Funding support: This research project was supported by grants from MAP Pharmaceuticals, Inc. and National Headache Foundation.
DHE Repression of ATP-Mediated Sensitization of Trigeminal Ganglion Neurons
Article first published online: 18 JUN 2010
© 2010 American Headache Society
Headache: The Journal of Head and Face Pain
Volume 50, Issue 9, pages 1424–1439, October 2010
How to Cite
Masterson, C. G. and Durham, P. L. (2010), DHE Repression of ATP-Mediated Sensitization of Trigeminal Ganglion Neurons. Headache: The Journal of Head and Face Pain, 50: 1424–1439. doi: 10.1111/j.1526-4610.2010.01714.x
Conflict of Interest: Paul Durham, PhD, and Caleb Masterson, MS, have received grant support from MAP Pharmaceuticals, Inc.
- Issue published online: 18 JUN 2010
- Article first published online: 18 JUN 2010
- Accepted for publication May 7, 2010.
- trigeminal ganglion;
Objective.— To investigate the mechanism by which adenosine triphosphate (ATP) causes sensitization of trigeminal neurons and how dihydroergotamine (DHE) represses this modulatory effect.
Background.— Dihydroergotamine is an effective treatment of migraine. The cellular mechanisms of action of DHE in treating migraine attacks remain unclear.
Methods.— In this study, neonatal rat trigeminal ganglia cultures were used to investigate effects of ATP, alpha, beta-methyl ATP (α,β-meATP), and DHE on intracellular calcium levels and calcitonin gene-related peptide (CGRP) secretion.
Results.— Pretreatment with ATP or α,β-meATP caused sensitization of neurons, via P2X3 receptors, such that a subthreshold amount of potassium chloride (KCl) significantly increased intracellular calcium levels and CGRP secretion. Pretreatment with DHE repressed increases in calcium and CGRP secretion in response to ATP-KCl or α,β-meATP-KCl treatment. Importantly, these inhibitory effects of DHE were blocked with an α2-adrenoceptor antagonist and unaffected by a 5HT1B/D receptor antagonist. DHE also decreased neuronal membrane expression of the P2X3 receptor.
Conclusions.— Our findings provide evidence for a novel mechanism of action for DHE that involves blocking ATP-mediated sensitization of trigeminal neurons, repressing stimulated CGRP release, and decreasing P2X3 membrane expression via activation of α2-adrenoceptors.