Cargando…

Enhancing neuronal chloride extrusion rescues α2/α3 GABA(A)-mediated analgesia in neuropathic pain

Spinal disinhibition has been hypothesized to underlie pain hypersensitivity in neuropathic pain. Apparently contradictory mechanisms have been reported, raising questions on the best target to produce analgesia. Here, we show that nerve injury is associated with a reduction in the number of inhibit...

Descripción completa

Detalles Bibliográficos
Autores principales: Lorenzo, Louis-Etienne, Godin, Antoine G., Ferrini, Francesco, Bachand, Karine, Plasencia-Fernandez, Isabel, Labrecque, Simon, Girard, Alexandre A., Boudreau, Dominic, Kianicka, Irenej, Gagnon, Martin, Doyon, Nicolas, Ribeiro-da-Silva, Alfredo, De Koninck, Yves
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018745/
https://www.ncbi.nlm.nih.gov/pubmed/32054836
http://dx.doi.org/10.1038/s41467-019-14154-6
_version_ 1783497384251097088
author Lorenzo, Louis-Etienne
Godin, Antoine G.
Ferrini, Francesco
Bachand, Karine
Plasencia-Fernandez, Isabel
Labrecque, Simon
Girard, Alexandre A.
Boudreau, Dominic
Kianicka, Irenej
Gagnon, Martin
Doyon, Nicolas
Ribeiro-da-Silva, Alfredo
De Koninck, Yves
author_facet Lorenzo, Louis-Etienne
Godin, Antoine G.
Ferrini, Francesco
Bachand, Karine
Plasencia-Fernandez, Isabel
Labrecque, Simon
Girard, Alexandre A.
Boudreau, Dominic
Kianicka, Irenej
Gagnon, Martin
Doyon, Nicolas
Ribeiro-da-Silva, Alfredo
De Koninck, Yves
author_sort Lorenzo, Louis-Etienne
collection PubMed
description Spinal disinhibition has been hypothesized to underlie pain hypersensitivity in neuropathic pain. Apparently contradictory mechanisms have been reported, raising questions on the best target to produce analgesia. Here, we show that nerve injury is associated with a reduction in the number of inhibitory synapses in the spinal dorsal horn. Paradoxically, this is accompanied by a BDNF-TrkB-mediated upregulation of synaptic GABA(A)Rs and by an α1-to-α2GABA(A)R subunit switch, providing a mechanistic rationale for the analgesic action of the α2,3GABA(A)R benzodiazepine-site ligand L838,417 after nerve injury. Yet, we demonstrate that impaired Cl(-) extrusion underlies the failure of L838,417 to induce analgesia at high doses due to a resulting collapse in Cl(-) gradient, dramatically limiting the benzodiazepine therapeutic window. In turn, enhancing KCC2 activity not only potentiated L838,417-induced analgesia, it rescued its analgesic potential at high doses, revealing a novel strategy for analgesia in pathological pain, by combined targeting of the appropriate GABA(A)R-subtypes and restoring Cl(-) homeostasis.
format Online
Article
Text
id pubmed-7018745
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-70187452020-02-21 Enhancing neuronal chloride extrusion rescues α2/α3 GABA(A)-mediated analgesia in neuropathic pain Lorenzo, Louis-Etienne Godin, Antoine G. Ferrini, Francesco Bachand, Karine Plasencia-Fernandez, Isabel Labrecque, Simon Girard, Alexandre A. Boudreau, Dominic Kianicka, Irenej Gagnon, Martin Doyon, Nicolas Ribeiro-da-Silva, Alfredo De Koninck, Yves Nat Commun Article Spinal disinhibition has been hypothesized to underlie pain hypersensitivity in neuropathic pain. Apparently contradictory mechanisms have been reported, raising questions on the best target to produce analgesia. Here, we show that nerve injury is associated with a reduction in the number of inhibitory synapses in the spinal dorsal horn. Paradoxically, this is