(139) Effect of inhibition of Ca2+-permeable AMPA receptors on nitroglycerin-induced migraine headache

Migraine is a common primary headache disorder, which affects approximately 37 million of Americans. However, currently available therapies for migraine headache are inadequate. And the potential mechanisms for the pathogenesis of migraine remain to be illuminated. Previous studies have demonstrated that AMPA receptor phosphorylation promotes the switch from Ca2+-impermeable to Ca2+-permeable receptors in the central nervous system and plays a critical role in activity-dependent changes in synaptic processing of nociceptive information and pain signal transmission. In the present study, we employed an established nitroglycerin (NTG)-induced migraine headache mouse model to investigate whether the activation of Ca2+-permeable AMPA receptors in trigeminal nucleus caudalis (TNC) is involved in the development of migraine headache. C57BL/6N male and female mice were used in this study. Intraperitoneal injection of NTG (10 mg/kg) was carried out to induce migraine headache. Light-aversive behaviors (immediately following the injection) and hindpaw mechanical hypersensitivity (120 min after the injection) were measured using a light-dark box and von Frey filaments, respectively. 1-naphthyl acetyl spermine (NASPM), a selective Ca2+-permeable AMPA receptor channel blocker, was administrated to examine the effects of blockade of Ca2+-permeable AMPA receptors on NTG-induced migraine headache. In addition, Ca2+ imaging was carried out to analyze Ca2+ activities in cultured brainstem neurons following the treatment with NTG and/or NASPM. Administration of NTG induced photophobia and decreased paw withdrawal threshold both in both male and female mice. Intra-TNC injection of NASPM (3 mM, 0.9 μl) significantly inhibited NTG-induced mechanical hypersensitivity, but had no effect on NTG-induced photophobia. In cultured brainstem neurons, NTG produced a robust calcium influx, which was partially blocked by the incubation of NASPM (5 μM). Our results suggest that activities of Ca2+-permeable AMPA receptors in the TNC are involved in NTG-induced migraine headache. Supported by NIH/NIDCR Grants R01 DE022880 and K02 DE023551.