Abstract
We have previously established a thrombus-induced ischemic pain (TIIP) model in the
rat, which mimics the pathophysiology of ischemic pain in patients with peripheral
arterial disease. Because ischemia commonly induces acidosis and ATP release, one
of the goals of this study was to investigate the role of acid-sensing ion channels
(ASICs), transient receptor potential vanilloid-1 (TRPV1) receptors, and P2X receptors
in the maintenance of ischemia-induced mechanical allodynia (MA). To test this, amiloride
(an ASIC blocker), AMG-9810 (a TRPV1 blocker), or PPADS (a P2Xs antagonist) was intraplantarly
injected at day 3 after FeCl2 application onto the femoral artery. Ipsilateral administration of amiloride or PPADS
but not AMG-9810 dose-dependently reduced MA. However, contralateral amiloride or
PPADS did not suppress contralateral MA. Interestingly, co-administration of submaximal
doses of amiloride and PPADS produced a significantly prolonged suppression of MA.
Furthermore, ipsilateral EGTA (a calcium chelator) or chelerythrine (a protein kinase
C inhibitor) also significantly reduced MA. Collectively, these findings suggest that
peripheral ASICs and P2X receptors are involved in the maintenance of TIIP, which
is possibly mediated by a Ca2+–protein kinase C signaling mechanism. These results provide mechanistic information
about peripheral ischemic nociception that may be useful for developing better therapeutic
management of ischemic pain in patients with peripheral arterial disease.
Perspective
The results of the current study demonstrate that peripheral administration of an
ASICs blocker or P2X antagonist significantly suppress TIIP. Co-administration of
submaximal doses of ASIC and P2X antagonists produced an even greater effect. These
results implicate peripheral ASICs and P2X receptors in the maintenance of thrombus-induced
ischemic pain.
Key words
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Article info
Publication history
Published online: March 25, 2010
Accepted:
October 14,
2009
Received in revised form:
October 1,
2009
Received:
May 14,
2009
Footnotes
Supported by a grant (M103KV010015-08K2201-01510) from Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology, the Republic of Korea.
Drs Seo and Roh contributed equally to this study.
The authors declare no conflict of interest.
Identification
Copyright
© 2010 Published by Elsevier Inc.