accompanied by a BDNF-TrkB-mediated upregulation of synaptic GABA(A)Rs and by an α1-to-α2GABA(A)R subunit switch, providing a mechanistic rationale for the analgesic action of the α2,3GABA(A)R benzodiazepine-site ligand L838,417 after nerve injury. Yet, we demonstrate that impaired Cl(-) extrusion underlies the failure of L838,417 to induce analgesia at high doses due to a resulting collapse in Cl(-) gradient, dramatically limiting the benzodiazepine therapeutic window. In turn, enhancing KCC2 activity not only potentiated L838,417-induced analgesia, it rescued its analgesic potential at high doses, revealing a novel strategy for analgesia in pathological pain, by combined targeting of the appropriate GABA(A)R-subtypes and restoring Cl(-) homeostasis. Nature Publishing Group UK 2020-02-13 /pmc/articles/PMC7018745/ /pubmed/32054836 http://dx.doi.org/10.1038/s41467-019-14154-6 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Lorenzo, Louis-Etienne
Godin, Antoine G.
Ferrini, Francesco
Bachand, Karine
Plasencia-Fernandez, Isabel
Labrecque, Simon
Girard, Alexandre A.
Boudreau, Dominic
Kianicka, Irenej
Gagnon, Martin
Doyon, Nicolas
Ribeiro-da-Silva, Alfredo
De Koninck, Yves
Enhancing neuronal chloride extrusion rescues α2/α3 GABA(A)-mediated analgesia in neuropathic pain
title Enhancing neuronal chloride extrusion rescues α2/α3 GABA(A)-mediated analgesia in neuropathic pain
title_full Enhancing neuronal chloride extrusion rescues α2/α3 GABA(A)-mediated analgesia in neuropathic pain
title_fullStr Enhancing neuronal chloride extrusion rescues α2/α3 GABA(A)-mediated analgesia in neuropathic pain
title_full_unstemmed Enhancing neuronal chloride extrusion rescues α2/α3 GABA(A)-mediated analgesia in neuropathic pain
title_short Enhancing neuronal chloride extrusion rescues α2/α3 GABA(A)-mediated analgesia in neuropathic pain
title_sort enhancing neuronal chloride extrusion rescues α2/α3 gaba(a)-mediated analgesia in neuropathic pain
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018745/
https://www.ncbi.nlm.nih.gov/pubmed/32054836
http://dx.doi.org/10.1038/s41467-019-14154-6
work_keys_str_mv AT lorenzolouisetienne enhancingneuronalchlorideextrusionrescuesa2a3gabaamediatedanalgesiainneuropathicpain
AT godinantoineg enhancingneuronalchlorideextrusionrescuesa2a3gabaamediatedanalgesiainneuropathicpain
AT ferrinifrancesco enhancingneuronalchlorideextrusionrescuesa2a3gabaamediatedanalgesiainneuropathicpain
AT bachandkarine enhancingneuronalchlorideextrusionrescuesa2a3gabaamediatedanalgesiainneuropathicpain
AT plasenciafernandezisabel enhancingneuronalchlorideextrusionrescuesa2a3gabaamediatedanalgesiainneuropathicpain
AT labrecquesimon enhancingneuronalchlorideextrusionrescuesa2a3gabaamediatedanalgesiainneuropathicpain
AT girardalexandrea enhancingneuronalchlorideextrusionrescuesa2a3gabaamediatedanalgesiainneuropathicpain
AT boudreaudominic enhancingneuronalchlorideextrusionrescuesa2a3gabaamediatedanalgesiainneuropathicpain
AT kianickairenej enhancingneuronalchlorideextrusionrescuesa2a3gabaamediatedanalgesiainneuropathicpain
AT gagnonmartin enhancingneuronalchlorideextrusionrescuesa2a3gabaamediatedanalgesiainneuropathicpain
AT doyonnicolas enhancingneuronalchlorideextrusionrescuesa2a3gabaamediatedanalgesiainneuropathicpain
AT ribeirodasilvaalfredo enhancingneuronalchlorideextrusionrescuesa2a3gabaamediatedanalgesiainneuropathicpain
AT dekoninckyves enhancingneuronalchlorideextrusionrescuesa2a3gabaamediatedanalgesiainneuropathicpain