A Novel Drug Target for Migraine: The GABA_A Receptor α6 Subtype in Trigeminal Ganglia

Abstract

Migraine, an unmet medical need, is due to an overactive trigeminovascular system (TGVS). The trigeminal ganglion (TG), a hub of the TGVS, transmits the pain signals arising from neurogenic inflammation in the meninges to the brainstem. Previously, we have revealed an unprecedented role of the α6 subunit‐containing GABAA receptor (the GABAA receptor α6 subtype, α6GABAAR) on TG in the neuropathogenesis of migraine using the α6GABAAR‐specific positive allosteric modulators (PAMs)1 we developed. In a rat model of migraine induced by intracisternal injection of capsaicin, we showed that Compound 6, a potent α6GABAAR‐selective PAM via acting on TG, attenuated TGVS activation‐induced peripheral and central responses, using immunohistochemical approaches.2 Here, we further investigated whether positive modulating TG α6GABAARs would attenuate migraine‐related nociceptive behaviors induced by repetitive injections of nitroglycerin (NTG), which induces headache in human due to dural vasodilatation. We gave NTG (10 mg/kg, i.p.) to mice (6–8 weeks, male ICR) once every two days for 5 times. The mouse grimace scale (MGS) was used to score, from 0–2, the headache‐like behaviors, including orbital tightening, nose bulge, cheek bulge, and the changes of ear position and whisker. The severity of migraine was assessed by the MGS on day 9 (the 5th session). To evaluate the abortive treatment efficacy of α6GABAAR PAMs, drug were administered 20 min after NTG injection on day 9. For their prevention efficacy, drugs were given 30 min before NTG injection in each session. Repeated NTG injections significantly increased MGS. Compound 6 and its deuterated derivative that has a longer half‐life, DK‐56‐I, significantly attenuated the elevated MGS induced by NTG. Importantly, the effect of the α6GABAAR‐selective PAM was antagonized by i.p. injection of furosemide (20 mg/kg), an α6GABAA R‐selective antagonist that is blood‐brain barrier‐impermeable. It was mimicked by sumatriptan, an effective drug for migraine abortion. Besides, we found that DK‐56‐I was effective in preventing repeated NTG‐induced elevation of MGS, like topiramate, an effective drug for migraine prevention. We also found that α6GABAARs are expressed in TG neurons and satellite glial cells of mice. These results suggest that the TG α6GABAAR is a novel therapeutic target for migraine and that the α6GABAAR‐selective PAM is a novel treatment for migraine abortion and prevention.Support or Funding InformationSupported grants: MOST 107‐2321‐B‐002‐010 and NHRI‐EX107‐10733NI.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.