Development and persistence of neuropathic pain through microglial activation and KCC2 decreasing after mouse tibial nerve injury

Brain Res. 2020 Apr 15;1733:146718. doi: 10.1016/j.brainres.2020.146718. Epub 2020 Feb 8.

Abstract

Gamma-amino butyric acid (GABA) is an inhibitory neurotransmitter in the mature brain, but is excitatory during development and after motor nerve injury. This difference in GABAergic action depends on the intracellular chloride ion concentration ([Cl-]i), primarily regulated by potassium chloride co-transporter 2 (KCC2). To reveal precise processes of the neuropathic pain through changes in GABAergic action, we prepared tibial nerve ligation and severance models using male mice, and examined temporal relationships amongst changes in (1) the mechanical withdrawal threshold in the sural nerve area, (2) localization of the molecules involved in GABAergic transmission and its upstream signaling in the dorsal horn, and (3) histology of the tibial nerve. In the ligation model, tibial nerve degeneration disappeared by day 56, but mechanical allodynia, reduced KCC2 localization, and increased microglia density remained until day 90. Microglia density was higher in the tibial zone than the sural zone before day 21, but this result was inverted after day 28. In contrast, in the severance model, all above changes were detected until day 28, but were simultaneously and significantly recovered by day 90. These results suggested that in male mice, allodynia may be caused by reduced GABAergic synaptic inhibition, resulting from elevated [Cl-]i after the reduction of KCC2 by activated microglia. Furthermore, our results suggested that factors from degenerating nerve terminals may diffuse into the sural zone, whereby they induced the development of allodynia in the sural nerve area, while other factors in the sural zone may mediate persistent allodynia through the same pathway.

Keywords: Mechanical allodynia; Microglia; Nerve degeneration; Nerve ligation; Nerve severance; Potassium chloride co-transporter 2 (KCC2).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Male
  • Mice, Inbred C57BL
  • Microglia / metabolism*
  • Neuralgia / metabolism*
  • Neuralgia / pathology
  • Pain Threshold
  • Symporters / metabolism*
  • Tibial Nerve / injuries*
  • Tibial Nerve / metabolism*
  • Tibial Nerve / pathology

Substances

  • Symporters
  • potassium-chloride symporters