Chloride Dysregulation through Downregulation of KCC2 Mediates Neuropathic Pain in Both Sexes

Cell Rep. 2019 Jul 16;28(3):590-596.e4. doi: 10.1016/j.celrep.2019.06.059.


The behavioral features of neuropathic pain are not sexually dimorphic despite sex differences in the underlying neuroimmune signaling. This raises questions about whether neural processing is comparably altered. Here, we test whether the K+-Cl- co-transporter KCC2, which regulates synaptic inhibition, plays an equally important role in development of neuropathic pain in male and female rodents. Past studies on KCC2 tested only males. We find that inhibiting KCC2 in uninjured animals reproduces behavioral and electrophysiological features of neuropathic pain in both sexes and, consistent with equivalent injury-induced downregulation of KCC2, that counteracting chloride dysregulation reverses injury-induced behavioral and electrophysiological changes in both sexes. These findings demonstrate that KCC2 downregulation contributes equally to pain hypersensitivity in males and females. Whereas diverse (and sexually dimorphic) mechanisms regulate KCC2, regulation of intracellular chloride relies almost exclusively on KCC2. Directly targeting KCC2 thus remains a promising strategy for treatment of neuropathic pain in both sexes.

Keywords: BDNF; GABA; K(+)-Cl(−) co-transporter KCC2; degeneracy; disinhibition; glycine; neuropathic pain; sex differences.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetazolamide / pharmacology
  • Animals
  • Brain-Derived Neurotrophic Factor / pharmacology
  • Carbonic Anhydrase Inhibitors / pharmacology
  • Chlorides / metabolism*
  • Down-Regulation
  • Female
  • Hyperalgesia / chemically induced
  • Hyperalgesia / genetics
  • Hyperalgesia / metabolism
  • K Cl- Cotransporters
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuralgia / genetics
  • Neuralgia / metabolism*
  • Neuralgia / physiopathology
  • Posterior Horn Cells / drug effects
  • Posterior Horn Cells / metabolism*
  • Posterior Horn Cells / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Sex Characteristics
  • Spinal Cord / cytology
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism*
  • Spinal Cord / surgery
  • Symporters / antagonists & inhibitors*
  • Symporters / genetics
  • Symporters / metabolism*
  • Thiazoles / pharmacology
  • Thioglycolates / pharmacology


  • Brain-Derived Neurotrophic Factor
  • Carbonic Anhydrase Inhibitors
  • Chlorides
  • N-(4-methylthiazol-2-yl)-2-(6-phenylpyridazin-3-ylthio)acetamide
  • Symporters
  • Thiazoles
  • Thioglycolates
  • Acetazolamide