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A central mechanism of analgesia in mice and humans lacking the sodium channel Na(V)1.7
Deletion of SCN9A encoding the voltage-gated sodium channel Na(V)1.7 in humans leads to profound pain insensitivity and anosmia. Conditional deletion of Na(V)1.7 in sensory neurons of mice also abolishes pain, suggesting that the locus of analgesia is the nociceptor. Here we demonstrate, using in vi...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110947/ https://www.ncbi.nlm.nih.gov/pubmed/33823138 http://dx.doi.org/10.1016/j.neuron.2021.03.012 |
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author | MacDonald, Donald Iain Sikandar, Shafaq Weiss, Jan Pyrski, Martina Luiz, Ana P. Millet, Queensta Emery, Edward C. Mancini, Flavia Iannetti, Gian D. Alles, Sascha R.A. Arcangeletti, Manuel Zhao, Jing Cox, James J. Brownstone, Robert M. Zufall, Frank Wood, John N. |
author_facet | MacDonald, Donald Iain Sikandar, Shafaq Weiss, Jan Pyrski, Martina Luiz, Ana P. Millet, Queensta Emery, Edward C. Mancini, Flavia Iannetti, Gian D. Alles, Sascha R.A. Arcangeletti, Manuel Zhao, Jing Cox, James J. Brownstone, Robert M. Zufall, Frank Wood, John N. |
author_sort | MacDonald, Donald Iain |
collection | PubMed |
description | Deletion of SCN9A encoding the voltage-gated sodium channel Na(V)1.7 in humans leads to profound pain insensitivity and anosmia. Conditional deletion of Na(V)1.7 in sensory neurons of mice also abolishes pain, suggesting that the locus of analgesia is the nociceptor. Here we demonstrate, using in vivo calcium imaging and extracellular recording, that Na(V)1.7 knockout mice have essentially normal nociceptor activity. However, synaptic transmission from nociceptor central terminals in the spinal cord is greatly reduced by an opioid-dependent mechanism. Analgesia is also reversed substantially by central but not peripheral application of opioid antagonists. In contrast, the lack of neurotransmitter release from olfactory sensory neurons is opioid independent. Male and female humans with Na(V)1.7-null mutations show naloxone-reversible analgesia. Thus, inhibition of neurotransmitter release is the principal mechanism of anosmia and analgesia in mouse and human Nav1.7-null mutants. |
format | Online Article Text |
id | pubmed-8110947 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-81109472021-05-14 A central mechanism of analgesia in mice and humans lacking the sodium channel Na(V)1.7 MacDonald, Donald Iain Sikandar, Shafaq Weiss, Jan Pyrski, Martina Luiz, Ana P. Millet, Queensta Emery, Edward C. Mancini, Flavia Iannetti, Gian D. Alles, Sascha R.A. Arcangeletti, Manuel Zhao, Jing Cox, James J. Brownstone, Robert M. Zufall, Frank Wood, John N. Neuron Article Deletion of SCN9A encoding the voltage-gated sodium channel Na(V)1.7 in humans leads to profound pain insensitivity and anosmia. Conditional deletion of Na(V)1.7 in sensory neurons of mice also abolishes pain, suggesting that the locus of analgesia is the nociceptor. Here we demonstrate, using in vivo calcium imaging and extracellular recording, that Na(V)1.7 knockout mice have essentially normal nociceptor activity. However, synaptic transmission from nociceptor central terminals in the spinal cord is greatly reduced by an opioid-dependent mechanism. Analgesia is also reversed substantially by central but not peripheral application of opioid antagonists. In contrast, the lack of neurotransmitter release from olfactory sensory neurons is opioid independent. Male and female humans with Na(V)1.7-null mutations show naloxone-reversible analgesia. Thus, inhibition of neurotransmitter release is the principal mechanism of anosmia and analgesia in mouse and human Nav1.7-null mutants. Cell Press 2021-05-05 /pmc/articles/PMC8110947/ /pubmed/33823138 http://dx.doi.org/10.1016/j.neuron.2021.03.012 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article MacDonald, Donald Iain Sikandar, Shafaq Weiss, Jan Pyrski, Martina Luiz, Ana P. Millet, Queensta Emery, Edward C. Mancini, Flavia Iannetti, Gian D. Alles, Sascha R.A. Arcangeletti, Manuel Zhao, Jing Cox, James J. Brownstone, Robert M. Zufall, Frank Wood, John N. A central mechanism of analgesia in mice and humans lacking the sodium channel Na(V)1.7 |
title | A central mechanism of analgesia in mice and humans lacking the sodium channel Na(V)1.7 |
title_full | A central mechanism of analgesia in mice and humans lacking the sodium channel Na(V)1.7 |
title_fullStr | A central mechanism of analgesia in mice and humans lacking the sodium channel Na(V)1.7 |
title_full_unstemmed | A central mechanism of analgesia in mice and humans lacking the sodium channel Na(V)1.7 |
title_short | A central mechanism of analgesia in mice and humans lacking the sodium channel Na(V)1.7 |
title_sort | central mechanism of analgesia in mice and humans lacking the sodium channel na(v)1.7 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110947/ https://www.ncbi.nlm.nih.gov/pubmed/33823138 http://dx.doi.org/10.1016/j.neuron.2021.03.012 |
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