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Sci Rep. 2017 Jun 20;7(1):3870. doi: 10.1038/s41598-017-04209-3.

Enhancing KCC2 function counteracts morphine-induced hyperalgesia.

Author information

1
Department of Veterinary Sciences, University of Turin, Turin, Italy.
2
CERVO Brain Research Centre, Institut universitaire en santé mentale de Québec, Québec, Canada.
3
CERVO Brain Research Centre, Institut universitaire en santé mentale de Québec, Québec, Canada. yves.dekoninck@neuro.ulaval.ca.
4
Department of Psychiatry and Neuroscience, Université Laval, Québec, Canada. yves.dekoninck@neuro.ulaval.ca.

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.

PMID:
28634406
PMCID:
PMC5478677
DOI:
10.1038/s41598-017-04209-3
[Indexed for MEDLINE]
Free PMC Article

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