Involvement of gap junction channels in the pathophysiology of migraine with aura

Abstract

Migraine is a common, recurrent, and disabling primary headache disorder with a genetic component which affects up to 20% of the population. One third of all patients with migraine experiences aura, a focal neurological disturbance that manifests itself as visual, sensitive or motor symptoms preceding the headache. In the pathophysiology of migraine with aura, activation of the trigeminovascular system from the meningeal vessels mediates migraine pain via the brainstem and projections ascend to the thalamus and cortex. Cortical spreading depression (CSD) was proposed to trigger migraine aura and to activate perivascular trigeminal nerves in the cortex. Quinine, quinidine and the derivative mefloquine are able to inhibit CSD suggesting an involvement of neuronal connexin36 channels in CSD propagation. More recently, CSD was shown to induce headache by activating the trigeminovascular system through the opening of stressed neuronal Pannexin1 channels. A novel benzopyran compound, tonabersat, was selected for clinical trial on the basis of its inhibitory activity on CSD and neurogenic inflammation in animal models of migraine. Interestingly, in the time course of animal model trials, tonabersat was shown to inhibit trigeminal ganglion (TGG) neuronal-glial cell gap junctions, suggesting that this compound could prevent peripheral sensitization within the ganglion. Three clinical trials aimed at investigating the effectiveness of tonabersat as a preventive drug were negative, and conflicting results were obtained in other trials concerning its ability to relieve attacks. In contrast, in another clinical trial, tonabersat showed a preventive effect on attacks of migraine with aura but had no efficacy on non-aura attacks. Gap junction channels seem to be involved in several ways in the pathophysiology of migraine with aura and emerge as a new promising putative target in treatment of this disorder.

Assessment of Cranial Imaging Findings in Patients with Migraines

“…Aura preceding the migraine episode might manifest itself with visual, auditory, or speech disturbances and is present in approximately one third of migraine patients. Although rare occurrences of aura associated with sensory and motor deficits have been reported, the most frequent symptoms are of a visual nature (7). In this regard, our results are in line with the reported figures, and 22% of our patients had migraines with aura, mostly associated with visual disturbances.…”

Serum MicroRNA Signatures in Migraineurs During Attacks and in Pain-Free Periods

“…Migraine is known to be associated with activation and sensitization of the trigeminal pain pathways, vascular endothelial cells, meningeal inflammation, and most likely dysregulation in glial cell activities [2,23]. The present study design does not allow for delineation of the serum miRNA cell origin, and as such, it cannot be determined which structures are responsible for the release of the investigated miRNAs.…”

A Randomized, Double‐Blind, Placebo‐Controlled Study of Breath Powered Nasal Delivery of Sumatriptan Powder (AVP‐825) in the Treatment of Acute Migraine (The TARGET Study)

“…Therefore, it is possible that migraine relief observed with AVP‐825 is also partially mediated by local effects at trigeminal nerve endings in the nasal mucosa and direct transport of sumatriptan to brain (via olfactory and trigeminal nerves), to the trigeminal ganglion, and to the pterygopalatine ganglion, all of which have been implicated in the pathophysiology of migraine. In addition, it is possible that sumatriptan action at serotonin receptors on the nerve could have a direct role in modulating migraine‐associated inflammation . Other effects related to the device may also have a role in migraine relief.…”