Anti-allodynic effects of systemic inhibitors of Acid-Sensing Ion Channels 1 (ASIC1) against acute and chronic migrainein rodents

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Background and purpose: Acid-sensing ion channels (ASICs) are neuronal proton sensors emerging as potential therapeutic targets in pain of the orofacial region. Amiloride, a non‐specific ASIC blocker, has been shown to exert beneficial effects in animal models of migraine and in patients. We explored the involvement of the ASIC1‐subtype in cutaneous allodynia, a hallmark of migraine affecting cephalic and extra‐cephalic regions in about 70% of migrainers.Experimental Approach: We investigated the effects of systemic injections of amiloride and mambalgin‐1, a specific inhibitor of ASIC1a‐ and ASIC1b‐containing channels, on cephalic and extra‐cephalic mechanical sensitivity in a rodent model of acute and chronic migraine induced by i.p. injections of isosorbide dinitrate.Key Results: I.v. injections of these inhibitors reversed cephalic and extra‐cephalic acute cutaneous mechanical allodynia in rats, a single injection inducing a delay in the subsequent establishment of chronic allodynia. Both mambalgin‐1 and amiloride also reversed established chronic allodynia. The anti‐allodynic effects of mambalgin‐1 were not altered in ASIC1a‐knockout mice, showing the ASIC1a subtype is not involved in these effects which were comparable to those of the anti‐migraine drug sumatriptan and of the preventive drug topiramate on acute and chronic allodynia respectively. A single daily injection of mambalgin‐1 also had a significant preventive effect on allodynia chronification.Conclusions and Implications; These pharmacological data support the involvement of peripheral ASIC1‐containing channels in migraine cutaneous allodynia as well as in its chronification. They highlight the therapeutic potential of ASIC1 inhibitors as both an acute and prophylactic treatment for migraine.

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