AMPA receptor GluA1 Ser831 phosphorylation is critical for nitroglycerin-induced migraine-like pain

Abstract

Migraine is the third most common disease worldwide; however, the mechanisms underlying migraine headache are still not fully understood. Previous studies have demonstrated that α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor phosphorylation plays an important role in central sensitization of pain transmission. In the present study, we observed that AMPA receptor GluA1 Ser831 phosphorylation was enhanced in the spinal trigeminal nucleus caudalis (Sp5C) after intraperitoneal injection of nitroglycerin (NTG). The NTG injection induced acute migraine-like pain including photophobia and mechanical hypersensitivity as reported previously. Interestingly, targeted mutation of GluA1 Ser831 site to prevent phosphorylation significantly inhibited NTG-induced migraine-like pain. Moreover, NTG incubation caused a robust Ca influx in cultured brainstem neurons, which was dramatically inhibited by GluA1 S831A (serine at the 831 site of GluA1 is mutated to alanine) phospho-deficient mutation, and treatment with 1-naphthyl acetyl spermine (NASPM), a selective Ca-permeable AMPA receptor channel blocker, dose-dependently blocked the NTG-evoked increase of Ca influx in the cultured neurons. We further found that intra-Sp5C injection of NASPM significantly inhibited NTG-produced mechanical hypersensitivity. These results suggest that AMPA receptor phosphorylation at the Ser831 site in the Sp5C is critical for NTG-induced migraine-like pain.

A Pre-Existing Myogenic Temporomandibular Disorder Increases Trigeminal Calcitonin Gene-Related Peptide and Enhances Nitroglycerin-Induced Hypersensitivity in Mice

“…In this study, we focused on the comorbid myogenic TMD and migraine-like hypersensitivity. A systemic injection of NTG has been used extensively to induce migraine-like hypersensitivity [17][18][19][20]43]. Our results are consistent with these previous studies: 10 mg/kg of NTG induces acute periorbital hypersensitivity, while 1 mg/kg of NTG is not enough to induce significant hypersensitivity.…”

“…Previous studies have shown that masseter muscle tendon ligation (MMTL) in rats can produce myogenic TMD pain [15,16] and that systemic injection of nitroglycerin (NTG) can induce acute migraine-like hypersensitivity [17][18][19][20]. An essential role for calcitonin gene-related peptide (CGRP) has been indicated in migraine pathophysiology [21][22][23].…”

P2X7R-mediated Autophagic Impairment Contributes to Central Sensitization in a chronic Migraine Model with Recurrent Nitroglycerin Stimulation in Mice

“…The pain hypersensitivity in the periorbit and hind paw produced by NTG injection corresponds to the cutaneous allodynia of the cephalic and extracephalic region in patients with CM [54,78]. Furthermore, NTG treatment also elicits some migraine-speci c symptoms in mice, comprising photophobia, hypoactivity, and facial grimace behaviors, which are similar to the characteristics of photophobia and activities aggravating headache in patients with CM [79][80][81].…”

P2X7R-mediated autophagic impairment contributes to central sensitization in a chronic migraine model with recurrent nitroglycerin stimulation in mice

“…The pain hypersensitivity in the periorbit and hind paw produced by NTG injection corresponds to the cutaneous allodynia of the cephalic and extracephalic region in patients with CM [32]. Furthermore, NTG treatment also elicits some migraine-speci c symptoms in mice, comprising photophobia, hypoactivity, and facial grimace behaviors, which are similar to the characteristics of photophobia and activities aggravating headache in patients with CM [45,46]. Central sensitization is an abnormal state of increased responsiveness of the nociceptive system, which is caused by the enhanced excitability of neurons and circuits in the nociceptive pathway [39].…”