The α6 subunit-containing GABA receptor: A novel drug target for inhibition of trigeminal activation.

Novel treatments against migraine are an urgent medical requirement. The α6 subunit-containing GABA receptors (α6GABARs) are expressed in trigeminal ganglia (TG), the hub of the trigeminal vascular system (TGVS) that is involved in the pathogenesis of migraine. Here we reveal an unprecedented role of α6GABARs in ameliorating TGVS activation using several pharmacological approaches in an animal model mimicking pathological changes in migraine. TGVS activation was induced by intra-cisternal (i.c.) instillation of capsaicin in Wistar rats. Centrally, i.c. capsaicin activated the trigeminal cervical complex (TCC) measured by the increased number of c-Fos-immunoreactive (c-Fos-ir) TCC neurons. Peripherally, it elevated calcitonin gene-related peptide immunoreactivity (CGRP-ir) in TG and depleted CGRP-ir in the dura mater. Pharmacological approaches included a recently identified α6GABAR-selective positive allosteric modulator (PAM), the pyrazoloquinolinone Compound 6, two α6GABAR-active PAMs (Ro15-4513 and loreclezole), an α6GABAR-inactive benzodiazepine (diazepam), an α6GABAR-selective antagonist (furosemide), and a clinically effective antimigraine agent (topiramate). We examined effects of these compounds on both central and peripheral TGVS responses induced by i.c. capsaicin. Compound 6 (3-10 mg/kg, i.p.) significantly attenuated the TCC neuronal activation and TG CGRP-ir elevation, and dural CGRP depletion induced by capsaicin. All these effects of Compound 6 were mimicked by topiramate, Ro15-4513 and loreclezole, but not by diazepam. The brain-impermeable furosemide antagonized the peripheral, but not central, effects of Compound 6. These results suggest that the α6GABAR in TG is a novel drug target for TGVS activation and that α6GABAR-selective PAMs have the potential to be developed as a novel pharmacotherapy for migraine.