Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug

We have investigated the regulation of calcitonin gene-related peptide (CGR P) release from trigeminal neurons by the serotonergic antimigraine drug su matriptan. Serum levels of the neuropeptide CGRP are elevated during migrai ne. Treatment with the drug sumatriptan returns CGRP levels to normal coinc ident with the alleviation of headache. However, despite this clinical effi cacy, the cellular target and mechanism of sumatriptan action are not well understood beyond the pharmacology of its recognition of the 5-HT1 class of serotonin receptors, We have used cultured trigeminal neurons to demonstra te that sumatriptan can directly repress CGRP secretion from sensory neuron s. The stimulated secretion in response to depolarization or inflammatory a gents was inhibited, but not the basal secretion rate, Unexpectedly, sumatr iptan did not lower cAMP levels, in contrast to the classical role ascribed to the 5-HT1 receptors, Instead, activation of 5-HT1 receptors caused a sl ow and remarkably prolonged increase in intracellular calcium. The inhibiti on of CGRP secretion is attenuated by the phosphatase inhibitor okadaic aci d, suggesting that sumatriptan action is mediated by calcium-recruited phos phatases. These results suggest that 5-HT1 agonists may block a deleterious feedback loop in migraine at the trigeminal neurons and provide a general mechanism by which this class of drugs can attenuate stimulated neuropeptid e release.