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Regulation of neuropathic pain by microglial Orai1 channels

Shogo Tsujikawa1, Kaitlyn E DeMeulenaere1, Maria V Centeno2

  • 1Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Science Advances
|January 27, 2023
PubMed

Insights

Orai1 channels in microglia regulate neuroinflammation and neuropathic pain. Inhibiting Orai1 reduces pain, but this effect differs between sexes, highlighting a sexually dimorphic role in pain regulation.

Area of Science:

  • Neuroscience
  • Immunology
  • Pain Research

Background:

  • Microglia are key players in neuroinflammation and neuropathic pain.
  • Molecular mechanisms controlling microglial activation remain unclear.

Purpose of the Study:

  • To investigate the role of Orai1 channels in microglia-mediated neuroinflammation and neuropathic pain.
  • To explore the potential of Orai1 as a therapeutic target.

Main Methods:

  • Conditional knockout of Orai1 in microglia.
  • Assessment of calcium signaling and cytokine production.
  • Evaluation of pain behaviors (hyperalgesia, allodynia) in mouse models of nerve injury.
  • Pharmacological inhibition of Orai1 using CM4620.

Main Results:

  • Orai1 deletion in microglia reduced calcium influx and inflammatory cytokine release.
  • Microglial Orai1 knockout attenuated spinal cord inflammation and pain hypersensitivity.
  • Orai1 inhibition mitigated pain in male mice but not female mice, indicating sexual dimorphism.
  • Orai1 channels are crucial for microglial reactivity in neuropathic pain.

Conclusions:

  • Orai1 channels are critical regulators of microglial function in neuropathic pain.
  • Targeting Orai1 presents a potential therapeutic strategy for pain management.
  • Sexual dimorphism exists in Orai1-mediated pain pathways, necessitating sex-specific treatment considerations.

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