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The Role of Substance P in Opioid Induced Reward Item Type text; Electronic Dissertation Authors Sandweiss, Alexander Jordan Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 02/10/2021 14:53:26 Link to Item http://hdl.handle.net/10150/621568 THE ROLE OF SUBSTANCE P IN OPIOID INDUCED REWARD by Alexander J. Sandweiss __________________________ Copyright © Alexander J. Sandweiss 2016 A Dissertation Submitted to the Faculty of the DEPARTMENT OF PHARMACOLOGY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 2016 1 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Alexander J. Sandweiss, titled The Role of Substance P in Opioid Induced Reward and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy. _______________________________________________________________ Date: June 13, 2016 Edward D. French, Ph.D. _______________________________________________________________ Date: June 13, 2016 Rajesh Khanna, Ph.D. _______________________________________________________________ Date: June 13, 2016 Victor H. Hruby, Ph.D. _______________________________________________________________ Date: June 13, 2016 Naomi Rance, M.D., Ph.D. _______________________________________________________________ Date: June 13, 2016 Todd W. Vanderah, Ph.D. Final approval and acceptance of this dissertation is contingent upon the candidate’s submission of the final copies of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. __________________________________________ Date: June 13, 2016 Dissertation Director: Todd W. Vanderah, Ph.D. 2 STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of the requirements for an advanced degree at the University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that an accurate acknowledgement of the source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his or her judgment the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author. SIGNED: Alexander J. Sandweiss 3 ACKNOWLEDGEMENTS The following text would not exist without the support of many individuals. First, Dr. Todd Vanderah, who offered me a position in the lab as an undergraduate while I attempted to figure things out about life and my future. On the same track as every other premed, I joined the lab to help myself get into medical school-- and maybe learn a few things along the way. It didn’t take long while working in this lab before I switched gears and deeply considered a career as a Ph.D. The science was fascinating. The process of asking the right questions and knowing how to answer them was intriguing. Watching the critical thinking unfold in others was awe-inspiring. All the cool stuff in the lab had this nerd hooked: I was going to be a scientist. But the prospect of not seeing patients and having a direct influence in their care bothered me. This naïve undergrad pondered how one could combine two careers into one. Dr. Vanderah lent a great deal of effort and time to help me reach my goals, starting with acceptance into medical school via the MD/Ph.D. program. It was easy to see why every single student in medical school likes Dr. Vanderah. He is inviting. He loves to teach, and he loves seeing the “ah-ha!” moment. He is non-judgmental. And he knows the brain! I hope one day, in my future career as a physician- scientist, professor, and mentor, I can be half as well-respected as Dr. Vanderah. This text likewise would not exist if it weren’t for Dr. Tally Largent-Milnes. As an undergrad, I contacted her (then Tally) and asked if she could help me find a lab to join, since she was my sister’s college roommate and good friend (now 4 great family friend). She had me in the lab by the end of the week and told me about these great peptides she was characterizing to inhibit pain. I asked “what the heck is a peptide?” She has seen me grow into the medical student and Ph.D. student I have become, and I have seen her grow into the magnificent scientist and mentor she has become. Thank you Tally; I wouldn’t be in the extremely lucky position I’m in without you. The members of my committee, Dr. Naomi Rance, Dr. Raj Khanna, Dr. Ed French, and Dr. Victor Hruby, have been extraordinarily helpful along the way. They have all provided great wisdom, sometimes scientific, sometimes philosophical. I have realized how important BOTH are to the success of a Ph.D. and M.D. After all, it’s called a ‘Doctor of Philosophy’ for a reason. The M.D./Ph.D. program director, Dr. Kenneth Ramos, has been instrumental in my success as well. He has asked extremely pertinent question regarding my project, helped with my NIH grant application, and has done a superb job reinvigorating the program here at the University of Arizona. The following text describes one of four major projects I spent much of my time participating in during my Ph.D. The other three major projects I worked on relate to migraine, conducting a clinical pilot study, and traumatic brain injury. The migraine project has come a long way; it was my first project in the lab as an undergraduate working with the now Dr. David Skinner. In addition, the TBI project was a very relevant/exciting project that I knew I wanted to be a part of to gain additional experience in the neurosciences, learn new scientific techniques, 5 and begin the networking process with those on the other side: the physicians. Dr. Bellal Joseph and Dr. Kareem Ibraheem have helped in my development into a physician-scientist more than they probably know. The pilot clinical study is related to my thesis written here. It would have fit nicely into this manuscript, but just as clinical research has gone for decades, we haven’t been able to recruit enough patients just yet. This is a critical skill I have learned from Dr. Kai Schoenage in the Department of Anesthesiology; a necessary component of my training as a physician-scientist that I would not have otherwise received. Thank you to each of you. I would like to acknowledge all of the other students in the Vanderah lab, past and present, graduate, undergraduate, and medical students. Dr. Kat Hanlon, Dr. Alysia Ondoua, Dr. Ashley Simons, Dr. Lauren Slosky, Warren Wang, Shaness Grenald, Karissa Cottier and Hong Zhang, all who will make excellent scientists as they complete their degrees. Dr. Aswini Giri has been a great friend and colleague to have in the chemistry department. The first undergraduate to help me on my project was Martin Faridian. He is now finishing up pharmacy school and will make an outstanding pharmacist. Likewise, Jackie Hu and Saul Ortega are finishing up their pharmacy degrees and Josh Stark provided vital assistance. Dr. Alex Podolsky is on his way to becoming an excellent neurologist at the prestigious University of Michigan. Mary McIntosh has been the most helpful undergraduate student to grace a lab. Her tireless 6 work ethic and devotion to doing good for the world will make her an outstanding doctor one day. Of course I wouldn’t have gotten through this phase in my life without my family. My mom, dad, Rebecca, Joshy-poo (supplied the Fruigees), Howie, and the lovely Dr. Dana McKee have pushed me and supported me along the way. Fruigees will be a household name soon and Dana will make an awesome Ob/Gyn, delivering babies tirelessly for the next 4 years. 7 DEDICATION This manuscript is dedicated to my grandparents. My late grandmother Jan Hyman was one of the kindest people I ever knew. She has a lasting impression on me with her gratitude, selflessness, and warm personality. She cared so much about her grandchildren and the future they would have. She died in 2005 when I was sixteen. The last thing she said to me--while on high dose morphine-- was “your skin hasn’t cleared up yet!” It’s cleared up now grandma, I promise. My grandpa Ed couldn’t wait until I was 13 so he could take his first son/grandson to the shooting range to teach me how to aim and shoot a 0.22. I’ve had my sights on the target ever since. My dad’s dad died before I had the chance to meet him but I’m told I get many of my superficial traits including my left-handedness and musicality from him. That was very right of him. My Bubbe is a super-grandma. She has so many grandchildren and now great grandchildren I don’t know how she keeps up with all of it. She’s constantly calling her children, grandchildren, and greatgrandchildren to hear what’s up. She suffers from a painful hip, one of the things that drives me in this field.
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