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

Abstract

Novel treatments against migraine are an urgent medical requirement. The α6 subunit-containing GABA_A receptors (α6GABA_ARs) 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 α6GABA_ARs 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 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 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 α6GABA_AR in TG is a novel drug target for TGVS activation and that α6GABA_AR-selective PAMs have the potential to be developed as a novel pharmacotherapy for migraine.

Keywords: Calcitonin gene-related peptide; Positive allosteric modulator; Trigeminal ganglia; Trigeminovascular activation; α6GABA(A)R.