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Peripheral Regulation of Pain and Itch

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Peripheral Regulation of Pain and Itch Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1596 Peripheral Regulation of Pain and Itch ELÍN INGIBJÖRG MAGNÚSDÓTTIR ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-513-0746-6 UPPSALA urn:nbn:se:uu:diva-392709 2019 Dissertation presented at Uppsala University to be publicly examined in A1:107a, BMC, Husargatan 3, Uppsala, Friday, 25 October 2019 at 13:00 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Faculty examiner: Professor emeritus George H. Caughey (University of California, San Francisco). Abstract Magnúsdóttir, E. I. 2019. Peripheral Regulation of Pain and Itch. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1596. 71 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0746-6. Pain and itch are diverse sensory modalities, transmitted by the somatosensory nervous system. Stimuli such as heat, cold, mechanical pain and itch can be transmitted by different neuronal populations, which show considerable overlap with regards to sensory activation. Moreover, the immune and nervous systems can be involved in extensive crosstalk in the periphery when reacting to these stimuli. With recent advances in genetic engineering, we now have the possibility to study the contribution of distinct neuron types, neurotransmitters and other mediators in vivo by using gene knock-out mice. The neuropeptide calcitonin gene-related peptide (CGRP) and the ion channel transient receptor potential cation channel subfamily V member 1 (TRPV1) have both been implicated in pain and itch transmission. In Paper I, the Cre- LoxP system was used to specifically remove CGRPα from the primary afferent population that expresses TRPV1. CGRPα-mCherrylx/lx;Trpv1-Cre mice had attenuated responses to visceral pain induced by acid, while mechanosensitivity of the colon and somatic pain sensation remained unaffected. Mast cell proteases (MCPs) are stored in high quantities within mast cell (MC) granules and have been linked to both protective and pro-inflammatory properties, but little is known about their exact roles in vivo. In Papers II, IV and V, we used knock-out mice to investigate the contribution of MCs and their MCPs (the chymase mMCP4, tryptase mMCP6 and carboxypeptidase CPA3) in pain resulting from tissue injury, inflammation-induced heat hypersensitivity and different types of itch. Surprisingly, we found that neither MCPs nor MCs were essential for the pain behavior tested (Paper II). Our data indicate that mMCP6 and CPA3 have a protective role in scratching behavior induced by the peptide endothelin-1 (ET-1; Paper IV) and in scratching induced by the MC degranulator compound 48/80 (Paper V), but no differences were observed with the other pruritogens histamine, chloroquine or SLIGRL. In Paper III, we saw that a novel single-stranded oligonucleotide (ssON) attenuated compound 48-induced scratching in BALB/c mice by blocking MC degranulation. ssON could also block degranulation in human MC in vitro and we determined that this was due to ssON interfering with Mas-related G protein-coupled receptor X2 (MRGPRX2), a receptor involved in non-allergic MC degranulation. By better understanding the contribution of individual components of the nervous and immune systems in pain and itch, we hopefully increase the possibilities of developing better treatments for burdensome pain- and itch-related disorders in the future. Keywords: Pain, itch, CGRP, TRPV1, mast cell, mast cell protease, mMCP4, mMCP6, CPA3, endothelin-1, compound 48/80, MRGPRX2, single-stranded oligonucleotide Elín Ingibjörg Magnúsdóttir, Department of Neuroscience, Box 593, Uppsala University, SE-75124 Uppsala, Sweden. © Elín Ingibjörg Magnúsdóttir 2019 ISSN 1651-6206 ISBN 978-91-513-0746-6 urn:nbn:se:uu:diva-392709 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-392709) Til Steinars, Ylfu og Aríu List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Spencer, N. J.*, Magnúsdóttir, E. I.