The antimigraine drugs ergotamine and dihydroergotamine are potent 5-HT1C receptor agonists in piglet choroid plexus.
1. Fozard & Gray (1989) proposed that migraine is mediated by stimulation of 5-HT1C receptors. We have examined the interaction of two effective anti-migraine agents, ergotamine and dihydroergotamine (DHE), with these receptors. Binding (inhibition of labelling by [3H]-mesulergine) and agonist activity (phosphoinositide hydrolysis) were measured in piglet choroid plexus, a tissue rich in 5-HT1C receptors. 2. The pKD for [3H]-mesulergine binding was 8.4. Ergotamine and DHE both inhibited [3H]-mesulergine binding with a pKD of 7.1. This was similar to the potency of m-chlorophenylpiperazine (m-CPP) (pKD 7.4) and rather less than that of 5-hydroxytryptamine (5-HT) (pKD 8.1). 3. Both ergotamine and DHE were full agonists (pEC50S 7.5 and 7.6 respectively) with potencies similar to that of 5-HT (pEC50 7.7) and greater than that of m-CPP (pEC50 7.1). Mesulergine 10(-7) M produced near-parallel rightward shifts of the concentration-response curves for all these agents of 1.8-2.2 log units, consistent with an action of the agonists at the same receptor. 4. There was no effect of prazosin, spiperone, mepyramine or atropine on the phosphoinositide hydrolysis induced by ergotamine, ruling out an action via alpha 1-adrenoceptors, 5-HT2, histamine H1, or muscarinic receptors. 5. It is concluded that, together with 5-HT, ergotamine and DHE are the most potent 5-HT1C agonists reported so far. These findings do not support the theory that 5-HT1C receptor activation causes migraine.
Brown
A M
AM
SmithKline Beecham Pharmaceuticals, Welwyn, Herts.
Patch
T L
TL
Kaumann
A J
AJ
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002831:Choroid Plexus / Q000187:drug effects*; D004087:Dihydroergotamine / Q000494:pharmacology*; D004873:Ergolines / Q000494:pharmacology; D004878:Ergotamine / Q000494:pharmacology*; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008881:Migraine Disorders / Q000188:drug therapy; D010879:Piperazines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology; D013552:Swine; D013816:Thermodynamics
D004873:Ergolines; D007295:Inositol Phosphates; D010879:Piperazines; D011985:Receptors, Serotonin; D012701:Serotonin; D004087:Dihydroergotamine; D004878:Ergotamine; C015068:1-(3-chlorophenyl)piperazine; C031649:mesulergine