Cell Reports
Volume 28, Issue 3, 16 July 2019, Pages 590-596.e4
Journal home page for Cell Reports

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

https://doi.org/10.1016/j.celrep.2019.06.059Get rights and content
Under a Creative Commons license
open access

Highlights

  • Different neuroimmune signaling pathways cause neuropathic pain in males and females

  • Downregulation of KCC2 is equally important for pain pathogenesis in each sex

  • KCC2 is regulated in many ways but is uniquely responsible for regulating chloride

  • KCC2 is a conceptually better therapeutic target than sex-specific mechanisms

Summary

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

K+-Cl co-transporter KCC2
sex differences
degeneracy
neuropathic pain
disinhibition
GABA
glycine
BDNF

Cited by (0)

7

Lead Contact