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

Abstract

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-HT1D antagonist BRL 15572 prevented inhibition while the selective 5-HT1B antagonist SB 224289 did not, suggesting this effect was mediated selectively through the 5-HT1D 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.