The Involvement of ATP Sensitive Potassium Channel in Migraine Aura and Migraine Pain.

Structural and Functional Cerebral Changes After Infusion of ATP Sensitive Potassium Channel Opener Levcromakalim.

The aim of the present study to investigate whether Opening of KATP channels causes migraine pain by activation of meningeal nociceptors and ascending trigeminal nociceptive pathways. Opening of KATP channels causes migraine aura by induction of CSD.

Migraine Pain The trigeminovascular system is the anatomical and physiological substrate of migraine pain. Nociceptive transmission originates from activation and sensitization of first-order trigeminovascular neurons. Their cell bodies are in the trigeminal ganglion, and their afferent fibers innervate the meninges and its vessels. Ascending nociceptive transmission from the trigeminal ganglion is projected to the brain stem, activating and sensitizing second-order trigeminovascular neurons, including those in the spinal trigeminal nucleus. This, in turn, activates and sensitizes third-order trigeminovascular neurons in the thalamus, which subsequently relay the nociceptive transmission to the somatosensory cortex and other cortical areas, ultimately resulting in migraine pain. Although the biological underpinnings of migraine pain are incompletely understood, signaling pathways have been identified that are putatively responsible for the genesis of migraine pain. Recent human experimental data have implicated opening of KATP channels in migraine pathogenesis. In two randomized controlled trials, it was demonstrated that intravenous infusion of levcromakalim - an opener of KATP channels - induced migraine pain in people with migraine with and without aura. - It remains unknown whether KATP channel opening causes migraine pain by activation of meningeal nociceptors and ascending trigeminal nociceptive pathways, as proposed during spontaneous migraine attacks. Migraine Aura About one-third of people with migraine experience aura symptoms, which are characterized by reversible focal neurologic symptoms, typically comprising visual or hemisensory disturbances. The physiological substrate of the aura phase of migraine is thought to be cortical spreading depression (CSD), a self-propagating wave of depolarization across the cerebral cortex that disrupts ionic gradients and is followed by cerebral hypoperfusion. Recently, it was reported that intravenous infusion of levcromakalim - an opener of KATP channels - induced migraine aura in migraine with aura patients. - It remains unknown whether KATP channel opening causes CSD which leads to migraine aura, as observed during spontaneous migraine attacks.

Intravenous administration of levcromakalim or placebo over 20 minutes. After 3 hours from the administration of levcromakalim or placebo, participants will receive intravenous infusion of sumatriptan over 10 minutes.

To measure transient diffusivity changes related to levcromakalim-induced CSD during the aura phase of migraine in subjects with migraine with aura.

Before and after infusion of levcromakalim compared with before and after infusion of saline. Time of measurements is baseline, 20 minutes and 160 minutes after the infusion.

To investigate the diameter of middle meningeal arteries (MMA), superficial temporal arteries (STA) and middle cerebral arteries (MCA) measured by millimeters (mm).

Before and after infusion of levcromakalim compared with before and after infusion of saline. Time of measurements is baseline, 20 minutes and 160 minutes after the infusion.

To investigate the diameter of middle meningeal arteries (MMA), superficial temporal arteries (STA) and middle cerebral arteries (MCA) measured by millimeters (mm).

Before and after infusion of sumatriptan. Time of measurements is 200 minutes and 210 minutes after the infusion.

Inclusion Criteria: Migraine patients 18-60 years. 50-100 kg. Women of childbearing potential must use adequate contraception. Exclusion Criteria: A history of serious somatic disease Any other type of headache (except episodic tension-type headache less than once a month) Daily intake of any medication except contraceptives Contraindications for MRI scan.