The inhibition of Kir2.1 potassium channels depolarizes spinal microglial cells, reduces their proliferation, and attenuates neuropathic pain.
Animals
Cell Line, Transformed
Cell Proliferation
/ drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Imidazoles
/ administration & dosage
Injections, Spinal
Male
Mice
Mice, Transgenic
Microglia
/ drug effects
Neuralgia
/ metabolism
Phenanthrolines
/ administration & dosage
Potassium Channel Blockers
/ administration & dosage
Potassium Channels, Inwardly Rectifying
/ antagonists & inhibitors
Spinal Cord
/ cytology
Kir2.1
membrane potential
microglia
neuropathic pain
proliferation
Journal
Glia
ISSN: 1098-1136
Titre abrégé: Glia
Pays: United States
ID NLM: 8806785
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
17
07
2019
revised:
11
03
2020
accepted:
13
03
2020
pubmed:
29
3
2020
medline:
12
11
2021
entrez:
29
3
2020
Statut:
ppublish
Résumé
Spinal microglia change their phenotype and proliferate after nerve injury, contributing to neuropathic pain. For the first time, we have characterized the electrophysiological properties of microglia and the potential role of microglial potassium channels in the spared nerve injury (SNI) model of neuropathic pain. We observed a strong increase of inward currents restricted at 2 days after injury associated with hyperpolarization of the resting membrane potential (RMP) in microglial cells compared to later time-points and naive animals. We identified pharmacologically and genetically the current as being mediated by Kir2.1 ion channels whose expression at the cell membrane is increased 2 days after SNI. The inhibition of Kir2.1 with ML133 and siRNA reversed the RMP hyperpolarization and strongly reduced the currents of microglial cells 2 days after SNI. These electrophysiological changes occurred coincidentally to the peak of microglial proliferation following nerve injury. In vitro, ML133 drastically reduced the proliferation of BV2 microglial cell line after both 2 and 4 days in culture. In vivo, the intrathecal injection of ML133 significantly attenuated the proliferation of microglia and neuropathic pain behaviors after nerve injury. In summary, our data implicate Kir2.1-mediated microglial proliferation as an important therapeutic target in neuropathic pain.
Substances chimiques
2-(2-methyl-1H-indol-3-yl)-1H-imidazol(4,5-f)(1,10)phenanthroline
0
Imidazoles
0
Kir2.1 channel
0
Phenanthrolines
0
Potassium Channel Blockers
0
Potassium Channels, Inwardly Rectifying
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2119-2135Subventions
Organisme : NINDS NIH HHS
ID : R21 NS106264
Pays : United States
Informations de copyright
© 2020 Wiley Periodicals, Inc.
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