PGE2 Potentiates Orai1-Mediated Calcium Entry Contributing to Peripheral Sensitization

Area of Science:

• Neuroscience
• Pain Research
• Molecular Biology

Background:

• Peripheral sensitization is key to chronic pain pathogenesis, but involved molecules are not fully understood.
• Store-operated calcium channels (SOCs) are present in dorsal root ganglion (DRG) neurons, but their role in inflammatory pain is unclear.

Purpose of the Study:

• To investigate the role of Orai1, a component of SOCs, in peripheral sensitization and inflammatory pain.
• To elucidate the mechanisms by which prostaglandin E2 (PGE2) modulates Orai1 function in DRG neurons.

Main Methods:

• Utilized global and conditional Orai1 knockout mouse models.
• Induced inflammatory pain using Complete Freund's Adjuvant (CFA) and carrageenan.
• Performed calcium imaging and patch-clamp recordings on DRG neurons.
• Investigated the effects of PGE2, EP1 receptor antagonists/agonists, and downstream signaling inhibitors (Gq/11, PKC, ERK).

Main Results:

• Orai1 deletion attenuated CFA-induced pain hypersensitivity in male and female mice.
• SOC function was enhanced in DRG neurons from inflamed wild-type mice but not Orai1 knockout mice.
• PGE2-induced neuronal hyperexcitability and pain hypersensitivity were reduced in Orai1 knockout mice.
• PGE2 potentiated SOC entry (SOCE) via the EP1 receptor and downstream signaling (Gq/11, PKC, ERK) in WT but not Orai1 KO neurons.

Conclusions:

• Orai1 plays a significant role in peripheral sensitization underlying inflammatory pain.
• PGE2 enhances SOCE in DRG neurons through an EP1-mediated signaling cascade.
• Orai1 represents a potential therapeutic target for managing pathological pain conditions.