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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| Format: | Article |
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Nature Portfolio
2017-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-04209-3 |
| _version_ | 1818571669804941312 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T14:59:03Z |
| format | Article |
| id | doaj.art-0eca9d636d3343e999ceb6e781d6238c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T14:59:03Z |
| publishDate | 2017-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-0eca9d636d3343e999ceb6e781d6238c2022-12-21T22:56:53ZengNature PortfolioScientific Reports2045-23222017-06-01711810.1038/s41598-017-04209-3Enhancing KCC2 function counteracts morphine-induced hyperalgesiaFrancesco Ferrini0Louis-Etienne Lorenzo1Antoine G. Godin2Miorie Le Quang3Yves De Koninck4Department of Veterinary Sciences, University of TurinCERVO Brain Research Centre, Institut universitaire en santé mentale de QuébecCERVO Brain Research Centre, Institut universitaire en santé mentale de QuébecCERVO Brain Research Centre, Institut universitaire en santé mentale de QuébecCERVO Brain Research Centre, Institut universitaire en santé mentale de QuébecAbstract 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.https://doi.org/10.1038/s41598-017-04209-3 |
| spellingShingle | Francesco Ferrini Louis-Etienne Lorenzo Antoine G. Godin Miorie Le Quang Yves De Koninck Enhancing KCC2 function counteracts morphine-induced hyperalgesia Scientific Reports |
| title | 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_short | Enhancing KCC2 function counteracts morphine-induced hyperalgesia |
| title_sort | enhancing kcc2 function counteracts morphine induced hyperalgesia |
| url | https://doi.org/10.1038/s41598-017-04209-3 |
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