Meningeal KATP channels contribute to behavioral responses in preclinical migraine models

Human experimental studies have shown that levcromakalim, an ATP-sensitive potassium (KATP) channel opener, induces migraine attacks in people with migraine but not in healthy volunteers. However, the exact site of action for KATP channels in migraine pathophysiology remains unclear. This study investigates the role of these channels in the meninges in eliciting behavioral hypersensitivity responses in mice. The effects of KATP channel signaling were assessed using preclinical migraine models induced by repetitive stress or dural stimulation. Prolactin, CGRP, sodium nitroprusside (SNP), and KATP channel openers or blockers were administered systemically or onto the dura of mice followed by behavioral testing using periorbital von Frey or facial grimace measurements. Repetitive stress sensitized mice to a normally subthreshold systemic dose of levcromakalim. The KATP blocker glibenclamide significantly reduced responses to systemic SNP following repetitive stress. In naive mice, direct dural application of levcromakalim or SNP elicited periorbital hypersensitivity. Responses to dural levcromakalim were inhibited by coinjection with glibenclamide or sumatriptan. By contrast, injection of levcromakalim in the periorbital skin did not induce hypersensitivity. Moreover, repetitive stress sensitized mice to dural injection of normally subthreshold doses of levcromakalim or SNP. Finally, dural coinjection of glibenclamide inhibited periorbital hypersensitivity induced by CGRP or prolactin in female mice. These studies demonstrate that the meninges can be one site of action for the migraine-triggering effects of KATP channel openers. They also show that NO donors, CGRP, and prolactin can produce behavioral hypersensitivity through opening of KATP channels in the meninges.