*, Jakobsson, J. E. T., Kestell, G., Chen, B. N., Morris, D., Brookes, S. J., Lagerström, M. C. (2018). CGRPα within the Trpv1-Cre population contributes to visceral nociception. American Journal of Physiology – Gastro- intestinal and Liver Physiology, 314(2), G188-G200. *shared first authorship II Magnúsdóttir, E. I., Grujic, M., Roers, A., Hartmann, K., Pejler G., Lagerström, M. C. (2018). Mouse mast cells and mast cell proteases do not play a significant role in acute tissue injury pain induced by formalin. Molecular Pain, 14, 1-11. III Dondalska, A., Rönnberg, E., Ma, H., Pålsson, S., Magnúsdóttir, E. I., Gao, T., Adam, L., Lerner, E. A., Nilsson, G., Lagerström, M. C., Spetz, A. Amelioration of Mas-related G protein-coupled receptor X2-mediated itch and reduced mast cell degranulation by a single-stranded oligonucleotide. Manuscript. IV Magnúsdóttir, E. I., Grujic, M., Bergman, J., Pejler, G., Lager- ström, M. C. Mouse mast cell tryptase and carboxypeptidase A3 play a protective role in itch induced by endothelin-1. Manu- script. V Magnúsdóttir, E. I., Grujic, M., Pejler, G., Lagerström, M. C. Compound 48/80-induced itch is attenuated by mouse mast cell tryptase and carboxypeptidase A3. Manuscript. Reprints were made with permission from the respective publishers. Additional publications Rogoz, K., Aresh, B., Freitag, F. B., Pettersson, H., Magnúsdóttir, E. I., Larsson Ingwall, L., Haddadi Andersen, H., Franck, M. C., Nagaraja, C., Kullander, K., Lagerström, M. C. (2016). Identification of a neuronal receptor controlling anaphylaxis. Cell Reports, 14(2), 370-379. Contents Introduction ................................................................................................... 11 Background ................................................................................................... 13 The sensory pathways of pain and itch .................................................... 13 Ion channels and receptors in nociception ............................................... 14 Nociception in the gut .......................................................................... 15 Pruriception .............................................................................................. 16 Histaminergic itch ................................................................................ 17 Non-histaminergic itch ........................................................................ 18 A tale of two peptides involved in pain and itch ...................................... 21 Calcitonin gene-related peptide ........................................................... 21 Endothelin-1 ........................................................................................ 22 The effects of CGRP and ET-1 on immune cells ................................ 24 Mast cells.................................................................................................. 27 Mast cell receptor activation ................................................................ 27 Mast cell proteases ............................................................................... 29 Chymase .............................................................................................. 30 Tryptase ............................................................................................... 31 Carboxypeptidase ................................................................................ 31 Monoclonal antibodies against pain and itch ........................................... 34 Aims .............................................................................................................. 37 Results and discussion .................................................................................. 38 Paper I ...................................................................................................... 38 Paper II ..................................................................................................... 40 Paper III .................................................................................................... 42 Paper IV ................................................................................................... 43 Paper V ..................................................................................................... 45 Summary and future perspectives ................................................................. 48 Acknowledgments......................................................................................... 50 References ..................................................................................................... 52 Abbreviations 5HTR 5-hydroxytriptamine (serotonin) receptor AD Atopic dermatitis ATP Adenosine triphosphate BAM 8-22 Bovine adrenal medulla peptide 8-22 CBMC Cord blood-derived mast cell CGRP Calcitonin gene-related peptide CPA3 Carboxypeptidase A3 CRLR Calcitonin receptor-like receptor CTMC Connective tissue mast cell DRG Dorsal root ganglia ET-1, -2, -3 Endothelin-1, -2, -3 ETR, ETAR, ETBR Endothelin receptor, A, B GPCR G protein-coupled receptor H1, H2, H3, H4 Histamine receptor 1, 2, 3, 4 HEK293 Human embryonic kidney cell line 293 HMGB1 High mobility group protein B1 I.p. Intraperitoneal IB4 Isolectin B4 IFNγ Interferon gamma IgE, IgG Immunoglobulin E, G IL Interleukin mAb Monoclonal antibody MC, MMC Mast cell, mucosal mast cell mMCP Mouse mast cell protease moDC Monocyte-derived dendritic cell Mrgpr Mas-related G protein-coupled
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