Regulation of neuropathic pain by microglial Orai1 channels

Abstract

Microglia are important mediators of neuroinflammation that underlies neuropathic pain. However, the molecular checkpoints controlling microglial reactivity are not well-understood. We investigated the role of Orai1 channels for microglia-mediated neuroinflammation following nerve injury and find that deletion of Orai1 in microglia attenuates Ca2+ signaling and the production of inflammatory cytokines by proalgesic agonists. Conditional deletion of Orai1 attenuated microglia proliferation in the dorsal horn, spinal cytokines levels, and potentiation of excitatory neurotransmission following peripheral nerve injury. These cellular effects were accompanied by mitigation of pain hyperalgesia in Orai1 knockout mice. A small-molecule Orai1 inhibitor, CM4620, similarly mitigated allodynia in male mice. Surprisingly, these protective effects were not seen in female mice, revealing striking sexual dimorphism in Orai1 regulation of microglial reactivity and hyperalgesia. These findings indicate that Orai1 channels are key regulators of the sexually dimorphic role of microglia for the neuroinflammation that underlies neuropathic pain.