Cargando…
Increased expression of Trpv1 in peripheral terminals mediates thermal nociception in Fabry disease mouse model
Fabry disease is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme. α-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3) in the endothelium and vascular sm...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009828/ https://www.ncbi.nlm.nih.gov/pubmed/27531673 http://dx.doi.org/10.1177/1744806916663729 |
_version_ | 1782451584538509312 |
---|---|
author | Lakomá, Jarmila Rimondini, Roberto Ferrer Montiel, Antonio Donadio, Vincenzo Liguori, Rocco Caprini, Marco |
author_facet | Lakomá, Jarmila Rimondini, Roberto Ferrer Montiel, Antonio Donadio, Vincenzo Liguori, Rocco Caprini, Marco |
author_sort | Lakomá, Jarmila |
collection | PubMed |
description | Fabry disease is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme. α-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3) in the endothelium and vascular smooth muscles. A hallmark symptom of Fabry disease patients is neuropathic pain that appears in the early stage of the disease as a result of peripheral small fiber damage. The α-GalA gene null mouse model (α-GalA(−/0)) has provided molecular evidence for the molecular alterations in small type-C nociceptors in Fabry disease that may underlie their hyperexcitability, although the specific mechanism remains elusive. Here, we have addressed this question and report that small type-C nociceptors from α-GalA(−/0) mice exhibit a significant increase in the expression and function of the TRPV1 channel, a thermoTRP channel implicated in painful heat sensation. Notably, male α-GalA(−/0) mice displayed a ≈2-fold higher heat sensitivity than wild-type animals, consistent with the augmented expression levels and activity of TRPV1 in α-GalA(−/0) nociceptors. Intriguingly, blockade of neuronal exocytosis with peptide DD04107, a process that inhibits among others the algesic membrane recruitment of TRPV1 channels in peptidergic nociceptors, virtually eliminated the enhanced heat nociception of α-GalA(−/0) mice. Together, these findings suggest that the augmented expression of TRPV1 in α-GalA(−/0) nociceptors may underly at least in part their increased heat sensitivity, and imply that blockade of peripheral neuronal exocytosis may be a valuable pharmacological strategy to reduce pain in Fabry disease patients, increasing their quality of life. |
format | Online Article Text |
id | pubmed-5009828 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-50098282016-09-14 Increased expression of Trpv1 in peripheral terminals mediates thermal nociception in Fabry disease mouse model Lakomá, Jarmila Rimondini, Roberto Ferrer Montiel, Antonio Donadio, Vincenzo Liguori, Rocco Caprini, Marco Mol Pain Research Article Fabry disease is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme. α-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3) in the endothelium and vascular smooth muscles. A hallmark symptom of Fabry disease patients is neuropathic pain that appears in the early stage of the disease as a result of peripheral small fiber damage. The α-GalA gene null mouse model (α-GalA(−/0)) has provided molecular evidence for the molecular alterations in small type-C nociceptors in Fabry disease that may underlie their hyperexcitability, although the specific mechanism remains elusive. Here, we have addressed this question and report that small type-C nociceptors from α-GalA(−/0) mice exhibit a significant increase in the expression and function of the TRPV1 channel, a thermoTRP channel implicated in painful heat sensation. Notably, male α-GalA(−/0) mice displayed a ≈2-fold higher heat sensitivity than wild-type animals, consistent with the augmented expression levels and activity of TRPV1 in α-GalA(−/0) nociceptors. Intriguingly, blockade of neuronal exocytosis with peptide DD04107, a process that inhibits among others the algesic membrane recruitment of TRPV1 channels in peptidergic nociceptors, virtually eliminated the enhanced heat nociception of α-GalA(−/0) mice. Together, these findings suggest that the augmented expression of TRPV1 in α-GalA(−/0) nociceptors may underly at least in part their increased heat sensitivity, and imply that blockade of peripheral neuronal exocytosis may be a valuable pharmacological strategy to reduce pain in Fabry disease patients, increasing their quality of life. SAGE Publications 2016-08-16 /pmc/articles/PMC5009828/ /pubmed/27531673 http://dx.doi.org/10.1177/1744806916663729 Text en © The Author(s) 2016 http://creativecommons.org/licenses/by-nc/3.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Research Article Lakomá, Jarmila Rimondini, Roberto Ferrer Montiel, Antonio Donadio, Vincenzo Liguori, Rocco Caprini, Marco Increased expression of Trpv1 in peripheral terminals mediates thermal nociception in Fabry disease mouse model |
title | Increased expression of Trpv1 in peripheral terminals mediates thermal nociception in Fabry disease mouse model |
title_full | Increased expression of Trpv1 in peripheral terminals mediates thermal nociception in Fabry disease mouse model |
title_fullStr | Increased expression of Trpv1 in peripheral terminals mediates thermal nociception in Fabry disease mouse model |
title_full_unstemmed | Increased expression of Trpv1 in peripheral terminals mediates thermal nociception in Fabry disease mouse model |
title_short | Increased expression of Trpv1 in peripheral terminals mediates thermal nociception in Fabry disease mouse model |
title_sort | increased expression of trpv1 in peripheral terminals mediates thermal nociception in fabry disease mouse model |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009828/ https://www.ncbi.nlm.nih.gov/pubmed/27531673 http://dx.doi.org/10.1177/1744806916663729 |
work_keys_str_mv | AT lakomajarmila increasedexpressionoftrpv1inperipheralterminalsmediatesthermalnociceptioninfabrydiseasemousemodel AT rimondiniroberto increasedexpressionoftrpv1inperipheralterminalsmediatesthermalnociceptioninfabrydiseasemousemodel AT ferrermontielantonio increasedexpressionoftrpv1inperipheralterminalsmediatesthermalnociceptioninfabrydiseasemousemodel AT donadiovincenzo increasedexpressionoftrpv1inperipheralterminalsmediatesthermalnociceptioninfabrydiseasemousemodel AT liguorirocco increasedexpressionoftrpv1inperipheralterminalsmediatesthermalnociceptioninfabrydiseasemousemodel AT caprinimarco increasedexpressionoftrpv1inperipheralterminalsmediatesthermalnociceptioninfabrydiseasemousemodel |