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Compound 48/80-induced itch is attenuated by mouse mast cell tryptase and carboxypeptidase A3
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0002-6779-391x
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-392708OAI: oai:DiVA.org:uu-392708DiVA, id: diva2:1349312
Available from: 2019-09-08 Created: 2019-09-08 Last updated: 2019-09-08
In thesis
1. Peripheral Regulation of Pain and Itch
Open this publication in new window or tab >>Peripheral Regulation of Pain and Itch
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 71
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1596
Keywords
Pain, itch, CGRP, TRPV1, mast cell, mast cell protease, mMCP4, mMCP6, CPA3, endothelin-1, compound 48/80, MRGPRX2, single-stranded oligonucleotide
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-392709 (URN)978-91-513-0746-6 (ISBN)
Public defence
2019-10-25, A1:107a, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2019-10-02 Created: 2019-09-08 Last updated: 2019-10-15

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Magnúsdóttir, Elín IngibjörgGrujic, MirjanaPejler, GunnarLagerström, Malin C.

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Magnúsdóttir, Elín IngibjörgGrujic, MirjanaPejler, GunnarLagerström, Malin C.
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Department of NeuroscienceDepartment of Medical Biochemistry and Microbiology
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