DHE repression of ATP-mediated sensitization of trigeminal ganglion neurons.

Abstract

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 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.

• Authors: Caleb G Masterson, Paul L Durham
• Journal: Headache (Headache) Vol. 50 Issue 9 Pg. 1424-39 (Oct 2010) ISSN: 1526-4610 [Electronic] United States
• PMID: 20561068 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 American Headache Society.

Chemical References

• Vasoconstrictor Agents
• Dihydroergotamine
• Adenosine Triphosphate
• Calcitonin Gene-Related Peptide

Topics

• Adenosine Triphosphate (antagonists & inhibitors, physiology)
• Animals
• Calcitonin Gene-Related Peptide (antagonists & inhibitors, metabolism)
• Cells, Cultured
• Dihydroergotamine (pharmacology)
• Down-Regulation (drug effects, physiology)
• Female
• Migraine Disorders (drug therapy, metabolism, physiopathology)
• Neural Inhibition (drug effects, physiology)
• Rats
• Rats, Sprague-Dawley
• Sensory Receptor Cells (drug effects, metabolism)
• Trigeminal Ganglion (drug effects, metabolism)
• Vasoconstrictor Agents (pharmacology)