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Mechanisms of Peripheral Sensitization in Inflammatory Knee Pain

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Mechanisms of Peripheral Sensitization in Inflammatory Knee Pain Mechanisms of Peripheral Sensitization in Inflammatory Knee Pain Dissertation submitted for the degree of Doctor of Philosophy Sampurna Chakrabarti Department of Pharmacology Corpus Christi College, University of Cambridge December, 2019 I. Preface This thesis is the result of my own work and includes nothing which is the outcome of work done in collaboration except as declared in the Preface and specified in the text. All work presented was carried out at the Department of Pharmacology, University of Cambridge between October 2016 and November 2019. Some pilot data were obtained at the European Molecular Biology Laboratory, Rome, Italy. All other collaborations are detailed in the thesis, and the findings that resulted from such collaborations qualified by the pronoun “we” where appropriate. It is not substantially the same as any that I have submitted, or, is being concurrently submitted for a degree or diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. I further state that no substantial part of my dissertation has already been submitted, or, is being concurrently submitted for any such degree, diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. This thesis also adheres to the word limit of 60,000 not including the references. Part of the work has been published (or is in pre-print) as follows: Chakrabarti, S., Jadon, D.R., Bulmer, D.C., Smith, E.St.J., 2019a. Human osteoarthritic synovial fluid increases excitability of mouse dorsal root ganglion sensory neurons: an in-vitro translational model to study arthritic pain. Rheumatology. https://doi.org/10.1093/rheumatology/kez331 Chakrabarti, S., Pattison, L.A., Bhebhe, C.N., Callejo, G., Bulmer, D.C., Smith, E.St.J., 2019b. Sensitization of knee-innervating sensory neurons by tumor necrosis factor-α activated fibroblast-like synoviocytes: an in vitro, co-culture model of inflammatory pain. bioRxiv 791251. https://doi.org/10.1101/791251 Chakrabarti, S., Pattison, L.A., Singhal, K., Hockley, J.R.F., Callejo, G., Smith, E.St.J., 2018. Acute inflammation sensitizes knee-innervating sensory neurons and decreases mouse digging behavior in a TRPV1-dependent manner. Neuropharmacology 143, 49–62. https://doi.org/10.1016/j.neuropharm.2018.09.014 1 II. Acknowledgements This thesis would not have been possible without the kindness and support of my mentors, friends and family. Firstly, massive thanks to Dr Ewan St. John Smith for being the role model supervisor – I truly appreciated the independence of driving multiple projects all the while being supported by his wonderfully prompt intellect. The Smith Lab and later the Smith/Bulmer Lab was also a friendly environment where I formed bonds that I hope will continue beyond this PhD: I was very happy to be the “little grasshopper” to the wise Dr Gerard Callejo, enjoyed the long chats during digging experiments with Luke Pattison and sitting next to the (soon-to-be Dr) Toni Taylor. I would also like to thank my key collaborators Drs Deepak Jadon, David Bulmer, Paul Heppenstall and Frances Henson, each of whom has helped me to grow as a scientist. Beyond collaborators and the lab, my village consisted of incredible friends Young Mi Kwon, Sarianna Tuovinen and Dewi Safitri all of whom were my constant support throughout the last three years. As has been true since 2012, the primary node of this emotional support system was my partner-in-crime Suman Ghosh – our adventures across Europe were something I looked forward/backward to after every rough week in the lab. I was lucky to have been born in a family of academics who empathized with the very unique toils of academic life. I would like to thank my mother, Prof Sampa Chakrabarti (who was more worried about me finishing this thesis than I was) for being the first one to show me that research is fun and my father, Dipankar Chakrabarti, for his support and encouragement in all the diverse topics that I pursued since undergraduate. Furthermore, I am grateful to the Gates Cambridge Trust for generously funding my PhD, during which I had the opportunity to spend a few memorable months in Rome, Italy, thanks to the Department of Pharmacology fieldwork fund, Cambridge Philosophical Society Research fund and Corpus Christi research fund. Additionally, thanks to the Society for Neuroscience and the Wellcome Genome Center for their financial support which helped me to present my work at the Neuroscience Annual meeting 2018 (San Diego, USA) and the Chronic Pain conference 2019 (Hinxton, UK). Finally, I am indebted to my mentees and everyone else who contributed in making this PhD a fulfilling experience. I am grateful to have had the chance to stand on the shoulder of giants. 