Sumatriptan inhibits the electrophysiological activity of ASICs in rat trigeminal ganglion neurons

Abstract

Sumatriptan, a selective serotonin 5-HT1 receptor agonist, is an effective therapeutic for migraine attacks. However, the molecular mechanisms underlying sumatriptan migraine relief are still not fully understood. Here, we found that acid-sensing ion channels (ASICs), pH sensors, are peripheral targets of sumatriptan against migraine. Sumatriptan can inhibit the electrophysiological activity of ASICs in the trigeminal ganglion (TG) neurons. In the present study, sumatriptan decreased proton-gated currents mediated by ASICs in a concentration-dependent manner. In addition, sumatriptan shifted concentration-response curves for protons downwards, with a decrease of 37.3 ± 4.6% in the maximum current response but with no significant change in the pH0.5 value. Sumatriptan inhibition of ASIC currents was blocked by 5-HT1D receptor antagonist BRL 15572, but not by 5-HT1B antagonist SB 224289. Moreover, the sumatriptan inhibition of ASICs can be mimicked by the 5-HT1D receptor agonist L-694,247, but not by the 5-HT1B agonist CP-93129. Sumatriptan inhibition of ASIC currents was also reversed by G-protein αi subunit inhibitor PTX and 8-Br-cAMP, suggesting the inhibition may involve the intracellular signal transduction. Finally, sumatriptan decreased the number of action potentials induced by acid stimuli in rat TG neurons. Our results indicated that the anti-migraine drug, sumatriptan, inhibited ASICs in rat TG neurons via 5-HT1D receptor subtype and a cAMP-dependent signal pathway. These observations add to the understanding of the mechanisms that underlie the clinical effectiveness of anti-migraine sumatriptan.