Effects of systemic inhibitors of acid_sensing ion channels 1 -ASIC1- against acute and chronic mechanical allodynia in a rodent model of migraine

C Verkest, E Piquet, S Diochot, M Dauvois, M Lanteri_Minet, E Lingueglia, A Baron

UniversitŽ C™te d'Azur, CNRS, Institut de Pharmacologie MolŽculaire et Cellulaire, Valbonne, France

British Journal of Pharmacology

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.

BIOSEB Instruments Used:
Von Frey Filaments (Bio-VF-M)

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