The antimigraine drugs ergotamine and dihydroergotamine are potent 5‐HT_1C receptor agonists in piglet choroid plexus

Abstract

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 1i-7M 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 ocl-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.

Serotonin receptors: Subtypes, functional responses and therapeutic relevance

“…mianserin, sergolexole) are not particularly effective against migrainous headaches. Moreover, rather than being antagonists, the antimigraine drugs ergotamine and dihydroergotamine behave as potent agonists at the 5-HTlc receptor (Brown et al, 1991).…”

Endothelial 5‐HT receptors mediate relaxation of porcine pulmonary arteries in response to ergotamine and dihydroergotamine

“…Radioligand binding studies in brain membranes have shown that ergotamine and DHE possess high affinity for several 5-HT receptor subtypes such as 5-HTA, 5-HTlD, 5-HT2A, (Hoyer 1989;Hoyer & Schoeffter, 1991;Hoyer et al, 1994;Peroutka, 1994). In piglet choroid plexus, ergotamine and DHE proved to be potent agonists at 5-HT2c receptors inducing increases in inositol phosphates (Brown et al, 1991). This is of special interest since it has been hypothesised that 5-HT2B/5-HT2c receptors are probably involved in the initiation of migraine (Kalkman, 1994;Fozard & Kalkman, 1994).…”

The effects of 5‐HT and m‐chlorophenylpiperazine (m‐CPP) on the efflux of [3H]‐5‐HT from human perfused platelets.

“…If m-CPP were also to induce 5-HT release from human neurones or platelets, it might provide a possible explanation for the migraine-like headaches caused by the oral administration of m-CPP to patients (Brewerton et al, 1988;Brown et al, 1991).…”

“…This leaves 5-HT,c-receptor activation (Fozard & Gray, 1989) or neuronal 5-HT release (Brown et al, 1991) as the most likely explanation of m-CPP's headache-inducing property (Brewerton etal., 1988). The possible cephalalgic action of other 5-HT,c-receptor agonists, observed when agents such as ergotamine and dihydroergotamine are used chronically (Tfelt-Hansen, 1988), might be offset by their potent 5-HT1-like constrictor agonist activity on large dilated cerebral arteries (Brown et al, 1991) when used for the acute treatment of migraine.…”