A Novel Target for Migraine Therapy: the α6 Subunit-Containing GABA_A Receptor

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The α6 subunit-containing GABA_A receptors (α6GABA_ARs) are mainly expressed in the cerebellum but also in trigeminal ganglia (TG), the hub of the trigeminal vascular system (TGVS). TGVS activation is a hallmark of the pathogenesis of migraine, which remains an unmet medical need with a high prevalence. Here, using pharmacological approaches in a migraine-mimicking animal model, we revealed an important role of the TG α6GABA_ARs in TGVS activation and this GABA_AR subtype may be a druggable target for migraine therapy. TGVS activation was induced by intra-cisternal (i.c.) instillation of capsaicin in rats. Centrally, i.c.capsaicin activated the trigeminal cervical complex (TCC), which can be 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 using a recently identified α6GABA_AR-selective positive allosteric modulator (PAM), the pyrazoloquinolinone Compound 6, two α6GABA_AR-active PAMs (Ro15-4513 and loreclezole), an α6GABA_AR inactive benzodiazepine (diazepam), an α6GABA_AR-selective antagonist (furosemide), and a clinically effective antimigraine agent (topiramate). We examined effects of these agents and their interactions with furosemide 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 Ro15-4513, loreclezole and topiramate, but not diazepam. The brain-impermeable furosemide antagonized the peripheral, but not central, effects of Compound 6. These results suggest that the α6GABA_AR in TG is a novel target for inhibiting TGVS activation and hence α6GABA_AR-selective PAMs may be a potential anti-migraine pharmacotherapy.