Smooth muscle ATP-sensitive potassium channels mediate migraine-relevant hypersensitivity in mouse models
Sarah Louise Christensen, Rikke Holm Rasmussen, Sanne Hage la Cour, Charlotte Ernstsen, Thomas Folkmann Hansen, Lisette J. A. Kogelman, Sabrina P Lauritzen, Gintare Guzaite, Bjarne Styrishave, Christian Janfelt, Søren T Christensen, Qadeer Aziz, Andrew Tinker, Inger Jansen‐Olesen, Jes Olesen, David M. Kristensen
Abstract
Background Opening of K ATP channels by systemic levcromakalim treatment triggers attacks in migraine patients and hypersensitivity to von Frey stimulation in a mouse model. Blocking of these channels is effective in several preclinical migraine models. It is unknown in what tissue and cell type K ATP -induced migraine attacks are initiated and which K ATP channel subtype is targeted. Methods In mouse models, we administered levcromakalim intracerebroventricularly, intraperitoneally and intraplantarily and compared the nociceptive responses by von Frey and hotplate tests. Mice with a conditional loss-of-function mutation in the smooth muscle K ATP channel subunit Kir6.1 were given levcromakalim and GTN and examined with von Frey filaments. Arteries were tested for their ability to dilate ex vivo. mRNA expression, western blotting and immunohistochemical stainings were made to identify relevant target tissue for migraine induced by K ATP channel opening. Results Systemic administration of levcromakalim induced hypersensitivity but central and local administration provided antinociception respectively no effect. The Kir6.1 smooth muscle knockout mouse was protected from both GTN and levcromakalim induced hypersensitivity, and their arteries had impaired dilatory response to the latter. mRNA and protein expression studies showed that trigeminal ganglia did not have significant K ATP channel expression of any subtype, whereas brain arteries and dura mater primarily expressed the Kir6.1 + SUR2B subtype. Conclusion Hypersensitivity provoked by GTN and levcromakalim in mice is dependent on functional smooth muscle K ATP channels of extracerebral origin. These results suggest a vascular contribution to hypersensitivity induced by migraine triggers.