Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours

Abstract Inhibitory interneurons in the spinal dorsal horn (SDH) are crucial for processing somatosensory information originating in the periphery. However, the effects of the acute and selective inactivation of GABAergic SDH interneurons on pain processing are not fully understood. In this study, w...

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Autores principales:	Keisuke Koga, Kensho Kanehisa, Yuta Kohro, Miho Shiratori-Hayashi, Hidetoshi Tozaki-Saitoh, Kazuhide Inoue, Hidemasa Furue, Makoto Tsuda
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4f4ee16c812b42aa90d3945ed4dec20e
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spelling	oai:doaj.org-article:4f4ee16c812b42aa90d3945ed4dec20e2021-12-02T11:52:38ZChemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours10.1038/s41598-017-04972-32045-2322https://doaj.org/article/4f4ee16c812b42aa90d3945ed4dec20e2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04972-3https://doaj.org/toc/2045-2322Abstract Inhibitory interneurons in the spinal dorsal horn (SDH) are crucial for processing somatosensory information originating in the periphery. However, the effects of the acute and selective inactivation of GABAergic SDH interneurons on pain processing are not fully understood. In this study, we used designer receptors exclusively activated by designer drugs (DREADD) technology and vesicular GABA transporter-Cre (Vgat-Cre) mice to selectively express a modified human muscarinic Gi protein-coupled receptor (hM4Di) in Vgat-Cre + GABAergic SDH interneurons in the fourth lumbar segment. We found that clozapine-N-oxide (CNO) treatment rapidly hyperpolarized these neurons and induced spontaneous nocifensive behaviours in these mice. In Vgat-Cre neg lamina II neurons, CNO produced facilitation of A fibre-mediated polysynaptic excitatory responses, an effect that required N-methyl-D-aspartate (NMDA) receptor activation. The CNO-induced nocifensive behaviours were also reduced by NMDA receptor antagonism. Moreover, these nocifensive behaviours were suppressed by pregabalin but resistant to morphine. Our findings indicate that Vgat-Cre + SDH interneurons play an important role in morphine-resistant nocifensive behaviours and suggest that this approach may provide a useful model for understanding the mechanisms of opioid-resistant pain signalling and for developing novel analgesics.Keisuke KogaKensho KanehisaYuta KohroMiho Shiratori-HayashiHidetoshi Tozaki-SaitohKazuhide InoueHidemasa FurueMakoto TsudaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Keisuke Koga Kensho Kanehisa Yuta Kohro Miho Shiratori-Hayashi Hidetoshi Tozaki-Saitoh Kazuhide Inoue Hidemasa Furue Makoto Tsuda Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours
description	Abstract Inhibitory interneurons in the spinal dorsal horn (SDH) are crucial for processing somatosensory information originating in the periphery. However, the effects of the acute and selective inactivation of GABAergic SDH interneurons on pain processing are not fully understood. In this study, we used designer receptors exclusively activated by designer drugs (DREADD) technology and vesicular GABA transporter-Cre (Vgat-Cre) mice to selectively express a modified human muscarinic Gi protein-coupled receptor (hM4Di) in Vgat-Cre + GABAergic SDH interneurons in the fourth lumbar segment. We found that clozapine-N-oxide (CNO) treatment rapidly hyperpolarized these neurons and induced spontaneous nocifensive behaviours in these mice. In Vgat-Cre neg lamina II neurons, CNO produced facilitation of A fibre-mediated polysynaptic excitatory responses, an effect that required N-methyl-D-aspartate (NMDA) receptor activation. The CNO-induced nocifensive behaviours were also reduced by NMDA receptor antagonism. Moreover, these nocifensive behaviours were suppressed by pregabalin but resistant to morphine. Our findings indicate that Vgat-Cre + SDH interneurons play an important role in morphine-resistant nocifensive behaviours and suggest that this approach may provide a useful model for understanding the mechanisms of opioid-resistant pain signalling and for developing novel analgesics.
format	article
author	Keisuke Koga Kensho Kanehisa Yuta Kohro Miho Shiratori-Hayashi Hidetoshi Tozaki-Saitoh Kazuhide Inoue Hidemasa Furue Makoto Tsuda
author_facet	Keisuke Koga Kensho Kanehisa Yuta Kohro Miho Shiratori-Hayashi Hidetoshi Tozaki-Saitoh Kazuhide Inoue Hidemasa Furue Makoto Tsuda
author_sort	Keisuke Koga
title	Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours
title_short	Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours
title_full	Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours
title_fullStr	Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours
title_full_unstemmed	Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours
title_sort	chemogenetic silencing of gabaergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/4f4ee16c812b42aa90d3945ed4dec20e
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Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours

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