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Background  Tissue acidosis and inflammatory mediators play critical roles in pain. Pro-inflammatory agents trypsin and tryptase cleave and activate proteinase-activated receptor 2 (PAR 2 ) 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 PAR 2  and ASIC3 could contribute to acidosis-induced nociception.    Methods  Electrophysiological experiments were performed on both rat DRG neurons and Chinese hamster ovary (CHO) cells expressing ASIC3 and PAR 2 . Nociceptive behavior was induced by acetic acid in rats.    Results  PAR 2 -AP, PAR 2 -activating peptide, concentration-dependently increased the ASIC3 currents in CHO cells transfected with ASIC3 and PAR 2 . The proton concentration–response relationship was not changed, but that the maximal response increased 58.7 ± 3.8% after pretreatment of PAR 2 -AP. PAR 2  mediated the potentiation of ASIC3 currents via an intracellular cascade. PAR 2 -AP potentiation of ASIC3 currents disappeared after inhibition of intracellular G protein, PLC, PKC, or PKA signaling. Moreover, PAR 2  activation increased proton-evoked currents and spikes mediated by ASIC3 in rat dorsal root ganglion neurons. Finally, peripheral administration of PAR 2 -AP dose-dependently exacerbated acidosis-induced nocifensive behaviors in rats.    Conclusions  These results indicated that PAR 2  signaling sensitized ASIC3, which may contribute to acidosis-induced nociception. These represent a novel peripheral mechanism underlying PAR 2  involvement in hyperalgesia by sensitizing ASIC3 in primary sensory neurons.

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