Enhancing KCC2 function counteracts morphine-induced hyperalgesia

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Electrophysiological Phenomena
  • Gene Expression
  • Hyperalgesia / etiology*
  • Hyperalgesia / metabolism*
  • Male
  • Morphine / adverse effects*
  • Posterior Horn Cells / drug effects
  • Posterior Horn Cells / metabolism
  • Rats
  • Symporters / genetics
  • Symporters / metabolism*
  • Thiazolidines / pharmacology

Substances

  • CLP257
  • SLC12A5 protein, human
  • Symporters
  • Thiazolidines
  • Morphine