GAERS are resistant to migraine-provoking agents: The role of extrasynaptic GABAA receptors

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Abstract Background Migraine headache is a global health concern, and the role of GABA-related mechanisms is ill-defined in migraine pathogenesis. The role of GABAergic system has never been examined in a migraine model with clinically relevant behavioral readouts. We aimed to investigate the susceptibility to valid and depicted migraine-provoking substances in Genetic Absence Epilepsy of Rats Strasbourg (GAERS), in which GABAergic tonus was altered. Methods Male Wistar and GAERS rats were administered nitroglycerin (10 mg/kg) or levcromakalim (1 mg/kg). Rats were tested for mechanical allodynia with von Frey monofilaments and light aversion using a dark-light box. Effects of tiagabine (5 mg/kg), baclofen (2 mg/kg), diazepam (1 mg/kg), gaboxadol (4 mg/kg), and muscimol (0.75 mg/kg), ethosuximide (100 mg/kg) or flumazenil (15 mg/kg) on levcromakalim induced migraine phenotype were screened. Results In contrast to Wistar rats, mechanical periorbital and hind paw pain thresholds were not reduced in GAERS rats after nitroglycerin or levcromakalim injection. Additionally, GAERS were free of the light aversive effects of these substances as opposed to Wistar rats. Ethosuximide did not reverse the resistant phenotype in GAERS, indicating T-type calcium channel dysfunction did not contribute to this phenomenon. Tiagabine, GABA reuptake inhibitor, prevented levcromakalim-induced mechanical allodynia in Wistar rats, suggesting a key role of enhanced GABA spillover. GABAB receptor agonist baclofen did not alleviate mechanical allodynia. Synaptic GABAA receptor agonist diazepam failed to mitigate levcromakalim-induced migraine phenotype. Additionally, the resistant phenotype by levcromakalim in GAERS was not affected by flumazenil, a synaptic GABAA receptor antagonist. Extrasynaptic GABAA receptor agonists gaboxadol and muscimol successfully inhibited periorbital mechanical allodynia in Wistar rats. Conclusion Our study introduces a migraine-resistant rat strain and signifies a critical role of GABAergic system in migraine phenotype. Also, detailed pharmacological evaluation demonstrates extrasynaptic GABAA receptors as a novel drug target with a therapeutic potential in migraine susceptibility.

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