuroscience) Glial Mechanisms of Central Neuropathic Pain Thesis directed by Distinguished Professor Linda Watkins Neuropathic pain is a debilitating condition that is usually intractable to treatment. Spinal cord injury (SCI) is the leading cause of central neuropathic pain (CNP), and patients often describe their pain as severe and intolerable. Although most of the focus in the pain literature has been on neurons, it is now well known that non-neuronal cells of the central nervous system called microglia and astrocytes (herein referred to as “glial cells” or “glia”) play a key role in the induction and maintenance of neuropathic pain. Glia are immune cells that are normally in a surveying/quiescent state, but upon activation by an inflammatory stimulus, they release a host of proinflammatory mediators that can sustain neuropathic pain for weeks, months, and even years. Interestingly, glia can also release anti-inflammatory mediators, making them ideal for therapeutic targeting. The glial mechanisms underlying CNP have not been fully explored and understood, and Chapter II is a set of studies undertaken to determine the involvement of glia in a novel rat model of thoracic-13/lumbar-1 (T13/L1) dorsal root avulsion SCI termed Spinal Neuropathic Avulsion Pain (SNAP). SNAP induced a robust, reliable, long-lasting below-level hind paw allodynia that was reversed by 3 different glial activation inhibitors. These studies confirmed that glia are involved in the mechanism underlying SNAP and that use of therapies that target glial cells could provide a better route for treating CNP. The studies in Chapter III determined that CNP could be attenuated by a single injection of an adenosine A2A receptor agonist for at least 6 weeks. This attenuation is due to a decrease in glial activation and proinflammatory cytokine expression, and at least in part dependent on the anti-inflammatory cytokine IL-10. The studies in Chapter IV detail a phenomenon in which administering opioids iv shortly after SNAP increases the magnitude of allodynia and potentiates the expression of proinflammatory mediators. This mechanism is at least in part dependent on toll-like receptor 4 and the proinflammatory cytokine IL-1β. The evidence from this dissertation suggests that glial cells are critically involved in the mechanisms underlying CNP, and that they can be manipulated to attenuate or potentiate CNP depending on their microenvironment and pattern of receptor activation. v Dedication This dissertation is dedicated to my true love, soul mate, and husband Shane Michael, my other half and beautiful sister Anjelica “Jeli” Ellis, my wonderful parents Ben and Jeanne Ellis, my amazing grandma Jeannette Veltrie, my furry four legged children Shelby and Iacocca (Cocca), and to all the rats, especially Sneezy. vi Acknowledgments I would first like to thank my mentors Linda Watkins and Steve Maier. I am honored to have been a graduate student under you, and I couldn’t imagine having a better mentor. Linda, you have taught me so much and push me to be a better scientist every day. You care about me not just as a scientist, but as a person, and I will be forever grateful to have been a part of your lab. Thank you to my committee: Linda, Steve, Serge, Ben, and Mike for taking the time out of your busy lives and schedules to mentor me through this process. I would like to also thank my post-doc mentors Lisa Loram, Khara Ramos, Peter Grace, and especially Julie Wieseler. I must of course give a shout out to all my fellow grad students and lab mates who have been on this journey with me, especially my office mate Mike Weber who had to put up with everything from me buying a house, getting married, and writing my dissertation, and “Friend” Alexis Northcutt without whom there is NO WAY I would have gotten through grad school without. Last but not least I want to thank my husband and family. You have all been there with me from the beginning and have whole-heartedly supported me and showered me with love. There was never any doubt in my mind that I could do this because you all told me I could! I love you so very much Shane, Jeli, Mom, Dad, and Grammy Bear! vii Table of Contents Title Page .......................................................................................................................................... i Signature Page ................................................................................................................................. ii Abstract........................................................................................................................................... iii Dedication ........................................................................................................................................ v Acknowledgements ....................................................................................................................... vi List of Tables ................................................................................................................................... ix List of Figures ................................................................................................................................... x Chapter I: Introduction .................................................................................................................... 1 Preface ................................................................................................................................................. 1 The Role of Glia in Pain Processing ............................................................................................. 4 Non-pathological pain processing ...................................................................................... 4 Pathological pain processing in neurons and glia ............................................................... 5 Similarities and differences between peripheral and central neuropathic pain ................. 8 Glial activation in central neuropathy ................................................................................ 9 Glial activation and inflammation in spinal cord injury (SCI) ............................................. 9 Targeting glia for treating central neuropathic pain ........................................................ 11 Glia and Adenosine Signaling .................................................................................................... 14 Adenosine signaling .......................................................................................................... 14 Role of A2AR in SCI ............................................................................................................. 16 IL-10 and alternative activation ........................................................................................ 16 Glia and the Immune System ..................................................................................................... 19 Glia as immune cells ......................................................................................................... 19 TLR4 signaling ................................................................................................................... 20 Cytokine processing and inflammasomes ......................................................................... 22 Theoretical Considerations and Thesis Overview .................................................................... 24 Chapter II: Systemic Administration of Propentofylline, Ibudilast, and (+)-Naltrexone Each Reverses Mechanical Allodynia in Novel Rat Model of Central Neuropathic Pain ....................... 28 Abstract .......................................................................................................................................... 28 Introduction ................................................................................................................................... 29 viii Materials and Methods .................................................................................................................. 30 Results ............................................................................................................................................ 36 Discussion ......................................................................................................................................
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