Inhibition of persistent sodium current reduces spreading depression-evoked allodynia in a mouse model of migraine with aura

We present data demonstrating efficacy of inhibition of persistent sodium currents (INaP) in reducing optogenetic spreading depolarization (SD) induced nociceptive behavior and SD susceptibility. We investigated the efficacy of inhibiting persistent Na+ currents (INaP) in acute rodent models of migraine with aura. Cortical spreading depression (SD) is a slow wave of neuronal and glial depolarization that underlies the migraine aura. Minimally invasive optogenetic SD (opto-SD) causes periorbital mechanical allodynia in mice, suggesting SD activates trigeminal nociceptors. Persistent Na+ currents contribute to neuronal intrinsic excitability and have been implicated in peripheral and cortical excitation. We examined a preferential inhibitor of INaP, GS-458967, on SD-induced periorbital allodynia, SD susceptibility, and formalin-induced peripheral pain. Periorbital mechanical allodynia was tested in male and female Thy1-ChR2-YFP mice after a single opto-SD event using manual von Frey monofilaments. GS-458967 (1 mg/kg, s.c.) or vehicle was dosed immediately after opto-SD induction, and allodynia was tested 1 hour later. The electrical SD threshold and KCl-induced SD frequency were examined in the cortex in male Sprague-Dawley rats after 1 hour pretreatment with GS-458967 (3 mg/kg, s.c.) or vehicle. Effects of GS-458967 (0.5-5 mg/kg, p.o.) on spontaneous formalin hind paw behavior and locomotion were also examined in male CD-1 mice. GS-458967 suppressed opto-SD-induced periorbital allodynia and decreased susceptibility to SD. GS-458967 also diminished early and late phase formalin-induced paw-licking behavior with early phase paw licking responding to lower doses. GS-458967 up to 3 mg/kg had no impact on locomotor activity. These data provide evidence that INaP inhibition can reduce opto-SD-induced trigeminal pain behavior and support INaP inhibition as an antinociceptive strategy for both abortive and preventive treatment of migraine.