Background
Dihydroergotamine is an effective treatment of migraine. The cellular mechanisms of action of DHE in treating migraine attacks remain unclear.
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 α(2) -adrenoceptors.
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.
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.
Results
Pretreatment with ATP or α,β-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 α,β-meATP-KCl treatment. Importantly, these inhibitory effects of DHE were blocked with an α(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 α(2) -adrenoceptors.