Evidence for 5-HT1B/1D receptors mediating the antimigraine effect of sumatriptan and dihydroergotamine.
Neurogenic plasma extravasation, endothelial cell activation (increase in vesicle number and vacuole formation), platelet aggregation and adhesion, and mast cell degranulation occur selectively in post-capillary venules of the dura mater following electrical trigeminal ganglion stimulation, and are mediated by release of neuropeptides from perivascular unmyelinated C fibres. Pre-treatment with the antimigraine drugs dihydroergotamine and sumatriptan, two drugs that bind with high affinity to 5-HT1B/1D receptors, markedly attenuated plasma protein extravasation induced by electrical trigeminal ganglion stimulation. Trigeminal stimulation increased plasma calcitonin gene-related peptide levels in rat superior sagittal sinus. Pre-treatment with dihydroergotamine and, to a lesser extent, sumatriptan, attenuated this increase. Both drugs reduced morphological changes in post-capillary venules and mast cells within dura mater following electrical trigeminal ganglion stimulation. Plasma protein extravasation was selectively blocked in dura mater (but not in extracranial tissues) by pre-treatment with those receptor agonists showing a rank order of potency suggesting a 3-HT1B/1D interaction (5-CT greater than 5-BT greater than DHE greater than sumatriptan greater than 8-OH-DPAT). Pre-treatment with 5-HT2 and 5-HT3 antagonists was not effective. Taken together, these data are consistent with the interpretation that putative 5-HT-1B/1D receptors located on sensory fibres are coupled to inhibition of peptide release and blockade of neurogenic inflammation. An important therapeutic action of ergot alkaloids and sumatriptan in migraine headaches is so defined.
Buzzi
M G
MG
Dipartimento di Scienze Neurologiche, Università degli Studi La Sapienza, Roma, Italy.
Moskowitz
M A
MA
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000097:blood; D002199:Capillary Permeability; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003392:Cranial Sinuses; D004087:Dihydroergotamine / Q000494:pharmacology*; D004558:Electric Stimulation; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000648:ultrastructure; D008881:Migraine Disorders / Q000517:prevention & control*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D018170:Sumatriptan; D012668:Trigeminal Ganglion / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D001798:Blood Proteins; D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D012701:Serotonin; D004087:Dihydroergotamine; D018170:Sumatriptan; D015740:Calcitonin Gene-Related Peptide