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 carrageenan-evoked vasculitis as compared with ASIC3+/+ mice.


CONCLUSIONS
We provide a novel finding that ASIC3 participates in the maintenance of sub-acute-phase primary hyperalgesia in subcutaneous inflammation and mediates the process of granuloma formation and vasculitis in intramuscular inflammation.
Yen
Yi-Tin
YT
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan. yitinxxxx@gmail.com
Tu
Pan-Hsien
PH
Chen
Chien-Ju
CJ
Lin
Yi-Wen
YW
Hsieh
Sung-Tsang
ST
Chen
Chih-Cheng
CC
D062565:Acid Sensing Ion Channels; D000210:Acute-Phase Reaction / Q000503:physiopathology*; D000818:Animals; D006930:Hyperalgesia / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
C508378:ASIC3 protein, mouse; D062565:Acid Sensing Ion Channels; D015222:Sodium Channels; D013779:Tetrodotoxin