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GPER/GPR30 ESTROGEN RECEPTOR: A TARGET FOR PAIN MODULATION A Dissertation Submitted to The Temple University Graduate Board In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy By Elena Deliu May, 2012 Examination Committee Members: Dr. Nae J Dun (Advisor), Dept. of Pharmacology, Temple University Dr. Mary E Abood, Dept. of Anatomy and Cell Biology, Temple University Dr. Barrie Ashby, Dept. of Pharmacology, Temple University Dr. Eugen Brailoiu, Dept. of Pharmacology, Temple University Dr. Ellen M Unterwald, Dept. of Pharmacology, Temple University Dr. Hreday Sapru, (External Examiner), Depts. of Neurosciences, Neurosurgery & Pharmacology/Physiology, UMDNJ-NJMS i © 2012 By Elena Deliu All Rights Reserved ii ABSTRACT GPER/GPR30 ESTROGEN RECEPTOR: A TARGET FOR PAIN MODULATION Elena Deliu Doctor of Philosophy Temple University, 2012 Doctoral Advisory Committee Chair: Nae J. Dun, Ph.D. The G protein-coupled estrogen receptor GPER/GPER1, also known as GPR30, was originally cloned as an orphan receptor and later shown to be specifically activated by 17- β-estradiol. This has led to its classification as an estrogen receptor and expanded the perspective on the mechanisms underlying the rapid estrogenic effects reported over the years. GPER is strongly expressed in the central nervous system and peripheral tissues and appears to be involved in a wide variety of physiological and pathological processes. Estrogens are known to alter the processing of nociceptive sensory information and analgesic responses in the central nervous system. Both analgesic and pro-nociceptive effects of estrogens have been reported. Some pro-algesic estrogenic responses have a short latency, suggesting a non-genomic mechanism of action. Immunohistochemical studies in rodents prove the existence of GPER in pain-relevant areas of the nervous system such as dorsal root ganglia, superficial dorsal horn of the spinal cord, periaqueductal gray (PAG), amygdala, trigeminal sensory nucleus and thalamus. In the periphery, activation of GPER results in pro-nociceptive effects. However, GPER involvement in pain processing at central levels is largely unexplored. Thus, the work iii presented in this thesis was aimed at investigating whether GPER modulates nociception at spinal and supraspinal sites. The behavioral response to GPER activation in the spinal cord and PAG was evaluated in an acute grooming test (scratching, biting and licking behavior) and in the hot plate test, respectively. Intrathecal challenge of mice with the GPER agonist G-1 (0.1- 1 nmol) induced a dose-dependent increase in pain-related behaviors, that was abolished by pre-treatment with the GPER antagonist G15 (1-10 nmol), confirming GPER specificity of the response. Likewise, intra-PAG microinjection of G-1 (10-100 pmol) to rats reduced the nociceptive threshold in the hot plate test, an effect that was G15 sensitive. To obtain further insight on the mechanisms involved in the behavioral effects observed in whole animals, we tested the effect of GPER ligands on neuronal membrane 2+ potential, intracellular calcium concentration ([Ca ]i) and reactive oxygen species (ROS) 2+ accumulation. The membrane depolarization and the increases in [Ca ]i and ROS levels are markers of neuronal activation, underlying pain sensitization in the spinal cord and pain facilitation in the PAG. Electrophysiological recordings from superficial dorsal horn and lateral PAG neurons indicate neuronal depolarization upon G-1 application, an effect that was fully prevented by G15 pre-treatment. Both cultured spinal neurons and cultured 2+ PAG neurons responded to G-1 administration by elevating [Ca ]i and mitochondrial and cytosolic ROS levels. In the presence of G15, G-1 did not elicit the calcium and ROS responses. Collectively, these results demonstrate that GPER modulates both the ascending and descending pain pathways to increase nociception via cytosolic calcium elevation and ROS accumulation in spinal and PAG neurons, respectively. These findings broaden the iv current knowledge on GPER involvement in physiology and pathophysiology, providing the first evidence of its pro-nociceptive effects at central levels and characterizing some of the mechanisms involved. Moreover, we show for the first time ROS accumulation downstream of GPER activation, extending the current understanding of GPER signaling. v ACKNOWLEDGEMENTS I have learned a lot as a graduate student in the Department of Pharmacology at Temple University. It has been both a scientific and important life experience that contributed to who I am today. I owe my deepest gratitude to several people that helped me arrive at this moment. I would particularly like to express my thankfulness to Dr. Dun for welcoming me in his lab and for his coordination throughout