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Papers of the Week

Papers: 21 Jan 2023 - 3 Feb 2023

2023 Jan 27

Sci Adv



Editor's Pick

Regulation of neuropathic pain by microglial Orai1 channels.


Tsujikawa S, DeMeulenaere KE, Centeno MV, Ghazisaeidi S, Martin ME, Tapies MR, Maneshi MM, Yamashita M, Stauderman KA, Apkarian AV, Salter MW, Prakriya M
Sci Adv. 2023 Jan 27; 9(4):eade7002.
PMID: 36706180.


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