Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors
Background: Functional deletion of the Scn9a (sodium voltage-gated channel alpha subunit 9) gene encoding sodium channel Nav1.7 makes humans and mice pain-free. Opioid signalling contributes to this analgesic state. We have used pharmacological and genetic approaches to identify the opioid receptors...
| Autores: | , , , , , |
|---|---|
| Formato: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2018 |
| País: | España |
| Recursos: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10230/56621 |
| Acesso em linha: | http://hdl.handle.net/10230/56621 http://dx.doi.org/10.12688/wellcomeopenres.14687.1 |
| Access Level: | acceso abierto |
| Palavra-chave: | Nav1.7 channel Analgesia Behaviour Opioid receptors Pain |
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Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptorsPereira, VanessaMillet, QueenstaAramburu, José (Aramburu Beltrán)López Rodríguez, M. CristinaGaveriaux-Ruff, ClaireWood, John N.Nav1.7 channelAnalgesiaBehaviourOpioid receptorsPainBackground: Functional deletion of the Scn9a (sodium voltage-gated channel alpha subunit 9) gene encoding sodium channel Nav1.7 makes humans and mice pain-free. Opioid signalling contributes to this analgesic state. We have used pharmacological and genetic approaches to identify the opioid receptors involved in this form of analgesia. We also examined the regulation of proenkephalin expression by the transcription factor Nfat5 that binds upstream of the Penk gene. Methods: We used specific µ-, δ- and κ-opioid receptor antagonists alone or in combination to examine which opioid receptors were necessary for Nav1.7 loss-associated analgesia in mouse behavioural assays of thermal pain. We also used µ- and δ-opioid receptor null mutant mice alone and in combination in behavioural assays to examine the role of these receptors in Nav1.7 knockouts pain free phenotype. Finally, we examined the levels of Penk mRNA in Nfat5-null mutant mice, as this transcription factor binds to consensus sequences upstream of the Penk gene. Results: The pharmacological block or deletion of both µ- and δ-opioid receptors was required to abolish Nav1.7-null opioid-related analgesia. κ-opioid receptor antagonists were without effect. Enkephalins encoded by the Penk gene are upregulated in Nav1.7 nulls. Deleting Nfat5, a transcription factor with binding motifs upstream of Penk, induces the same level of enkephalin mRNA expression as found in Nav1 .7 nulls, but without consequent analgesia. These data confirm that a combination of events linked to Scn9a gene loss is required for analgesia. Higher levels of endogenous enkephalins, potentiated opioid receptors, diminished electrical excitability and loss of neurotransmitter release together contribute to the analgesic phenotype found in Nav1.7-null mouse and human mutants. Conclusions: These observations help explain the failure of Nav1.7 channel blockers alone to produce analgesia and suggest new routes for analgesic drug development.F1000Research202320232018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/56621http://dx.doi.org/10.12688/wellcomeopenres.14687.1reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésWellcome Open Res. 2018;3:101© 2018 Pereira V et al. This is an open access work distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/566212026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors |
| title |
Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors |
| spellingShingle |
Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors Pereira, Vanessa Nav1.7 channel Analgesia Behaviour Opioid receptors Pain |
| title_short |
Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors |
| title_full |
Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors |
| title_fullStr |
Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors |
| title_full_unstemmed |
Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors |
| title_sort |
Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors |
| dc.creator.none.fl_str_mv |
Pereira, Vanessa Millet, Queensta Aramburu, José (Aramburu Beltrán) López Rodríguez, M. Cristina Gaveriaux-Ruff, Claire Wood, John N. |
| author |
Pereira, Vanessa |
| author_facet |
Pereira, Vanessa Millet, Queensta Aramburu, José (Aramburu Beltrán) López Rodríguez, M. Cristina Gaveriaux-Ruff, Claire Wood, John N. |
| author_role |
author |
| author2 |
Millet, Queensta Aramburu, José (Aramburu Beltrán) López Rodríguez, M. Cristina Gaveriaux-Ruff, Claire Wood, John N. |
| author2_role |
author author author author author |
| dc.subject.none.fl_str_mv |
Nav1.7 channel Analgesia Behaviour Opioid receptors Pain |
| topic |
Nav1.7 channel Analgesia Behaviour Opioid receptors Pain |
| description |
Background: Functional deletion of the Scn9a (sodium voltage-gated channel alpha subunit 9) gene encoding sodium channel Nav1.7 makes humans and mice pain-free. Opioid signalling contributes to this analgesic state. We have used pharmacological and genetic approaches to identify the opioid receptors involved in this form of analgesia. We also examined the regulation of proenkephalin expression by the transcription factor Nfat5 that binds upstream of the Penk gene. Methods: We used specific µ-, δ- and κ-opioid receptor antagonists alone or in combination to examine which opioid receptors were necessary for Nav1.7 loss-associated analgesia in mouse behavioural assays of thermal pain. We also used µ- and δ-opioid receptor null mutant mice alone and in combination in behavioural assays to examine the role of these receptors in Nav1.7 knockouts pain free phenotype. Finally, we examined the levels of Penk mRNA in Nfat5-null mutant mice, as this transcription factor binds to consensus sequences upstream of the Penk gene. Results: The pharmacological block or deletion of both µ- and δ-opioid receptors was required to abolish Nav1.7-null opioid-related analgesia. κ-opioid receptor antagonists were without effect. Enkephalins encoded by the Penk gene are upregulated in Nav1.7 nulls. Deleting Nfat5, a transcription factor with binding motifs upstream of Penk, induces the same level of enkephalin mRNA expression as found in Nav1 .7 nulls, but without consequent analgesia. These data confirm that a combination of events linked to Scn9a gene loss is required for analgesia. Higher levels of endogenous enkephalins, potentiated opioid receptors, diminished electrical excitability and loss of neurotransmitter release together contribute to the analgesic phenotype found in Nav1.7-null mouse and human mutants. Conclusions: These observations help explain the failure of Nav1.7 channel blockers alone to produce analgesia and suggest new routes for analgesic drug development. |
| publishDate |
2018 |
| dc.date.none.fl_str_mv |
2018 2023 2023 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10230/56621 http://dx.doi.org/10.12688/wellcomeopenres.14687.1 |
| url |
http://hdl.handle.net/10230/56621 http://dx.doi.org/10.12688/wellcomeopenres.14687.1 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Wellcome Open Res. 2018;3:101 |
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http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf application/pdf |
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F1000Research |
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F1000Research |
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reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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Recercat. Dipósit de la Recerca de Catalunya |
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