In vitro inhibition of recombinant ligand-gated ion channels by high concentrations of milnacipran

Rationale Tricyclic antidepressants are known to inhibit various ligand-gated ion-channel (LGIC) receptors, and some of their clinical features may be associated with this activity. The effects of milnacipran, a selective inhibitor of the reuptake of serotonin and noradrenaline, on LGIC receptors have not yet been investigated on such ion-channel receptors.Objectives To determine the in vitro effect of milnacipran on four recombinant LGIC receptors, nicotinic acetylcholine, N-methyl-d-aspartate, -amino butyric acid (GABA) and 5-hydroxytryptamine_3A receptors.Methods Receptors were expressed in Xenopusoocytes and LGIC activity measured using a two-voltage clamp technique.Results There was no interaction at the GABA receptor. The results at the other LGIC receptors showed that they could be inhibited by high concentrations of milnacipran.Conclusions At high concentrations, milnacipran can inhibit certain LGICs. It is, however, unlikely that these interactions have any clinical consequence under normal therapeutic conditions, since the concentrations required are considerably higher than those achieved in plasma of treated patients.