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Truncated Mu Opioid Receptor Splice Variants As Targets for Powerful Pain Relief with Reduced Side Effects

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Truncated Mu Opioid Receptor Splice Variants As Targets for Powerful Pain Relief with Reduced Side Effects TRUNCATED MU OPIOID RECEPTOR SPLICE VARIANTS AS TARGETS FOR POWERFUL PAIN RELIEF WITH REDUCED SIDE EFFECTS A Dissertation Presented to the Faculty of the Weill Cornell Graduate School of Medical Sciences in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Steven G. Grinnell August 2015 © 2015 Steven G. Grinnell TRUNCATED MU OPIOID RECEPTOR SPLICE VARIANTS AS TARGETS FOR POWERFUL PAIN RELIEF WITH REDUCED SIDE EFFECTS Steven G. Grinnell, Ph.D. Cornell University, 2015 Relief from pain is a major goal of all branches of medicine, and poorly controlled pain is associated with substantial economic and human burden. Mu opioid receptors are targets for strong pain relief, mediating the analgesia of widely used analgesic drugs like morphine, hydrocodone, oxycodone, methadone, and fentanyl. Unfortunately, these drugs are associated with numerous side effects such as constipation, respiratory depression, physical dependence, abuse, and addiction. The mu opioid receptor gene undergoes extensive alternative splicing, although the physiological relevance of many of these splice variants is only now becoming clear. In particular, some of these splice variants produce truncated receptors possessing only 6 transmembrane domains, short of the canonical 7 transmembrane domain structure conserved across the G-protein coupled receptor superfamily. Initial studies suggested that these receptors were expressed in low levels relative to full length variants, and could not bind mu agonist drugs when they were transiently expressed in cell lines, calling into question their importance in opioid receptor pharmacology. Here, we show that these truncated receptors are in fact targets for a new pain reliever, IBNtxA, which is a potent pain reliever in mice and rats, yet exhibits a dramatically improved side effect profile over current clinically-used mu analgesics. IBNtxA shows only mild constipation, does not depress respiration or produce physical dependence, and shows neither rewarding nor aversive behavior in a conditioned place preference assay. We also examined the pharmacology and regional distribution of this target in rat brain using a radioiodinated form of the drug. Photoaffinity labels based on the structure of IBNtxA were also synthesized and characterized, and we present evidence consistent with the labeling of truncated mu opioid receptor splice variants in mouse brain. Other pain relievers were also found to require these truncated receptors for their analgesic effects, such as the clinically used opioid buprenorphine, as well as kappa 1 agonists and clinically used alpha 2 agonists. Importantly, dose- or use-limiting side effects for each of these drugs were found to be present in knockout animals lacking the truncated splice variant isoforms, suggesting that the desired analgesic properties can be separated from their unwanted side effects. BIOGRAPHICAL SKETCH Steven Grinnell graduated from Hampshire College in 2007 with a concentration in Neuroscience, writing an undergraduate thesis entitled “CB1 and Mu Opioid Receptor Oligomerization: A Literature and FRET Study” under advisors Dr. Christopher Jarvis and Dr. Cynthia Gill. After his undergraduate studies, he worked as a post-baccalaureate IRTA fellow at the National Institute of Drug Abuse in the laboratory of Dr. Roy Wise, in collaboration with Dr. Greg Elmer of the University of Maryland at Baltimore at the Maryland Psychiatric Research Center. In 2008, Dr. Grinnell joined the doctoral program in Neuroscience at the Weill Cornell Graduate School of Medical Sciences where did his thesis research under Dr. Gavril Pasternak, Anne Burnett Tandy Chair of Neurology at Memorial Sloan Kettering Cancer Center. Dr. Grinnell received a Predoctoral Fellowship in Pharmacology from the PhRMA Foundation in 2012, and has received travel awards to present work at the 2013 and 2014 Experimental Biology conferences from the American Society for Pharmacology and Experimental Therapeutics. He was also invited to present work at the 2012 NIDA/INSERM Workshop on US-France collaboration on Drug Abuse and Addiction Research. iii To Parker and Saoirse, I love your questions. iv ACKNOWLEDGMENTS Thank you to all the teachers I’ve had over the years that fostered my curiosity: Mrs Breton, Mrs. Lewis, and Mrs. Topolski, Mrs. Lambrose, Mr. Carwile, and Mr. Battaglia. Special thanks to Artie Cruz for both friendship and a push toward rigor, and Mr. Ambler who gave me a solid foundation in biology. To Dr. Lynn Miller, who let me in his overfull Jan term class that got me my first lab experience; Dr. Phil Kelleher for countless conversations, mentorship, and extensions to flesh