Alpha 6gaba(A) Receptor Positive Modulators Alleviate Migraine-Like Grimaces In Mice Via Compensating Gabaergic Deficits In Trigeminal Ganglia

Migraine is caused by hyperactivity of the trigeminovascular system, where trigeminal ganglia (TG) play an important role. This hyperactivity might originate from an underfunctional GABAergic system in TG. To investigate this possibility, we adapted a mouse model of migraine by inducing migraine-like grimaces in male mice via repeated injections of nitroglycerin (NTG, 10 mg/kg, i.p.), once every 2 days, for up to 5 sessions. Migraine-like facial pain scores were measured using the mouse grimace scale. Repeated NTG treatments in mice caused significant increases in migraine-like grimaces that were aborted and prevented by two anti-migraine agents sumatriptan and topiramate, respectively. After 5 sessions of NTG injections, the GABA-synthesizing enzyme, 65-kDa glutamate decarboxylase (GAD65), but not the GABA transporter 1 (GAT1) or the alpha 6 subunit-containing GABA(A) receptors (alpha 6GABA(A)Rs), was downregulated in mouse TG tissues. Taking advantage of the unaffected TG alpha 6GABA(A)R expression in NTG-treated mice, we demonstrated that an alpha 6GABA(A)R-selective positive allosteric modulator (PAM), DK-I-56-1, exhibited both abortive and prophylactic effects, comparable to those of sumatriptan and topiramate, respectively, in this migraine-mimicking mouse model. The brain-impermeable furosemide significantly prevented the effects of DK-I-56-1, suggesting its peripheral site of action, likely via preventing alpha 6GABA(A)R modulation in TG. Results suggest that a decreased GABA synthesis caused by the reduced GAD65 expression in TG contributes to the trigeminovascular activation in this repeated NTG-induced migraine-mimicking model and that the unaltered alpha 6GABA(A)Rs in TG are potential targets for migraine treatment. Thus, alpha 6GABA(A)R-selective PAMs are potential anti-migraine agents for both abortive and preventive therapies.