MYCOLab Ai Logo - gold and army green

Rac1/PAK1 signaling contributes to bone cancer pain by regulation dendritic spine remodeling in rats

Summary

Researchers studied how bone cancer pain develops in rats and found that a specific cellular signaling pathway called Rac1/PAK1 plays a key role. When tumors grow in bone, this pathway becomes overactive and causes changes in nerve cell structures called dendritic spines, which leads to increased pain sensitivity. By blocking this pathway with a drug called NSC23766, scientists were able to reduce pain and reverse the harmful changes to nerve cells, suggesting a new potential treatment approach for cancer patients suffering from bone pain.

Background

Bone cancer pain (BCP) is severe chronic pain caused by tumor metastasis to bones, often resulting in significant skeletal remodeling and fractures with no current curative treatment. Central sensitization involving dendritic spine remodeling has been recognized as a mechanism underlying BCP development. Rac1/PAK1 signaling pathway regulates cytoskeleton assembly and dendritic spine development, suggesting a potential role in BCP pathophysiology.

Objective

To investigate whether Rac1/PAK1 signaling is involved in the initiation and development of bone cancer pain by regulating plasticity of spinal cord dendritic spines in rats. The study aimed to determine if modulation of this pathway could reverse pain-related dendritic spine remodeling.

Results

TCI treatment caused time-dependent upregulation of activated GTP-Rac1 and phosphorylated PAK1 in the spinal dorsal horn, correlating with development of mechanical allodynia. Golgi staining revealed increased dendritic spine density and altered spine morphology (increased thin and mushroom spines) following TCI. Intrathecal injection of NSC23766 (Rac1 inhibitor) significantly reduced pain behavior and reversed dendritic spine remodeling, including reduced postsynaptic density length, decreased synaptic cleft width, and normalized PSD thickness.

Conclusion

Activation of Rac1/PAK1 signaling pathway in the spinal cord plays a critical role in the development of bone cancer pain through regulation of dendritic spine remodeling. Inhibition of Rac1/PAK1 signaling may represent a potential therapeutic strategy for treating bone cancer pain by reversing central sensitization mechanisms.
  • Published in:Molecular Pain,
  • Study Type:Animal Research Study,
  • Source: PMID: 36938611, DOI: 10.1177/17448069231161031
Scroll to Top