Microglia are essential mediators of neuroinflammation, which underlies neuropathic discomfort. However, the molecular checkpoints controlling microglial reactivity aren’t well-understood. Here, we investigated the function of Orai1 channels for microglia-mediated neuroinflammation following nerve injuries and discover that deletion of Orai1 in microglia attenuates Ca2 signaling and producing inflammatory cytokines by proalgesic agonists. Conditional deletion of Orai1 attenuated microglial proliferation within the dorsal horn, spine cytokine levels, and potentiation of excitatory neurotransmission following peripheral nerve injuries. These cellular effects were supported by minimization of discomfort hyperalgesia in microglial Orai1 knockout rodents. A little-molecule Orai1 inhibitor, CM4620, similarly mitigated allodynia in male rodents. Suddenly, these protective effects weren’t observed in female rodents, revealing sexual dimorphism in Orai1 regulating microglial reactivity and hyperalgesia. Together, these bits of information indicate that Orai1 channels are key regulators from the sexually dimorphic role of microglia for that neuroinflammation that underlies neuropathic discomfort.CM 4620