Role of acid-sensing ion channel 3 in sub-acute-phase inflammation

Background: Inflammation-mediated hyperalgesia involves tissue acidosis and sensitization of nociceptors. Many studies have reported increased expression of acid-sensing ion channel 3 (ASIC3) in inflammation and enhanced ASIC3 channel activity with pro-inflammatory mediators. However, the role of ASIC3 in inflammation remains inconclusive because of conflicting results generated from studies of ASIC3 knockout (ASIC3(-/-)) or dominant-negative mutant mice, which have shown normal, decreased or increased hyperalgesia during inflammation. Results: Here, we tested whether ASIC3 plays an important role in inflammation of subcutaneous tissue of paw and muscle in ASIC3(-/-) mice induced by complete Freund's adjuvant (CFA) or carrageenan by investigating behavioral and pathological responses, as well as the expression profile of ion channels. Compared with the ASIC3(+/+) controls, ASIC3(-/-) mice showed normal thermal and mechanical hyperalgesia with acute (4-h) intraplantar CFA- or carrageenan-induced inflammation, but the hyperalgesic effects in the sub-acute phase (1-2 days) were milder in all paradigms except for thermal hyperalgesia with CFA-induced inflammation. Interestingly, carrageenan-induced primary hyperalgesia was accompanied by an ASIC3-dependent Nav1.9 up-regulation and increase of tetrodotoxin (TTX)-resistant sodium currents. CFA-inflamed muscle did not evoke hyperalgesia in ASIC3(-/-) or ASIC3(+/+) mice, whereas carrageenan-induced inflammation in muscle abolished mechanical hyperalgesia in ASIC3(-/-) mice, as previously described. However, ASIC3(-/-) mice showed attenuated pathological features such as less CFA-induced granulomas and milder carrageenanevoked vasculitis as compared with ASIC3(+/+) mice. Conclusion: We provide a novel finding that ASIC3 participates in the maintenance of sub-acutephase primary hyperalgesia in subcutaneous inflammation and mediates the process of granuloma formation and vasculitis in intramuscular inflammation.