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The Journal of Neuroscience, May 1, 1999, 19(9):3423-3429

Regulation of Calcitonin Gene-Related Peptide Secretion by a Serotonergic Antimigraine Drug

Paul L. Durham and Andrew F. Russo

Department of Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242

We have investigated the regulation of calcitonin gene-related peptide (CGRP) release from trigeminal neurons by the serotonergic antimigraine drug sumatriptan. Serum levels of the neuropeptide CGRP are elevated during migraine. Treatment with the drug sumatriptan returns CGRP levels to normal coincident with the alleviation of headache. However, despite this clinical efficacy, 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 demonstrate that sumatriptan can directly repress CGRP secretion from sensory neurons. The stimulated secretion in response to depolarization or inflammatory agents was inhibited, but not the basal secretion rate. Unexpectedly, sumatriptan 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 slow and remarkably prolonged increase in intracellular calcium. The inhibition of CGRP secretion is attenuated by the phosphatase inhibitor okadaic acid, suggesting that sumatriptan action is mediated by calcium-recruited phosphatases. 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 neuropeptide release.

Key words: CGRP; serotonin receptors; trigeminal neurons; calcium; phosphatase; migraine; neuropeptide

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Copyright © 1999 Society for Neuroscience  0270-6474/99/1993423-07$05.00/0

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