Affiliated with Université Laval and the CERVO Research Centre

Enhancing KCC2 function counteracts morphine-induced hyperalgesia.

TitleEnhancing KCC2 function counteracts morphine-induced hyperalgesia.
Publication TypeJournal Article
Year of Publication2017
AuthorsFerrini F, Lorenzo L-E, Godin AG, Le Quang M, De Koninck Y
JournalSci Rep
Volume7
Issue1
Pagination3870
Date Published2017 Jun 20
ISSN2045-2322
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.

DOI10.1038/s41598-017-04209-3
Alternate JournalSci Rep
PubMed ID28634406
PubMed Central IDPMC5478677