Smooth muscle ATP-sensitive potassium channels mediate migraine-relevant hypersensitivity in mouse models
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Smooth muscle ATP-sensitive potassium channels mediate migraine-relevant hypersensitivity in mouse models. / Christensen, Sarah L.; Rasmussen, Rikke H.; Cour, Sanne La; Ernstsen, Charlotte; Hansen, Thomas F.; Kogelman, Lisette J.A.; Lauritzen, Sabrina P.; Guzaite, Gintare; Styrishave, Bjarne; Janfelt, Christian; Christensen, Søren T.; Aziz, Qadeer; Tinker, Andrew; Jansen-Olesen, Inger; Olesen, Jes; Kristensen, David M.
In: Cephalalgia, Vol. 42, No. 2, 2022, p. 93-107.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Smooth muscle ATP-sensitive potassium channels mediate migraine-relevant hypersensitivity in mouse models
AU - Christensen, Sarah L.
AU - Rasmussen, Rikke H.
AU - Cour, Sanne La
AU - Ernstsen, Charlotte
AU - Hansen, Thomas F.
AU - Kogelman, Lisette J.A.
AU - Lauritzen, Sabrina P.
AU - Guzaite, Gintare
AU - Styrishave, Bjarne
AU - Janfelt, Christian
AU - Christensen, Søren T.
AU - Aziz, Qadeer
AU - Tinker, Andrew
AU - Jansen-Olesen, Inger
AU - Olesen, Jes
AU - Kristensen, David M.
N1 - Publisher Copyright: © International Headache Society 2021.
PY - 2022
Y1 - 2022
N2 - Background: Opening of KATP 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 KATP-induced migraine attacks are initiated and which KATP 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 KATP 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 KATP 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 KATP 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 KATP channels of extracerebral origin. These results suggest a vascular contribution to hypersensitivity induced by migraine triggers.
AB - Background: Opening of KATP 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 KATP-induced migraine attacks are initiated and which KATP 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 KATP 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 KATP 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 KATP 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 KATP channels of extracerebral origin. These results suggest a vascular contribution to hypersensitivity induced by migraine triggers.
KW - Arterial dilation
KW - blood-brain barrier
KW - in vivo
KW - Kir6.1
KW - migraine
KW - nociception
U2 - 10.1177/03331024211053570
DO - 10.1177/03331024211053570
M3 - Journal article
C2 - 34816764
AN - SCOPUS:85120620454
VL - 42
SP - 93
EP - 107
JO - Cephalalgia
JF - Cephalalgia
SN - 0800-1952
IS - 2
ER -
ID: 286998194