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Identification of a Neuronal Receptor Controlling Anaphylaxis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Sensory circuits)
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 Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
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2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 2, p. 370-379Article in journal (Refereed) Published
Abstract [en]

Allergic reactions can in severe cases induce a state of circulatory shock referred to as anaphylaxis. Histamine, the primary mediator of this condition, is released from immune cells, and, therefore, anaphylaxis has so far been considered an immune system disorder. However, we here show that the glutamatergic receptor mGluR7, expressed on a subpopulation of both peripheral and spinal cord neurons, controls histamine-induced communication through calcium-dependent autoinhibition with implications for anaphylaxis. Genetic ablation of mGluR7, and thus altered regulation of histamine-sensing neurons, caused an anaphylaxis-like state in mGluR7(-/-) mice, which could be reversed by antagonizing signaling between neurons and mast cells but not by antagonizing a central itch pathway. Our findings demonstrate the vital role of nervous system control by mGluR7 in anaphylaxis and open up possibilities for preventive strategies for this life-threatening condition.

Place, publisher, year, edition, pages
2016. Vol. 14, no 2, p. 370-379
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-272637DOI: 10.1016/j.celrep.2015.12.033ISI: 000368101600019PubMedID: 26748715OAI: oai:DiVA.org:uu-272637DiVA, id: diva2:894475
Funder
Swedish Research CouncilRagnar Söderbergs stiftelseKnut and Alice Wallenberg FoundationÅke Wiberg FoundationMagnus Bergvall FoundationThe Royal Swedish Academy of SciencesAvailable from: 2016-01-15 Created: 2016-01-15 Last updated: 2020-02-03Bibliographically approved
In thesis
1. Functional Aspects of Peripheral and Spinal Cord Neurons Involved in Itch and Pain
Open this publication in new window or tab >>Functional Aspects of Peripheral and Spinal Cord Neurons Involved in Itch and Pain
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

We have investigated the role of the metabotropic glutamate receptor 7 (mGluR7) and the gastrin releasing peptide receptor (Grpr) population that are involved at different levels of itch transmission. We found that mGuR7 deficient mice displayed an anaphylaxis-like behavior when provoked with histamine. Analysis of blood revealed elevated plasma levels of histamine and mouse mast cell protease-1 (mMCP1), two indicators of anaphylaxis, in mGluR7 deficient mice compared with control mice. Inhibition of the neurokinin 1 receptor, by preventing binding of the corresponding ligand substance P (SP), prior to provocation with histamine prevented the development of anaphylaxis in mGluR7 deficient animals. However, blocking GRPR (gastrin releasing peptide receptor) only resulted in decreased itch levels in mGluR7 deficient mice but did not prevent the systemic anaphylaxis-like behavior. Our findings indicate that mGluR7 normally functions as a brake on histaminergic itch that is mediated through GRPR as well as anaphylaxis through Substance P.

Grpr has previously been shown to mediate both histaminergic and non-histaminergic itch but little is known about the GRPR neuronal population. We used a BAC cloning strategy to construct a Grpr-Cre line, which we crossed with the reporter lines tdTomato and Viaat-egfp as well as with Vglut2-lox. We could conclude that Grpr-Cre neurons are mainly excitatory interneurons located in lamina II-IV, that convey itch using VGLUT2-mediated glutamatergic transmission to the next, currently unknown, step in the labeled line of chemical itch.

To eventually deduce the function of the endogenous opioids dynorphin and enkephalin, which are hypothesized to be involved in gating pain and itch in the spinal cord, we constructed two Cre lines using BAC cloning that targeted the precursor proteins preprodynorphin and preproenkephalin, respectively. Preprodynorphin-Cre neurons were mainly located in lamina II-IV and overlapped to 47% with Vglut2 mRNA, while the co-expression with the inhibitory markers Viaat-egfp and PAX2 was 13% and 28% respectively in the spinal cord. Preproenkephalin neurons were more localized to lamina III in the dorsal horn, furthermore single cell analysis showed that they overlapped to 94% with Vglut2 mRNA while 7% and 13% expressed Viaat-egfp and PAX2 respectively.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. p. 48
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1222
Keywords
mGluR7, anaphylaxis, Grpr, Penk, Pdyn, Cre line, BAC cloning, spinal cord, transgenic line
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-284070 (URN)978-91-554-9568-8 (ISBN)
Public defence
2016-06-04, C2:301, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2016-05-13 Created: 2016-04-14 Last updated: 2016-06-01
2. Targeting and driving somatosensory neurons
Open this publication in new window or tab >>Targeting and driving somatosensory neurons
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pain and itch are two distinct sensations, but the fundamental question of how our nervous system distinguishes the processing and encoding of their related information is still far to be clearly delineated. At the spinal cord level, evidences have pointed out specific groups of neurons expressing the gastrin releasing peptide (Grp) and its receptor (Grpr) as responsible for carrying specifically itch-related information. Such important findings suggest a labeled line for itch and hypothesize the existence of separate pathways transmitting different sensory modalities already at this stage. Aiming at digging further on the pain/itch dualism, the present thesis focused first in addressing the GRPR-expressing dorsal horn interneurons and its roles in itch transmission. In the paper I, we observed that this population is composed mainly by excitatory interneurons, transmits itch through glutamate, and is at least partly downstream to the natriuretic peptide b (NPPB) signaling. Interestingly, increasing amount of behavior evidences have suggested that itch-related information is under local inhibition in the dorsal horn, since decrease of the local inhibitory tone by the peptide somatostatin is able to potentiate itch sensation in mice. In the paper II we complement these findings by showing in vitro that the itch-related GRPR-expressing dorsal horn neurons are under local tonic and phasic inhibition, besides being partly activated by somatostatin, corroborating that this population is indeed part of the disinhibition-induced itch circuitry. In order to confirm the itch-specific phenotype related to GRPR-expressing neurons and extend this theory to the rodent orofacial area, in the paper III we showed a new method developed to target and manipulate the orofacial-related trigeminal neurons. By using this method, we unexpectedly observed a functional switch in the GRPR population, from itch-related in the spinal cord to pain-related in the trigeminal nucleus caudalis, suggesting a labeled line of orofacial pain in this brainstem nucleus. As in the trigeminal nuclei, neuronal circuitry formed by defined cell types transmitting pain- and itch-related information has not been addressed yet in the somatosensory cortex. In the paper IV, we offer a mouse genetic tool that enables the target of barrel field spiny stellate cells, opening for more detailed knowledge of cortical circuitry encoding somatosensory information. In summary, the present thesis brings both complementary findings and new intriguing insights on how our nervous system transmits somatosensory stimuli from different modalities, paving basic knowledge on the mechanisms that build pain and itch as distinct percepts. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. p. 37
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1637
Keywords
Pain, Itch, GRPR interneurons, dorsal horn, trigeminal nucleus caudalis, Barrel field
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-403631 (URN)978-91-513-0870-8 (ISBN)
Public defence
2020-03-23, A1:107a, BMC Departament of Neuroscience B1:213a, Husargatan 3, Uppsala, 14:15 (English)
Opponent
Supervisors
Available from: 2020-03-02 Created: 2020-02-03 Last updated: 2020-05-19

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Aresh, BejanFreitag, Fabio BatistaPettersson, HannaMagnúsdóttir, Elín IngibjörgFranck, Marina Christina MikaelaNagaraja, ChetanKullander, KlasLagerström, Malin Charlotta

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