EXPRESS: Mitochondrial DAMPs produce inflammatory hyperalgesia via stimulator of interferon genes (STING) activation in DRG neurons

Damage-associated molecular patterns (DAMPs), including mitochondria-derived molecules, are known to trigger immune responses and produce nociceptor sensitization during tissue inflammation. This animal study investigated whether mitochondrial debris promotes inflammatory hyperalgesia through activation of the stimulator of interferon genes (STING) signaling pathway in dorsal root ganglion (DRG) neurons.The results showed that local administration of mitochondrial debris into the hind paws of rats induced significant mechanical hyperalgesia and increased STING expression in DRG neurons. Pretreatment with H-151, a selective STING inhibitor, attenuated both debris-induced hyperalgesia and neuronal STING upregulation. STING expression in DRG neurons was similarly upregulated in a model of tissue inflammation induced by Complete Freund's Adjuvant (CFA), and administration of H-151 significantly alleviated the inflammatory hyperalgesia and increase in STING expression. These findings suggest that mitochondrial debris released during tissue inflammation activates the STING pathway in primary afferent neurons. Effective suppression of hyperalgesia by pharmacological inhibition of STING in both debris-induced and CFA-induced models in this study highlights the pronociceptive role of STING activation in peripheral sensory neurons.In conclusion, mitochondrial debris-induced STING activation in DRG neurons plays a critical role in the development of inflammatory hyperalgesia, and targeting this pathway might represent a novel therapeutic strategy for inflammatory pain.