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Antihyperalgesia by α2-GABA(A) Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites

Drugs that enhance GABAergic inhibition alleviate inflammatory and neuropathic pain after spinal application. This antihyperalgesia occurs mainly through GABA(A) receptors (GABA(A)Rs) containing α2 subunits (α2-GABA(A)Rs). Previous work indicates that potentiation of these receptors in the spinal co...

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Autores principales: Paul, Jolly, Yévenes, Gonzalo E, Benke, Dietmar, Lio, Alessandra Di, Ralvenius, William T, Witschi, Robert, Scheurer, Louis, Cook, James M, Rudolph, Uwe, Fritschy, Jean-Marc, Zeilhofer, Hanns Ulrich
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870792/
https://www.ncbi.nlm.nih.gov/pubmed/24045508
http://dx.doi.org/10.1038/npp.2013.221
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author Paul, Jolly
Yévenes, Gonzalo E
Benke, Dietmar
Lio, Alessandra Di
Ralvenius, William T
Witschi, Robert
Scheurer, Louis
Cook, James M
Rudolph, Uwe
Fritschy, Jean-Marc
Zeilhofer, Hanns Ulrich
author_facet Paul, Jolly
Yévenes, Gonzalo E
Benke, Dietmar
Lio, Alessandra Di
Ralvenius, William T
Witschi, Robert
Scheurer, Louis
Cook, James M
Rudolph, Uwe
Fritschy, Jean-Marc
Zeilhofer, Hanns Ulrich
author_sort Paul, Jolly
collection PubMed
description Drugs that enhance GABAergic inhibition alleviate inflammatory and neuropathic pain after spinal application. This antihyperalgesia occurs mainly through GABA(A) receptors (GABA(A)Rs) containing α2 subunits (α2-GABA(A)Rs). Previous work indicates that potentiation of these receptors in the spinal cord evokes profound antihyperalgesia also after systemic administration, but possible synergistic or antagonistic actions of supraspinal α2-GABA(A)Rs on spinal antihyperalgesia have not yet been addressed. Here we generated two lines of GABA(A)R-mutated mice, which either lack α2-GABA(A)Rs specifically from the spinal cord, or, which express only benzodiazepine-insensitive α2-GABA(A)Rs at this site. We analyzed the consequences of these mutations for antihyperalgesia evoked by systemic treatment with the novel non-sedative benzodiazepine site agonist HZ166 in neuropathic and inflammatory pain. Wild-type mice and both types of mutated mice had similar baseline nociceptive sensitivities and developed similar hyperalgesia. However, antihyperalgesia by systemic HZ166 was reduced in both mutated mouse lines by about 60% and was virtually indistinguishable from that of global point-mutated mice, in which all α2-GABA(A)Rs were benzodiazepine insensitive. The major (α2-dependent) component of GABA(A)R-mediated antihyperalgesia was therefore exclusively of spinal origin, whereas supraspinal α2-GABA(A)Rs had neither synergistic nor antagonistic effects on antihyperalgesia. Our results thus indicate that drugs that specifically target α2-GABA(A)Rs exert their antihyperalgesic effect through enhanced spinal nociceptive control. Such drugs may therefore be well-suited for the systemic treatment of different chronic pain conditions.
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spelling pubmed-38707922014-01-01 Antihyperalgesia by α2-GABA(A) Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites Paul, Jolly Yévenes, Gonzalo E Benke, Dietmar Lio, Alessandra Di Ralvenius, William T Witschi, Robert Scheurer, Louis Cook, James M Rudolph, Uwe Fritschy, Jean-Marc Zeilhofer, Hanns Ulrich Neuropsychopharmacology Original Article Drugs that enhance GABAergic inhibition alleviate inflammatory and neuropathic pain after spinal application. This antihyperalgesia occurs mainly through GABA(A) receptors (GABA(A)Rs) containing α2 subunits (α2-GABA(A)Rs). Previous work indicates that potentiation of these receptors in the spinal cord evokes profound antihyperalgesia also after systemic administration, but possible synergistic or antagonistic actions of supraspinal α2-GABA(A)Rs on spinal antihyperalgesia have not yet been addressed. Here we generated two lines of GABA(A)R-mutated mice, which either lack α2-GABA(A)Rs specifically from the spinal cord, or, which express only benzodiazepine-insensitive α2-GABA(A)Rs at this site. We analyzed the consequences of these mutations for antihyperalgesia evoked by systemic treatment with the novel non-sedative benzodiazepine site agonist HZ166 in neuropathic and inflammatory pain. Wild-type mice and both types of mutated mice had similar baseline nociceptive sensitivities and developed similar hyperalgesia. However, antihyperalgesia by systemic HZ166 was reduced in both mutated mouse lines by about 60% and was virtually indistinguishable from that of global point-mutated mice, in which all α2-GABA(A)Rs were benzodiazepine insensitive. The major (α2-dependent) component of GABA(A)R-mediated antihyperalgesia was therefore exclusively of spinal origin, whereas supraspinal α2-GABA(A)Rs had neither synergistic nor antagonistic effects on antihyperalgesia. Our results thus indicate that drugs that specifically target α2-GABA(A)Rs exert their antihyperalgesic effect through enhanced spinal nociceptive control. Such drugs may therefore be well-suited for the systemic treatment of different chronic pain conditions. Nature Publishing Group 2014-01 2013-09-18 /pmc/articles/PMC3870792/ /pubmed/24045508 http://dx.doi.org/10.1038/npp.2013.221 Text en Copyright © 2014 American College of Neuropsychopharmacology http://creativecommons.org/licenses/by-nc-sa/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Original Article
Paul, Jolly
Yévenes, Gonzalo E
Benke, Dietmar
Lio, Alessandra Di
Ralvenius, William T
Witschi, Robert
Scheurer, Louis
Cook, James M
Rudolph, Uwe
Fritschy, Jean-Marc
Zeilhofer, Hanns Ulrich
Antihyperalgesia by α2-GABA(A) Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites
title Antihyperalgesia by α2-GABA(A) Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites
title_full Antihyperalgesia by α2-GABA(A) Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites
title_fullStr Antihyperalgesia by α2-GABA(A) Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites
title_full_unstemmed Antihyperalgesia by α2-GABA(A) Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites
title_short Antihyperalgesia by α2-GABA(A) Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites
title_sort antihyperalgesia by α2-gaba(a) receptors occurs via a genuine spinal action and does not involve supraspinal sites
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870792/
https://www.ncbi.nlm.nih.gov/pubmed/24045508
http://dx.doi.org/10.1038/npp.2013.221
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