Activation of the STING pathway induces peripheral sensitization via neuroinflammation in a rat model of bone cancer pain

Background Neuroinflammation in the peripheral nervous system has been linked to cancer metastasis-induced bone pain.

The stimulator of interferon genes (STING), an innate immune sensor for cytosolic DNA, plays an important role in inflammation and cancer metastasis and is reported to be a critical regulator of nociception.

Here, we examined the role of STING in primary nociceptive neurons and chronic pain to determine if it could be a new target for treating bone cancer pain (BCP).

Methods Walker 256 cancer cells were injected intratibially to induce bone cancer pain in rats.

STING and its downstream inflammatory factors in dorsal root ganglia (DRG) were detected using western blotting and immunofluorescent staining.

Transmission electron microscopy and the BCL2-associated X (Bax) expression were used to detect the mitochondrial stress in DRG neurons.

C-176, a specific inhibitor of STING, was used to block STING activation and to test the pain behavior.

Results Mechanical hyperalgesia and spontaneous pain were observed in BCP rats, accompanied by the upregulation of the STING expression in the ipsilateral L4-5 DRG neurons which showed significant mitochondrion stress.

The STING/TANK-binding kinase 1 (TBK1)/nuclear factor-kappa B (NF-κB) pathway activation was observed in the DRGs of BCP rats as well as increased IL-1β, IL-6, and TNF-α expression.

C-176 alleviated bone cancer pain and reduced the STING and its downstream inflammatory pathway.

Conclusion We provide evidence that STING pathway activation leads to neuroinflammation and peripheral sensitization.

Pharmacological blockade of STING may be a promising novel strategy for preventing BCP.