ATP-sensitive Potassium Channels in the Meninges Contribute to Priming Following Repeated Exposure to Stress

Editor’s note: The research described below comes from a recipient of a 2023 MSC Travel Grant supporting travel to the 65th Annual Scientific Meeting of the American Headache Society. These grants reimburse travel expenses for those who have had their abstract for a presentation or poster accepted at a meeting.

By Hao-Ruei Mei, PhD student, University of Texas at Dallas, US.

What is the research gap that your study addresses?

Human studies showed that infusion of levcromakalim (K_ATP channel opener) induced migraine attacks in patients who have migraine with or without aura. Animal studies demonstrated that repeated administration of levcromakalim evoked facial hypersensitivity. These studies suggest that the activation of K_ATP channels could be an underlying mechanism of migraine attacks. However, they do not uncover the activation location of the K_ATP channels. In this study, we aimed to determine whether the activation of K_ATP channels in the dura mater is essential.

What is your research hypothesis?

We proposed that the activation of K_ATP channels in the dura mater plays a crucial role in the development of periorbital hypersensitivity induced by NO donors, CGRP, and levcromakalim.

What methodology did you use to address your research hypothesis? 

In this study, we applied von Frey filaments to assess the periorbital mechanical threshold, a preclinical measure of headache-like behavior. We used 2 different models in this study, a repetitive stress model and dural stimulation. We have previously published that repetitive restraint stress in mice (2 hours per day, for three consecutive days) induces periorbital hypersensitivity as well as priming to the nitric oxide donor sodium nitroprusside (SNP; 0.1 mg/kg). To inject compounds to the dura mater, we utilized a technique that allowed for delivery of drugs directly to the dura mater in mice without the need for invasive surgery. The injections were applied through the intersection of the lambdoidal and sagittal sutures.

What are the main results of your study?

Repetitively stressed mice on day 14 post-stress were sensitive to a systemic dose of levcromakalim that was subthreshold in control mice or to a dural injection of subthreshold levcomakalim (0.1 μg). In naïve mice, dural administration of 0.3 μg or 1 μg levcromakalim, but not 0.1 μg, resulted in decreased periorbital withdrawal thresholds. In contrast, injection of 1 μg levcromakalim in the periorbital skin (i.e., not onto the dura) did not induce periorbital hypersensitivity. Finally, direct dural co-injection of glibenclamide could inhibit levcromakalim, NO donor, or CGRP-induced periorbital hypersensitivity.

What conclusions did you reach based on your results?

We suggest that opening K_ATP channels in the dura might contribute to migraine. Additionally, K_ATP channels can mediate the downstream effects of nitric oxide and CGRP. Together, these data and future studies using this model may help to further investigate the potential of K_ATP channel blockers as novel migraine therapeutics.

What are the limitations of your study?

We acknowledge that there are certain limitations to be considered in our study. First, our focus was primarily on testing periorbital sensitivity, although this is not the most common migraine symptom. We do not know whether the administration of levcromakalim induced other migraine symptoms, like photophobia. In addition, while it is unlikely for levcromakalim to diffuse into the brain due to the injected volume (5 μl) and the presence of the blood-brain barrier, we cannot exclude the possibility that levcromakalim induces responses through the activation of K_ATP channels in the brain.

What is the relevance of your study to migraine?

First, we demonstrated that stressed mice are sensitized to a subthreshold dose of levcromakalim. This finding is similar to migraine patients who are more sensitive to levcromakalim than healthy controls. In addition, we investigated 2 commonly known migraine triggers: the NO donor and CGRP. Remarkably, our results indicated that the inhibition of K_ATP channels effectively mitigated the periorbital hypersensitivity induced by both the NO donor and CGRP. This suggests that K_ATP channels play a crucial role in mediating the sensitivity to these migraine triggers.