Title | Enhancing KCC2 function counteracts morphine-induced hyperalgesia. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Ferrini, F, Lorenzo, L-E, Godin, AG, Le Quang, M, De Koninck, Y |
Journal | Sci Rep |
Volume | 7 |
Issue | 1 |
Pagination | 3870 |
Date Published | 2017 06 20 |
ISSN | 2045-2322 |
Keywords | Animals, Electrophysiological Phenomena, Gene Expression, Hyperalgesia, Male, Morphine, Posterior Horn Cells, Rats, Symporters, Thiazolidines |
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 GABA/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 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. |
DOI | 10.1038/s41598-017-04209-3 |
Alternate Journal | Sci Rep |
PubMed ID | 28634406 |
PubMed Central ID | PMC5478677 |
Grant List | MOP12942 / / CIHR / Canada |