2 III. Abbreviations 2-AG = 2-arachidonoylglycerol AA = Adjuvant -Ainduced arthritis AAV= Adeno-associated virus ACLT = Anterior cruciate ligament transection ACT = Acceptance and commitment therapy AHP = Afterhyperpolarization AEA = Anandamide AMPA = α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid AIA = Antigen-induced arthritis AS = Ankylosing spondylitis AP = Action potential BCE = Before common era ASIC = Acid-sensing ion channel C21 = Compound 21 BLC = B lymphocyte chemoattractant CBT = Cognitive and behavioral therapy Cav = Voltage-gated Ca2+ channel CDH-11 = Cadherin-11 CD = Cluster of differentiation CE = Commen era CFA = Complete Freund’s adjuvant CGRP = Calcitonin gene-related peptide CIA = Collagen-induced arthritis CNS = Central nervous system COX = Cyclooxygenase CRP = C-reactive protein DALY = Disability adjusted life years DMM = Destabilization of medial meniscus DNA = Deoxyribonucleic acid DREADD = Designer receptors exclusively activated by designer drugs DRG = Dorsal root ganglion ECS = Extracellular solution EMBL = European Molecular Biology ESR = Erythrocyte sedimentation rate Laboratory EULAR = European League Against FB = Fast Blue Rheumatism FLS = Fibroblast-like synoviocytes GABA = -amino butyric acid GBD = Global burden of disease GCSF = Granulocyte colony stimulating factor GECI = Genetically encoded calcium indicator GEVI = Genetically encoded voltage indicator GluCl = Glutamate-gated chloride channel GM-CSF = Granulocyte-macrophage colony stimulating factor GPCR = G protein-coupled receptors HA = Hyaluronic acid 3 HCN = Hyperpolarization activated cyclic HPD = Half peak duration nucleotide gated ion channel HSV = Herpes simplex virus IASP = International Association for the Study of Pain IF = Interferon IL = Interleukin IP3 = Inositol 1,4,5-trisphosphate receptors iPSC = Induced pluripotent stem cells I-TAC = interferon inducible T-cell apha KC = Keratinocyte chemoattractant chemoattractant protein Kv = Voltage-gated K+ channel L = Lumbar LIX = Lipopolysaccharide induced chemokine LMIC = Low to middle economic countries LPS = Lipopolysaccharide MCP = Monocyte chemoattractant protein MCSF = Macrophage colony stimulating MIA = Monoiodoacetate-induced arthritis factor MIG = Monokine-induced by gamma MIP = Macrophage inflammatory protein interferon MMP = Matrix metalloprotease MS = Mass spectrometry NA = Not applicable Nav = Voltage-gated Na+ channel NGF = Nerve growth factor NMDA= N-methyl-D-aspartate NO = Nitric oxide NSAID = Non-steroidal anti-inflammatory drugs OA = Osteoarthritis P = Passage PAD = Primary afferent depolarization PAG = Periaqueductal grey PAM = Pressure application measurement PBS = Phosphate buffered saline PFA = Paraformaldehyde PG = Prostaglandin PGIA = Proteoglycan induced arthritis PKC = Protein kinase C PNS = Peripheral nervous system q/PCR = Quantitative polymerase chain reaction RA = Rheumatoid arthritis RANTES = Regulated on activation, normal T cell expressed and secreted RhF = Rheumatoid factor RMP = Resting membrane potential 4 RNA = Ribonucleic acid RT = Reverse transcriptase S = Sustained current SCID = Severe combined immunodeficiency SDF = Stromal cell derived factor SF = Synovial fluid TCA = T cell activation gene TDAG8 = T cell death associated gene TECK = Thymus expressed chemokine TGF = Transforming growth factor THIP = 4,5,6,7-tetrahydroisoxazolo[5,4- TIMP = Tissue inhibitor of metalloproteinase c]pyridin-3-ol hydrochloride TNF = Tumor necrosis factor TrkA = Tropomyosin receptor kinase A TRP = Transient receptor potential TS = Transient + sustained current VAS = Visual analog score 5 IV. Summary Arthritis affects millions of people and costs billions to the global economy with painful, inflamed joints being the major clinical symptoms. Knee joints are innervated by the distal ends of dorsal root ganglion (DRG) neurons and hyperexcitability of knee-innervating DRG neurons (knee neurons), through a process called peripheral sensitization, underlies arthritic knee pain. My research goal was to elucidate the mechanisms of knee neuron peripheral sensitization by developing and utilizing several in vitro and in vivo disease models. Since experimental animal models of arthritis do not fully recapitulate the human disease, I developed a novel, in vitro translational model of arthritic pain by incubating mouse knee neurons with human synovial fluid obtained from osteoarthritic patients. Results from this disease model provide proof-of-concept that synovial fluid is a key modulator of arthritic pain. In order to reconcile the behavioral and neural correlates of arthritic pain, I utilized the mouse model of complete Freund’s adjuvant
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