my research endeavors. I strongly appreciate that he encouraged me to study electrophysiology and also that he supported my research independence. I have benefited a lot from his flexibility, openness to questions, prompt replies and germane observations. I am really grateful for everything he has done for me. It is difficult to overstate my gratitude for all the guidance, ideas and support Dr. E. Brailoiu provided, as well as for all the trust he put in me despite the little research experience I had. He generously shared his expertise, knowledge and enthusiasm and got me involved in several projects. It’s been a tremendous opportunity to work with him and learn so much about the beauty of research. I sincerely thank Dr. Ashby for giving me all the attention I needed at every stage. Throughout these years, he was always available and took his time to answer questions, revise some of the drafts for previous examinations, as well as to attend the rehearsals of my presentations. His suggestions were extremely useful and I truly appreciate all the valuable observations and genuine support he provided. I am very thankful to Dr. Unterwald and Dr. Abood for their insightful comments, very good questions regarding my project and for being so supportive. vi I will not forget my first interaction with Dr. Unterwald and her patience in advising me how to adjust the protocol for the locomotor activity test so that it would fit the timings of other behavioral experiments I was performing at the time. Her attitude allowed me to have a bit more confidence in my reasoning, although I was at a very early stage in my development as a scientist. I am very grateful for that. I also need to thank Dr. Abood for her enthusiasm and generous encouragement. I’m happy to have had the chance to interact with her and other people in her lab; I’ve learned research can often be rather enjoyable than stressful. I would like to thank Dr. Sapru for taking time to serve as an external examiner on my Committee. My special thanks go to Dr. Cristina Brailoiu for being a true prototype of hard work, dedication, generosity and cheerfulness. I have found in her a role model I so much longed to follow and I am truly blessed to have benefited from her friendship and scientific advice. I am very thankful to Dr. Khalid Benamar for helping me complete the behavioral study of GPER involvement in supraspinal pain. He shared his time, chemicals, experimental settings and technical expertise and his contribution has been extremely valuable. I am very appreciative of Dr. Lynn Kirby’s advice in electrophysiology. Her suggestions were priceless and helped me continue my experiments after stalling because of so many technical difficulties. I would also like to thank Dr. Alan Cowan for sharing his mice and observation boxes, which were helpful for learning the intrathecal injection procedure and performing behavioral tests, respectively. vii I would like to thank Dr. J.B. Arterburn and Dr. T.I. Oprea for providing the GPER ligands. I am very thankful to Mary Dun for sharing her immunohistochemical expertise and for so many discussions we’ve had in the lab, which greatly reduced my feeling of loneliness and created a more relaxed atmosphere. Also, lots of thanks to Xin Gao and Xiaofang Huang for helping me with RT-PCR, Western blotting and cell culture, as well as for being such dear presences in the lab and outside the lab. Among the graduate students Fan Yang and Neil Lamarre were my best friends; they have always been there to help and encourage me and I’m happy to express here my heartfelt gratitude towards them. I’ve also benefited from the help of, and the discussions with Nicole Enman, Bonnie Quattrochi, Bogdan Gurzu, Michael Jan and Saadet Inan, and I thank them very much. I am very thankful to the faculty in the Departments of Pharmacology, of Anatomy and Cell Biology, of Microbiology and Immunology and of Biochemistry, for sharing their knowledge and expertise during the courses and seminars at Temple University. I would also like to thank Liz Molina and Lor Hatch for their assistance and general positive attitude. I cannot leave out so many other people that encouraged me to pursue a Ph.D. degree, former Professors, research assistants and colleagues at the “Carol Davila” University of Medicine and Pharmacy in Bucharest and at the University of Iowa. Thank you very, very much! This thesis is dedicated to those very dear ones that supported me wholeheartedly and wiped my tears along the way. viii TABLE OF CONTENTS PAGE ABSTRACT ...................................................................................................................... iii ACKNOWLEDGEMENTS .............................................................................................
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