Sumatriptan inhibition of N-type calcium channel mediated signaling in dural CGRP terminal fibres

The selective 5-HT? 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-HT? 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-HT? 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-HT? receptor agonists such as sumatriptan and may provide insight for the development of novel peripherally targeted therapeutics for mitigating the pain of migraine.