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Keywords:

  • dihydroergotamine;
  • P2X3;
  • trigeminal ganglion;
  • adrenergic;
  • migraine

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.