out last-minute breakthroughs; and Dr. Chris Jarvis and Cynthia Gill for guidance through Div III and career choices. Thank you to the institutions that supported my love of learning, career ambitions, and research – Park School, Allendale Columbia, the Gifted Math Program at SUNY Buffalo, and Hampshire College, as well as the Society for Neuroscience, New York Academy of Sciences, and the American Society for Pharmacology and Experimental Therapeutics. Thanks especially to the PhRMA Foundation for the predoctoral fellowship that supported me and my research, and NIDA, for my post-baccalaureate fellowship and grants to Dr. Pan, Dr. Majumdar, and Dr. Pasternak. Thank you to Dr. Kazutoshi Nakazawa, who gave me my first job in the lab and Dr. Seiichiro Jinde and Dr. Juan Belforte for their patience as they taught me to work with mice. Thank you to Jeanne Pieper and Dr. Greg Elmer for daily mentorship and teaching me to really understand animal behavior. Thank you to Dr. E.G.D. Cohen for forever altering how I see the world in terms of equilibrium and non-equilibrium states. Thank you to my thesis committee, Dr. Anjali Rajadhyaksha, Dr. Chuck Inturrisi, and Dr. Samie Jaffrey, as well as my examining committee chair Dr. Francis Lee. Each of you gave me invaluable advice along the way and I could not have asked for a better set v of role models in science. Thank you also to Dr. BJ Casey for your perpetual willingness to listen and seemingly limitless energy to help out the students in your charge. Countless thanks to Dr. Gavril Pasternak, my mentor, who taught me to really look at the data, to live with ambiguity, to write and think scientifically; for unforgettable life and career advice; and for giving me the freedom and flexibility to be a part-time stay-at-home dad. I am forever grateful and my time in your lab has been a pleasure and an honor. Thank you to the many wonderful people of the Pasternak Lab over the years. Special thanks go to Dr. Susruta Majumdar, my partner in crime as we worked on the IBNtxA story, who took me under his wing and never stopped being my advocate, and who taught me how to make new drugs when we needed something that didn’t exist. Thank you to Dr. Julie Pickett for productive procrastination and trips to the nether regions of Wikipedia, and Dr. Joel Schrock for great advice throughout the thesis-writing and defense. Thank you to Dr. Lu Zhigang, for the mMOR-1G lentivirus and unstoppable drive. Thank you to Dr. Ying-Xian Pan, for the knockout mice and much help troubleshooting. Thank you to Dr. Takeshi Irie, for invaluable career advice and great conversations. Thank you to Jin Xu, for so much teaching, patience, and help. Thank you to Valerie LeRouzic for somehow always finding the time to lend me a hand, and performing the first U50,488 tail flick assays. Thanks to Joan Subrath for making the precursor to the alkynyl photolabel, for career advice and reaching out to your connections on my behalf. Thank you to Ankita Narayan for numerous truly wonderful conversations surrounded by imaginary proteins and competing signaling models, and for performing PathHunter assays and photolabel competitions. Thank you to Gina Marrone for superhuman productivity, organization, and drive, and for performing the vi i.c.v and i.t. (with Dr. Grace Rossi) studies herein, especially the rescue experiments….you’re next! Thank you to Luis and Yvette Vasquez, and Daniela Vasquez, for bringing me into your family and for watching the kids so I could work or just have a date with my beautiful wife. Thank you to my parents, Keith and Karen Grinnell, for always fighting on my behalf and for the thousands upon thousands of hours driving and waiting they did to make sure I got the best education possible. Thank you for teaching me honesty, integrity, and for valuing family over all. Finally, thank you to my wife Montana Vasquez-Grinnell. None of this would have been possible without your tireless love and support, your unparalleled mental clarity, or our talks that go on late into the night about what and who and where we want to be when we grow up. Thank you for your patience every time I said I just had to run into the lab for something quick and came back hours later, and for raising our children while I was away nights and weekends finishing up. Thank you for not taking any excuses and for making life a wonderful journey to share. vii TABLE OF CONTENTS BIOGRAPHICAL SKETCH ....................................................................................................... iii ACKNOWLEDGMENTS .......................................................................................................... v TABLE OF CONTENTS......................................................................................................... viii LIST OF FIGURES ..................................................................................................................
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