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Differential modulation of voltage-gated sodium channels by nerve growth factor in three major subsets of TrkA-expressing nociceptors
Nerve growth factor is an inflammatory mediator that induces long-lasting hyperalgesia, which can partially be attributed to nerve growth factor-induced sensitization of primary afferent nociceptors. It was shown that nerve growth factor increases the excitability of polymodal C-fibre nociceptors by...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856966/ https://www.ncbi.nlm.nih.gov/pubmed/30387376 http://dx.doi.org/10.1177/1744806918814640 |
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author | Schaefer, Irina Prato, Vincenzo Arcourt, Alice Taberner, Francisco J Lechner, Stefan G |
author_facet | Schaefer, Irina Prato, Vincenzo Arcourt, Alice Taberner, Francisco J Lechner, Stefan G |
author_sort | Schaefer, Irina |
collection | PubMed |
description | Nerve growth factor is an inflammatory mediator that induces long-lasting hyperalgesia, which can partially be attributed to nerve growth factor-induced sensitization of primary afferent nociceptors. It was shown that nerve growth factor increases the excitability of polymodal C-fibre nociceptors by modulating tetrodotoxin-sensitive and tetrodotoxin-resistant voltage-gated sodium channels, but hitherto only little is known about the effects of nerve growth factor on sodium currents in other nociceptor subtypes that express the nerve growth factor receptor TrkA. We previously characterized two reporter mouse lines that allow the unequivocal identification of two important subclasses of TrkA-expressing nociceptors – i.e. neuropeptide Y receptor type 2 (NPY2R(+) ) Aδ-fibre nociceptors that mediate pinprick pain and nicotinic acetylcholine receptor alpha-3 subunit (CHRNA3(+) ) silent nociceptors, which are the most abundant TrkA(+) nociceptors in visceral organs and deep somatic tissues. Here, we utilized these mouse lines to investigate the expression patterns and the possible nerve growth factor-dependent modulation of sodium channels in these neurons using whole-cell patch-clamp recordings and quantitative real-time polymerase chain reaction. We demonstrate that NPY2R(+) nociceptors, CHRNA3(+) ‘silent’ nociceptors and polymodal C-fibre nociceptors express different combinations of sodium channel α- and β-subunits and accordingly exhibit functionally different sodium currents. Moreover, we demonstrate that nerve growth factor produces robust hyperpolarizing shifts in the half-activation voltage of tetrodotoxin-resistant currents in NPY2R(+) nociceptors and polymodal C-fibre nociceptors and also shifts the half-activation of tetrodotoxin-sensitive currents in polymodal C-fibre nociceptors. In silent nociceptors, however, nerve growth factor solely increases the current density of the tetrodotoxin-resistant current but does not alter other sodium channel properties. Considering the different peripheral target tissues and the previously reported roles in different forms of pain of the nociceptor subpopulations that were examined here, our results suggest that nerve growth factor differentially contributes to the development visceral and cutaneous pain hypersensitivity and highlights the importance of developing different therapeutic strategies for different forms of pain. |
format | Online Article Text |
id | pubmed-6856966 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-68569662019-11-22 Differential modulation of voltage-gated sodium channels by nerve growth factor in three major subsets of TrkA-expressing nociceptors Schaefer, Irina Prato, Vincenzo Arcourt, Alice Taberner, Francisco J Lechner, Stefan G Mol Pain Research Article Nerve growth factor is an inflammatory mediator that induces long-lasting hyperalgesia, which can partially be attributed to nerve growth factor-induced sensitization of primary afferent nociceptors. It was shown that nerve growth factor increases the excitability of polymodal C-fibre nociceptors by modulating tetrodotoxin-sensitive and tetrodotoxin-resistant voltage-gated sodium channels, but hitherto only little is known about the effects of nerve growth factor on sodium currents in other nociceptor subtypes that express the nerve growth factor receptor TrkA. We previously characterized two reporter mouse lines that allow the unequivocal identification of two important subclasses of TrkA-expressing nociceptors – i.e. neuropeptide Y receptor type 2 (NPY2R(+) ) Aδ-fibre nociceptors that mediate pinprick pain and nicotinic acetylcholine receptor alpha-3 subunit (CHRNA3(+) ) silent nociceptors, which are the most abundant TrkA(+) nociceptors in visceral organs and deep somatic tissues. Here, we utilized these mouse lines to investigate the expression patterns and the possible nerve growth factor-dependent modulation of sodium channels in these neurons using whole-cell patch-clamp recordings and quantitative real-time polymerase chain reaction. We demonstrate that NPY2R(+) nociceptors, CHRNA3(+) ‘silent’ nociceptors and polymodal C-fibre nociceptors express different combinations of sodium channel α- and β-subunits and accordingly exhibit functionally different sodium currents. Moreover, we demonstrate that nerve growth factor produces robust hyperpolarizing shifts in the half-activation voltage of tetrodotoxin-resistant currents in NPY2R(+) nociceptors and polymodal C-fibre nociceptors and also shifts the half-activation of tetrodotoxin-sensitive currents in polymodal C-fibre nociceptors. In silent nociceptors, however, nerve growth factor solely increases the current density of the tetrodotoxin-resistant current but does not alter other sodium channel properties. Considering the different peripheral target tissues and the previously reported roles in different forms of pain of the nociceptor subpopulations that were examined here, our results suggest that nerve growth factor differentially contributes to the development visceral and cutaneous pain hypersensitivity and highlights the importance of developing different therapeutic strategies for different forms of pain. SAGE Publications 2018-11-02 /pmc/articles/PMC6856966/ /pubmed/30387376 http://dx.doi.org/10.1177/1744806918814640 Text en © The Author(s) 2018 http://creativecommons.org/licenses/by-nc/4.0/ Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) 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 pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
spellingShingle | Research Article Schaefer, Irina Prato, Vincenzo Arcourt, Alice Taberner, Francisco J Lechner, Stefan G Differential modulation of voltage-gated sodium channels by nerve growth factor in three major subsets of TrkA-expressing nociceptors |
title | Differential modulation of voltage-gated sodium channels by nerve
growth factor in three major subsets of TrkA-expressing
nociceptors |
title_full | Differential modulation of voltage-gated sodium channels by nerve
growth factor in three major subsets of TrkA-expressing
nociceptors |
title_fullStr | Differential modulation of voltage-gated sodium channels by nerve
growth factor in three major subsets of TrkA-expressing
nociceptors |
title_full_unstemmed | Differential modulation of voltage-gated sodium channels by nerve
growth factor in three major subsets of TrkA-expressing
nociceptors |
title_short | Differential modulation of voltage-gated sodium channels by nerve
growth factor in three major subsets of TrkA-expressing
nociceptors |
title_sort | differential modulation of voltage-gated sodium channels by nerve
growth factor in three major subsets of trka-expressing
nociceptors |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856966/ https://www.ncbi.nlm.nih.gov/pubmed/30387376 http://dx.doi.org/10.1177/1744806918814640 |
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