Inhibition of trigeminovascular dural nociceptive afferents by Ca(2+)-activated K(+) (MaxiK/BK(Ca)) channel opening.
Migraine is an episodic brain disorder with a significant morbidity. It is thought that activation of trigeminal afferents innervating the dura mater and large cerebral blood vessels is involved in the expression of the disorder. The selective large conductance calcium-activated potassium channels, the BK(Ca) or MaxiK channels, are intrinsic membrane proteins that are widely distributed in the brain. These channels are thought to be involved in controlling neuronal excitability and perhaps transmitter release, possibly in the trigeminocervical complex. We sought to investigate the role of MaxiK/BK(Ca) channels opening in several models of trigeminovascular nociception using NS1619, a benzimidazolone analogue. Intravenously administered NS1619 (10 mg kg(-1)) was able to inhibit neurogenic dural vasodilation (F(4,20)=19.23, P<0.05, n=6). NS1619 (intravenous) was not able to inhibit Aδ-fiber (F(3.01,18.06)=0.79, P=0.52) or C-fiber (F(3.14,18.84)=0.76, P=0.54) afferents in the trigeminal nucleus caudalis and C(1) region of the dorsal horn after dural electrical stimulation, but it was able to inhibit Aδ-fiber afferents after iontophoretic application of NS1619 (t(5)=3.23, P<0.05, n=6) after 5 min. Iontophoresed NS1619 was also able to inhibit l-glutamate induced firing in the trigeminocervical complex, in a dose-dependent manner (F(3,54)=3.06, P<0.05). The data taken together indicate that the MaxiK/BK(Ca) channel may represent a novel therapeutic target in migraine.
Akerman
Simon
S
UCSF Headache Group, Department of Neurology, University of California, San Francisco, CA, USA.
Holland
Philip R
PR
Lasalandra
Michele P
MP
Goadsby
Peter J
PJ
D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004388:Dura Mater / Q000098:blood supply / Q000502:physiology; D004558:Electric Stimulation / Q000379:methods; D018698:Glutamic Acid / Q000494:pharmacology; D007478:Iontophoresis / Q000379:methods; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008576:Meningeal Arteries / Q000294:innervation / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014275:Trigeminal Caudal Nucleus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D014276:Trigeminal Nerve / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D001562:Benzimidazoles; D051036:Large-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; C086491:NS 1619; D018698:Glutamic Acid