G2A as a Threshold Regulator of Inflammatory Hyperalgesia Modulates Chronic Hyperalgesia

Tissue injury, pathogen infection, and diseases are often accompanied by inflammation to release mediators that sensitize nociceptors and further recruit immune cells, which can lead to chronic hyperalgesia and inflammation. Tissue acidosis, occurring at the inflammatory site, is a major factor contributing to pain and hyperalgesia. The receptor G2 accumulation (G2A), expressed in neurons and immune cells, responds to protons or oxidized free fatty acids such as 9-hydroxyoctadecadienoic acid produced by injured cells or oxidative stresses. We previously found increased G2A expression in mouse dorsal root ganglia (DRG) at 90 min after complete Freund’s adjuvant (CFA)-induced inflammatory pain, but whether G2A is involved in the inflammation or hyperalgesia remained unclear. In this study, we overexpressed or knocked-down G2A gene expression in DRG to explore the roles of G2A. G2A overexpression reduced the infiltration of acute immune cells (granulocytes) and attenuated hyperalgesia at 90 to 240 min after CFA injection. G2A knockdown increased the number of immune cells before CFA injection and prolonged the inflammatory hyperalgesia after CFA injection. G2A may serve as a threshold regulator in neurons to attenuate the initial nociceptive and inflammatory signals, modulating the chronic state of hyperalgesia.