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Peripheral Regulation of Pain and Itch
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Developmental Genetics; Sensory Circuits)
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 [en]
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: urn:nbn:se:uu:diva-392709ISBN: 978-91-513-0746-6 (print)OAI: oai:DiVA.org:uu-392709DiVA, id: diva2:1349314
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
List of papers
1. CGRP alpha within the Trpv1-Cre population contributes to visceral nociception
Open this publication in new window or tab >>CGRP alpha within the Trpv1-Cre population contributes to visceral nociception
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2018 (English)In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 314, no 2, p. G188-G200Article in journal (Refereed) Published
Abstract [en]

The role of calcitonin gene-related peptide (CGRP) in visceral and somatic nociception is incompletely understood. CGRP alpha is highly expressed in sensory neurons of dorsal root ganglia and particularly in neurons that also express the transient receptor potential cation channel subfamily V member 1 (Trpv1). Therefore, we investigated changes in visceral and somatic nociception following deletion of CGRP alpha from the Trpv1-Cre population using the Cre/lox system. In control mice, acetic acid injection (0.6%, ip) caused significant immobility (time stationary), an established indicator of visceral pain. In CGRP alpha-mCherry(lx/lx); Trpv1-Cre mice, the duration of immobility was significantly less than controls, and the distance CGRP alpha-mCherry(lx/lx); Trpv1-Cre mice traveled over 20 min following acetic acid was significantly greater than controls. However, following acetic acid injection, there was no difference between genotypes in the writhing reflex, number of abdominal licks, or forepaw wipes of the cheek. CGRP alpha-mCherry(lx/lx); Trpv1-Cre mice developed more pronounced inflammation-induced heat hypersensitivity above baseline values compared with controls. However, analyses of noxious acute heat or cold transmission revealed no difference between genotypes. Also, odor avoidance test, odor preference test, and buried food test for olfaction revealed no differences between genotypes. Our findings suggest that CGRP alpha-mediated transmission within the Trpv1-Cre population plays a significant role in visceral nociceptive pathways underlying voluntary movement. Monitoring changes in movement over time is a sensitive parameter to identify differences in visceral nociception, compared with writhing reflexes, abdominal licks, or forepaw wipes of the cheek that were unaffected by deletion of CGRP alpha- from Trpv1-Cre population and likely utilize different mechanisms. NEW & NOTEWORTHY The neuropeptide calcitonin gene-related peptide (CGRP) is highly colocalized with transient receptor potential cation channel subfamily V member 1 (TRPV1)-expressing primary afferent neurons, but the functional role of CGRP alpha specifically in these neurons is unknown in pain processing from visceral and somatic afferents. We used cre-lox recombination to conditionally delete CGRP alpha from TRPV1-expressing neurons in mice. We show that CGRP alpha from within TRPV1-cre population plays an important role in visceral nociception but less so in somatic nociception.

Place, publisher, year, edition, pages
AMER PHYSIOLOGICAL SOC, 2018
Keywords
calcitonin gene-related peptide, nociception, pain, transient receptor potential cation channel subfamily V member 1, visceral
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-349363 (URN)10.1152/ajpgi.00188.2017 (DOI)000425923800005 ()28971837 (PubMedID)
Funder
Swedish Research CouncilRagnar Söderbergs stiftelseÅke Wiberg Foundation
Available from: 2018-04-26 Created: 2018-04-26 Last updated: 2019-09-08Bibliographically approved
2. Mouse mast cells and mast cell proteases do not play a significant role in acute tissue injury pain induced by formalin
Open this publication in new window or tab >>Mouse mast cells and mast cell proteases do not play a significant role in acute tissue injury pain induced by formalin
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2018 (English)In: Molecular Pain, ISSN 1744-8069, E-ISSN 1744-8069, Vol. 14, article id 1744806918808161Article in journal (Refereed) Published
Abstract [en]

Subcutaneous formalin injections are used as a model for tissue injury-induced pain where formalin induces pain and inflammation indirectly by crosslinking proteins and directly through activation of the transient receptor potential A1 receptor on primary afferents. Activation of primary afferents leads to both central and peripheral release of neurotransmitters. Mast cells are found in close proximity to peripheral sensory nerve endings and express receptors for neurotransmitters released by the primary afferents, contributing to the neuro/immune interface. Mast cell proteases are found in large quantities within mast cell granules and are released continuously in small amounts and upon mast cell activation. They have a wide repertoire of proposed substrates, including Substance P and calcitonin gene-related peptide, but knowledge of their in vivo function is limited. We evaluated the role of mouse mast cell proteases (mMCPs) in tissue injury pain responses induced by formalin, using transgenic mice lacking either mMCP4, mMCP6, or carboxypeptidase A3 (CPA3), or mast cells in their entirety. Further, we investigated the role of mast cells in heat hypersensitivity following a nerve growth factor injection. No statistical difference was observed between the respective mast cell protease knockout lines and wild-type controls in the formalin test. Mast cell deficiency did not have an effect on formalin-induced nociceptive responses nor nerve growth factor-induced heat hypersensitivity. Our data thus show that mMCP4, mMCP6, and CPA3 as well as mast cells as a whole, do not play a significant role in the pain responses associated with acute tissue injury and inflammation in the formalin test. Our data also indicate that mast cells are not essential to heat hypersensitivity induced by nerve growth factor.

Keywords
Pain formalin, transgenic, mast cell, protease
National Category
Immunology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-372455 (URN)10.1177/1744806918808161 (DOI)000451284400001 ()30280636 (PubMedID)
Funder
Swedish Research CouncilRagnar Söderbergs stiftelse
Available from: 2019-01-08 Created: 2019-01-08 Last updated: 2019-09-08Bibliographically approved
3. Compound 48/80-induced itch is attenuated by mouse mast cell tryptase and carboxypeptidase A3
Open this publication in new window or tab >>Compound 48/80-induced itch is attenuated by mouse mast cell tryptase and carboxypeptidase A3
(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-392708 (URN)
Available from: 2019-09-08 Created: 2019-09-08 Last updated: 2019-09-08
4. Mouse mast cell tryptase and carboxypeptidase A3 play a protective role in itch induced by endothelin-1
Open this publication in new window or tab >>Mouse mast cell tryptase and carboxypeptidase A3 play a protective role in itch induced by endothelin-1
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(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-392707 (URN)
Available from: 2019-09-08 Created: 2019-09-08 Last updated: 2019-09-08
5. Amelioration of Mas-related G protein-coupled receptor X2-mediated itch and reduced mast cell degranulation by a single-stranded oligonucleotide
Open this publication in new window or tab >>Amelioration of Mas-related G protein-coupled receptor X2-mediated itch and reduced mast cell degranulation by a single-stranded oligonucleotide
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(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-392537 (URN)
Available from: 2019-09-08 Created: 2019-09-08 Last updated: 2019-09-08

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