DHE Repression of ATP-Mediated Sensitization of Trigeminal Ganglion Neurons

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 (alpha,beta-meATP), and DHE on intracellular calcium levels and calcitonin gene-related peptide (CGRP) secretion. Results.- Pretreatment with ATP or alpha,beta-meATP caused sensitization of neurons, via P2X(3) 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 alpha,beta-meATP-KCl treatment. Importantly, these inhibitory effects of DHE were blocked with an alpha(2) -adrenoceptor antagonist and unaffected by a 5HT(1B/D) receptor antagonist. DHE also decreased neuronal membrane expression of the P2X(3) 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 P2X(3) membrane expression via activation of alpha(2) -adrenoceptors.