Store-operated calcium entry mediates hyperalgesic responses during neuropathy

Area of Science:

• Neuroscience
• Pain Research
• Molecular Biology

Background:

• Neuropathic pain (NP) arises from nerve injury, altering neural plasticity through inflammatory mediators.
• Store-operated calcium entry (SOCE), involving STIM1 and Orai1 proteins, is critical for neural plasticity and neurotransmitter release, but its role in NP is unclear.

Purpose of the Study:

• To investigate the role of SOCE in neuropathic pain.
• To identify molecular targets for pain relief by manipulating SOCE signaling.

Main Methods:

• Measured SOCE-mediated calcium refilling in neuropathic pain models.
• Administered intrathecal SOCE antagonists (SKF96365, YM-58483) and assessed pain behaviors.
• Utilized RNA sequencing and weighted gene co-expression network analysis (WGCNA) to identify gene expression changes.
• Performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.

Main Results:

• SOCE-mediated calcium refilling was elevated in neuropathic pain.
• SKF96365 and YM-58483 significantly alleviated pain behaviors and reduced c-Fos expression.
• RNA sequencing revealed SKF96365 altered expression of spinal transcription factors (Fos, Junb, Socs3).
• WGCNA identified the MEsalmon module as highly correlated with SKF96365 effects, enriched in pathways like Toll-like receptor signaling.

Conclusions:

• Spinal SOCE signaling is upregulated in neuropathic pain.
• Inhibition of SOCE demonstrates significant analgesic effects.
• Targeting spinal SOCE may offer a novel therapeutic strategy for neuropathic pain by modulating neurotransmitter production and transcription factor expression.