Nefopam blocks voltage-sensitive sodium channels and modulates glutamatergic transmission in rodents

Abstract In order to specify the nature of interactions between the analgesic compound nefopam and the glutamatergic system, we examined the effects of nefopam on binding of specific ligands on the three main subtypes ionotropic glutamate receptors: N -methyl- d -aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), or quisqualic acid (QA) and kainic acid (KA) in rat brain membrane preparations. Functionally, we investigated the effects of nefopam against the seizures induced by agonists of these excitatory glutamate receptors in mice. Since the synaptic release of glutamate mainly depends upon the activation of membrane voltage-sensitive sodium channels (VSSC s ), the nature of interactions between nefopam and these ionic channels was studied by evaluating the effects of nefopam on binding of 3 H-batrachotoxinin, a specific ligand of the VSSC s in rat brain membrane preparations. The functional counterpart of the binding of nefopam on VSSC s was evaluated by its effects on the 22 Na uptake-stimulated by veratridine on human neuroblastoma cells and in the maximal electroshock test in mice. Nefopam showed no affinity for the subtypes of ionotropic glutamate receptors up to 100 μM. On the other hand, nefopam was effective against NMDA, QA and KA induced clonic seizures in mice. Nefopam displaced 3 H-batrachotoxinin and inhibited the uptake of 22 Na in the micromolar range and it protected mice against electroshock induced seizures. Nefopam may block the VSSC s activity: consequently, at the presynaptic level, this effect led to a reduction of glutamate release and at the postsynaptic level, it led to a decrease of the neuronal excitability following activation of the glutamate receptors.