Store-operated calcium entry mediates hyperalgesic responses during neuropathy

FEBS Open Bio, 2023 · DOI: 10.1002/2211-5463.13699 · Published: January 1, 2023

Simple Explanation

Neuropathic pain, resulting from nerve injury, changes the spinal cord and brain through inflammatory substances. Store-operated calcium entry (SOCE), involving calcium refilling in the endoplasmic reticulum via STIM1 and Orai1 proteins, is important for neural plasticity and neurotransmitter release. This study found that SOCE-mediated calcium refilling was significantly higher during neuropathic pain, with Orai1 specifically located with neuronal markers. Blocking SOCE with SKF96365 reduced nerve injury- and formalin-induced pain and suppressed c-Fos expression upon mechanical stimulation. Blocking SOCE signaling in the spine may be a promising target for pain relief by regulating neurotransmitter production and spinal transcription factor expression.

Study Duration

Not specified

Participants

Adult male Wistar rats

Evidence Level

Level 2; Experimental study

Key Findings

1
SOCE-mediated calcium influx was significantly increased following nerve injury in neuropathic rats.
2
Intrathecal SKF96365 treatment significantly alleviated hypersensitivity in SNL and formalin pain.
3
SKF96365 treatment induced a strong reversal in the expression of these SNL-associated genes, such as Fos, Junb, and Socs3.

Research Summary

This study identified a significant increase in SOCE-mediated calcium influx following injury-induced neuropathic pain. Pharmacologically inhibition of SOCE by both SKF96365 and YM-58483 had an analgesic effect on NP. SKF96365 treatment rescued neuronal c-Fos+ expression in neuropathic rats. Electrophysiological recordings demonstrated that SOCE inhibition was crucially involved in spinal synaptic plasticity during pain. The findings of this study revealed that SKF96365 and YM58483 produced antinociception in neuropathic rats after pharmacologically blocking SOCE in the spinal cord.

Practical Implications

Potential Therapeutic Target

Spinal SOCE signaling could be a promising target for pain relief.

Drug Development

SKF96365 and YM-58483 offer a pharmacological basis for novel drug development targeting SOCE.

Understanding Neuropathic Pain

Further research into SOCE's role can enhance our understanding of neuropathic pain mechanisms.

Study Limitations

1
The study primarily used male Wistar rats, limiting generalizability to other populations.
2
Viral manipulation of calcium ion activity and in vivo recording may provide the causal evidence, be essential for a deeper understanding of the signiﬁcance of SOCE.
3
The mechanism for SOCE-mediated behavioral sensitization, including neuronal plasticity and subsequent gene expression during neuropathic pain, remains largely unknown.

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