Sensitization of ASIC3 by proteinase-activated receptor 2 signaling contributes to acidosis-induced nociception

Tissue acidosis and inflammatory mediators play critical roles in pain. Pro-inflammatory agents trypsin and tryptase cleave and activate proteinase-activated receptor 2 (PAR₂) expressed on sensory nerves, which is involved in peripheral mechanisms of inflammation and pain. Extracellular acidosis activates acid-sensing ion channel 3 (ASIC3) to trigger pain sensation. Here, we show that a functional interaction of PAR₂ and ASIC3 could contribute to acidosis-induced nociception.

Electrophysiological experiments were performed on both rat DRG neurons and Chinese hamster ovary (CHO) cells expressing ASIC3 and PAR₂. Nociceptive behavior was induced by acetic acid in rats.

PAR₂-AP, PAR₂-activating peptide, concentration-dependently increased the ASIC3 currents in CHO cells transfected with ASIC3 and PAR₂. The proton concentration-response relationship was not changed, but that the maximal response increased 58.7 ± 3.8% after pretreatment of PAR₂-AP. PAR₂ mediated the potentiation of ASIC3 currents via an intracellular cascade. PAR₂-AP potentiation of ASIC3 currents disappeared after inhibition of intracellular G protein, PLC, PKC, or PKA signaling. Moreover, PAR₂ activation increased proton-evoked currents and spikes mediated by ASIC3 in rat dorsal root ganglion neurons. Finally, peripheral administration of PAR₂-AP dose-dependently exacerbated acidosis-induced nocifensive behaviors in rats.

These results indicated that PAR₂ signaling sensitized ASIC3, which may contribute to acidosis-induced nociception. These represent a novel peripheral mechanism underlying PAR₂ involvement in hyperalgesia by sensitizing ASIC3 in primary sensory neurons.