Titre du document / Document title

Interactions of metoclopramide and ergotamine with human 5-HT_3A receptors and human 5-HT reuptake carriers

Auteur(s) / Author(s)

WALKEMBACH Jran ⁽¹⁾ ; BRÜSS Michael ⁽²⁾ ; URBAN Bernd W. ⁽¹⁾ ; BARANN Martin ^{(1 2)} ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Universitätskliniken Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, ALLEMAGNE
⁽²⁾ Institut für Pharmakologie und Toxikologie, Universität Bonn, Reuterstr. 2 b, 53113 Bonn, ALLEMAGNE

Résumé / Abstract

1 The actions of metoclopramide and ergotamine, drugs which are used as a combined migraine medication, on human (h)5-HT_3A receptors and 5-HT reuptake carriers, stably expressed in HEK-293 cells, were studied with patch-clamp- and ([³H]5-HT)-uptake techniques. 2 At clinical concentrations, metoclopramide inhibited peak and integrated currents through h5-HT_3A receptors concentration-dependently (IC₅₀ = 0.064 and 0.076 μM, respectively) when it was applied in equilibrium (60s before and during 5-HT (30 μM) exposure). The onset and offset time constants of metoclopramide action were 1.3 and 2.1 s, respectively. The potency of metoclopramide when exclusively applied during the agonist pulse decreased more than 200-fold (IC₅₀ = 19.0 μM, peak current suppression). 3 Metoclopramide (0.10 μM) did not alter the EC₅₀ of 5-HT-induced peak currents. In contrast to the lack of competitive interaction between metoclopramide and 5-HT in this functional assay, metoclopramide inhibited specific [³H]GR65630 binding to human h5-HT_3A receptors in a surmountable manner. This seeming discrepancy between functional studies and radioligand binding experiments may be accounted for by (1) the slow kinetics of inhibition of peak currents by metoclopramide compared with the fast onset and offset kinetics of 5-HT-induced currents and (2) the low efficacy of metoclopramide in inhibiting radioligand binding (e.g. only 20% binding inhibition compared to 79% peak current suppression by 200 nM metoclopramide). 4 At low concentrations (1-10 nM), ergotamine had no effect on 5-HT (30 μM)-induced peak currents. Above clinical concentrations, ergotamine (> 3 μM) inhibited them. 5 When both drugs were applied together (0.10 μM metoclopramide + 0.001 to 0.01 μM ergotamine), an inhibition of both, peak and integrated current responses was observed. 6 Neither metoclopramide (≤30 μM) nor ergotamine (≤30 μM) had an effect on the 5-HT reuptake carrier as they did not alter the citalopram-sensitive [³H]5-HT uptake.

Revue / Journal Title

British journal of pharmacology   ISSN 0007-1188   CODEN BJPCBM 

Source / Source

2005, vol. 146, n^o4, pp. 543-552 [10 page(s) (article)] (1 p.1/4)

Langue / Language

Anglais

Editeur / Publisher

Nature Publishing, Basingstoke, ROYAUME-UNI  (1968) (Revue)

Mots-clés anglais / English Keywords

Vascular disease ; Nervous system diseases ; Central nervous system disease ; Cerebral disorder ; Cerebrovascular disease ; Cardiovascular disease ; Neurotransmitter ; Ergot derivatives ; Alpha blocking agent ; D2 Dopamine receptor ; Benzamide derivatives ; Dopamine antagonist ; Pain ; Vasoconstrictor agent ; Antimigrainous agent ; Antiemetic ; Migraine ; Serotonin ; 5-HT3 Serotonine receptor ; Serotonine receptor ; 5-HT3A serotonin receptor ; Human ; Ergotamine ; Metoclopramide ; Interaction ;

Mots-clés français / French Keywords

Vaisseau sanguin pathologie ; Système nerveux pathologie ; Système nerveux central pathologie ; Encéphale pathologie ; Cérébrovasculaire pathologie ; Appareil circulatoire pathologie ; Neurotransmetteur ; Ergot dérivé ; Bloquant α-adrénergique ; Récepteur dopaminergique D2 ; Benzamide dérivé ; Antagoniste dopamine ; Douleur ; Vasoconstricteur ; Antimigraineux ; Antiémétique ; Migraine ; Sérotonine ; Récepteur sérotoninergique 5-HT3 ; Récepteur sérotoninergique ; Récepteur sérotoninergique 5-HT3A ; Homme ; Ergotamine ; Métoclopramide ; Interaction ;

Mots-clés espagnols / Spanish Keywords

Vaso sanguíneo patología ; Sistema nervioso patología ; Sistema nervosio central patología ; Encéfalo patología ; Vaso sanguíneo encéfalo patología ; Aparato circulatorio patología ; Neurotransmisor ; Ergot derivado ; Bloqueador α-adrenérgico ; Receptor dopaminérgico D2 ; Benzamida derivado ; Antagonista dopamina ; Dolor ; Vasoconstrictor ; Agente antimigrañoso ; Antiemético ; Jaqueca ; Serotonina ; Receptor serotoninérgico 5-HT3 ; Receptor serotoninérgico ; Receptor serotoninérgico 5-HT3A ; Hombre ; Ergotamina ; Metoclopramida ; Interacción ;

Mots-clés d'auteur / Author Keywords

5-HT3 receptor ; 5-HT reuptake carrier ; metoclopramide ; migraine ; ergotamine ; emesis ;

Localisation / Location

INIST-CNRS, Cote INIST : 4509, 35400013259388.0080