Sumatriptan inhibition of N-type calcium channel mediated signaling in dural CGRP terminal fibres.
The selective 5-HT₁ receptor agonist sumatriptan is an effective therapeutic for migraine pain yet the antimigraine mechanisms of action remain controversial. Pain-responsive fibres containing calcitonin gene-related peptide (CGRP) densely innervating the cranial dura mater are widely believed to be an essential anatomical substrate for the development of migraine pain. 5-HT₁ receptors in the dura colocalize with CGRP fibres in high density and thus provide a possible peripheral site of action for sumatriptan. In the present study, we used high-resolution optical imaging selectively within individual mouse dural CGRP nociceptive fibre terminations and found that application of sumatriptan caused a rapid, reversible dose-dependent inhibition in the amplitude of single action potential evoked Ca²⁺ transients. Pre-application of the 5-HT₁ antagonist GR 127935 or the selective 5-HT(1D) antagonist BRL 15572 prevented inhibition while the selective 5-HT(1B) antagonist SB 224289 did not, suggesting this effect was mediated selectively through the 5-HT(1D) receptor subtype. Sumatriptan inhibition of the action potential evoked Ca²⁺ signaling was mediated selectively through N-type Ca²⁺ channels. Although the T-type Ca²⁺ channel accounted for a greater proportion of the Ca²⁺ signal it did not mediate any of the sumatriptan inhibition. Our findings support a peripheral site of action for sumatriptan in inhibiting the activity of dural pain fibres selectively through a single Ca²⁺ channel subtype. This finding adds to our understanding of the mechanisms that underlie the clinical effectiveness of 5-HT₁ receptor agonists such as sumatriptan and may provide insight for the development of novel peripherally targeted therapeutics for mitigating the pain of migraine.
Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. ldb874@mail.usask.ca
Landon D
LD
Baillie
Andrew H
AH
Ahn
Sean J
SJ
Mulligan
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000502:physiology*; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects*; D004388:Dura Mater / Q000187:drug effects; D004558:Electric Stimulation; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009412:Nerve Fibers / Q000187:drug effects*; D010146:Pain / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000187:drug effects*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D017366:Serotonin Receptor Agonists; D018170:Sumatriptan; D015740:Calcitonin Gene-Related Peptide