Enhancing KCC2 function counteracts morphine-induced hyperalgesia

Abstract Morphine-induced hyperalgesia (MIH) is a severe adverse effect accompanying repeated morphine treatment, causing a paradoxical decrease in nociceptive threshold. Previous reports associated MIH with a decreased expression of the Cl− extruder KCC2 in the superficial dorsal horn (SDH) of the...

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Autores principales:	Francesco Ferrini, Louis-Etienne Lorenzo, Antoine G. Godin, Miorie Le Quang, Yves De Koninck
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0eca9d636d3343e999ceb6e781d6238c
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spelling	oai:doaj.org-article:0eca9d636d3343e999ceb6e781d6238c2021-12-02T11:40:58ZEnhancing KCC2 function counteracts morphine-induced hyperalgesia10.1038/s41598-017-04209-32045-2322https://doaj.org/article/0eca9d636d3343e999ceb6e781d6238c2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04209-3https://doaj.org/toc/2045-2322Abstract Morphine-induced hyperalgesia (MIH) is a severe adverse effect accompanying repeated morphine treatment, causing a paradoxical decrease in nociceptive threshold. Previous reports associated MIH with a decreased expression of the Cl− extruder KCC2 in the superficial dorsal horn (SDH) of the spinal cord, weakening spinal GABAA/glycine-mediated postsynaptic inhibition. Here, we tested whether the administration of small molecules enhancing KCC2, CLP257 and its pro-drug CLP290, may counteract MIH. MIH was typically expressed within 6–8 days of morphine treatment. Morphine-treated rats exhibited decreased withdrawal threshold to mechanical stimulation and increased vocalizing behavior to subcutaneous injections. Chloride extrusion was impaired in SDH neurons measured as a depolarizing shift in E GABA under Cl− load. Delivering CLP257 to spinal cord slices obtained from morphine-treated rats was sufficient to restore Cl− extrusion capacity in SDH neurons. In vivo co-treatment with morphine and oral CLP290 prevented membrane KCC2 downregulation in SDH neurons. Concurrently, co-treatment with CLP290 significantly mitigated MIH and acute administration of CLP257 in established MIH restored normal nociceptive behavior. Our data indicate that enhancing KCC2 activity is a viable therapeutic approach for counteracting MIH. Chloride extrusion enhancers may represent an effective co-adjuvant therapy to improve morphine analgesia by preventing and reversing MIH.Francesco FerriniLouis-Etienne LorenzoAntoine G. GodinMiorie Le QuangYves De KoninckNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Francesco Ferrini Louis-Etienne Lorenzo Antoine G. Godin Miorie Le Quang Yves De Koninck Enhancing KCC2 function counteracts morphine-induced hyperalgesia
description	Abstract Morphine-induced hyperalgesia (MIH) is a severe adverse effect accompanying repeated morphine treatment, causing a paradoxical decrease in nociceptive threshold. Previous reports associated MIH with a decreased expression of the Cl− extruder KCC2 in the superficial dorsal horn (SDH) of the spinal cord, weakening spinal GABAA/glycine-mediated postsynaptic inhibition. Here, we tested whether the administration of small molecules enhancing KCC2, CLP257 and its pro-drug CLP290, may counteract MIH. MIH was typically expressed within 6–8 days of morphine treatment. Morphine-treated rats exhibited decreased withdrawal threshold to mechanical stimulation and increased vocalizing behavior to subcutaneous injections. Chloride extrusion was impaired in SDH neurons measured as a depolarizing shift in E GABA under Cl− load. Delivering CLP257 to spinal cord slices obtained from morphine-treated rats was sufficient to restore Cl− extrusion capacity in SDH neurons. In vivo co-treatment with morphine and oral CLP290 prevented membrane KCC2 downregulation in SDH neurons. Concurrently, co-treatment with CLP290 significantly mitigated MIH and acute administration of CLP257 in established MIH restored normal nociceptive behavior. Our data indicate that enhancing KCC2 activity is a viable therapeutic approach for counteracting MIH. Chloride extrusion enhancers may represent an effective co-adjuvant therapy to improve morphine analgesia by preventing and reversing MIH.
format	article
author	Francesco Ferrini Louis-Etienne Lorenzo Antoine G. Godin Miorie Le Quang Yves De Koninck
author_facet	Francesco Ferrini Louis-Etienne Lorenzo Antoine G. Godin Miorie Le Quang Yves De Koninck
author_sort	Francesco Ferrini
title	Enhancing KCC2 function counteracts morphine-induced hyperalgesia
title_short	Enhancing KCC2 function counteracts morphine-induced hyperalgesia
title_full	Enhancing KCC2 function counteracts morphine-induced hyperalgesia
title_fullStr	Enhancing KCC2 function counteracts morphine-induced hyperalgesia
title_full_unstemmed	Enhancing KCC2 function counteracts morphine-induced hyperalgesia
title_sort	enhancing kcc2 function counteracts morphine-induced hyperalgesia
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/0eca9d636d3343e999ceb6e781d6238c
work_keys_str_mv	AT francescoferrini enhancingkcc2functioncounteractsmorphineinducedhyperalgesia AT louisetiennelorenzo enhancingkcc2functioncounteractsmorphineinducedhyperalgesia AT antoineggodin enhancingkcc2functioncounteractsmorphineinducedhyperalgesia AT miorielequang enhancingkcc2functioncounteractsmorphineinducedhyperalgesia AT yvesdekoninck enhancingkcc2functioncounteractsmorphineinducedhyperalgesia
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Enhancing KCC2 function counteracts morphine-induced hyperalgesia

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