The inhibition of Kir2.1 potassium channels depolarizes spinal microglial cells, reduces their proliferation, and attenuates neuropathic pain

• Published in: Glia Vol. 68; no. 10; pp. 2119 - 2135
• Main Authors: Gattlen, Christophe, Deftu, Alexandru‐Florian, Tonello, Raquel, Ling, Yuejuan, Berta, Temugin, Ristoiu, Violeta, Suter, Marc René
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.10.2020; Wiley Subscription Services, Inc
• Subjects: Cell culture; Cell membranes; Cell proliferation; Depolarization; Hyperpolarization; Injury prevention; Ion channels; Kir2.1; Membrane potential; Microglia; Microglial cells; Neuralgia; neuropathic pain; Pain; Phenotypes; Potassium; Potassium channels; Potassium channels (inwardly-rectifying); proliferation; siRNA; neuropathic pain; proliferation; microglia; Kir2.1; membrane potential
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23831

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. Two days after SNI, increase Kir2.1 expression and current density in dorsal horn microglial cells coincidently with cell proliferation. Intrathecal administration of ML133, a Kir2.1 inhibitor, reduces allodynia and cell proliferation.