ATP sensitive potassium (KATP) channel inhibition: A promising new drug target for migraine.

Abstract

BACKGROUND:

Recently, the adenosine triphosphate (ATP) sensitive potassium channel opener levcromakalim was shown to induce migraine attacks with a far higher incidence than any previous provoking agent such as calcitonin gene-related peptide. Here, we show efficacy of ATP sensitive potassium channel inhibitors in two validated rodent models of migraine.

METHODS:

In female spontaneous trigeminal allodynic rats, the sensitivity of the frontal region of the head was tested by an electronic von Frey filament device. In mice, cutaneous hypersensitivity was induced by repeated glyceryl trinitrate or levcromakalim injections over nine days, as measured with von Frey filaments in the hindpaw. Release of calcitonin gene-related peptide from dura mater and trigeminal ganglion was studied ex vivo.

RESULTS:

The ATP sensitive potassium channel inhibitor glibenclamide attenuated the spontaneous cephalic hypersensitivity in spontaneous trigeminal allodynic rats and glyceryl trinitrate-induced hypersensitivity of the hindpaw in mice. It also inhibited CGRP release from dura mater and the trigeminal ganglion isolated from spontaneous trigeminal allodynic rats. The hypersensitivity was also diminished by the structurally different ATP sensitive potassium channel inhibitor gliquidone. Mice injected with the ATP sensitive potassium channel opener levcromakalim developed a progressive hypersensitivity that was completely blocked by glibenclamide, confirming target engagement.

CONCLUSION:

The results suggest that ATP sensitive potassium channel inhibitors could be novel and highly effective drugs in the treatment of migraine.

• Authors: Sarah L Christensen, Gordon Munro, Steffen Petersen, Anmool Shabir, Inger Jansen-Olesen, David M Kristensen, Jes Olesen
• Journal: Cephalalgia : an international journal of headache (Cephalalgia) Vol. 40 Issue 7 Pg. 650-664 (06 2020) ISSN: 1468-2982 [Electronic] England
• PMID: 32418458 (Publication Type: Journal Article)

Chemical References

• KATP Channels
• Sulfonylurea Compounds
• gliquidone
• Calcitonin Gene-Related Peptide
• Glyburide

Topics

• Animals
• Calcitonin Gene-Related Peptide (drug effects, metabolism)
• Dura Mater (drug effects)
• Glyburide (pharmacology)
• Hyperalgesia (drug therapy)
• KATP Channels (antagonists & inhibitors)
• Mice
• Mice, Inbred C57BL
• Migraine Disorders (drug therapy)
• Pain Threshold (drug effects)
• Rats
• Rats, Sprague-Dawley
• Sulfonylurea Compounds (pharmacology)
• Trigeminal Ganglion (drug effects)