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 (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.
Masterson
Caleb G
CG
Center for Biomedical and Life Sciences, Missouri State University, Springfield, MO 65806, USA.
Durham
Paul L
PL
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors* / Q000502:physiology*; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D004087:Dihydroergotamine / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D008881:Migraine Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000187:drug effects* / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D004087:Dihydroergotamine; D000255:Adenosine Triphosphate; D015740:Calcitonin Gene-Related Peptide