dextromethorphan and neramexane

The objective of this study was to investigate the effects of three low-affinity NMDA receptor antagonists, MRZ 2/279 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane HCl), AR-R 15896AR ([+]-alpha-phenyl-2-pyridine-ethanamine diHCl) and dextromethorphan on epileptiform activity in vitro. Epileptiform discharges were elicited in DBA/2 mouse cortical slices by perfusion with Mg(2+)-free artificial cerebrospinal fluid. MRZ 2/279, AR-R 15896AR and dextromethorphan all reversibly decreased the frequency of the discharges in a concentration-dependent manner. The IC(50)'s for MRZ 2/279, AR-R 15896AR and dextromethorphan were 5.2, 10.8 and 55.9 microM, respectively. These low-affinity NMDA receptor antagonists may be proved to be clinically effective with fewer adverse effects than drugs with high-affinity for the NMDA receptor-operated channel.

Topics: Animals; Cerebral Cortex; Cyclopentanes; Dextromethorphan; Electric Conductivity; Electrophysiology; Epilepsy; Excitatory Amino Acid Antagonists; Female; In Vitro Techniques; Male; Mice; Mice, Inbred DBA; Pyridines; Receptors, N-Methyl-D-Aspartate

The tail-flick test was used to investigate the effects of chronic administration of the N-methyl-D-aspartate (NMDA) receptor antagonists, dextromethorphan, memantine and MRZ 2/579, on the development and reversal of morphine tolerance in mice in three separate experiments. Experiment 1 investigated the effects of NMDA receptor antagonists on the development of tolerance. Morphine (10 mg/kg for 6 days, twice daily) produced a 5.9-fold rightward shift of the cumulative dose-response curves. Co-administration of dextromethorphan, memantine or MRZ 2/579 between tests 1 and 2 dose-dependently (5-10 mg/kg) inhibited the development of morphine tolerance. In experiment 2, in which the effects on the reversal were investigated, morphine-tolerant mice were treated b.i.d. for an additional 6 days (between tests 2 and 3) with vehicle+vehicle, NMDA receptor antagonist+vehicle, vehicle+morphine or NMDA receptor antagonist+morphine. Morphine-tolerant mice treated with vehicle+vehicle remained morphine tolerant, whereas this residual morphine tolerance was inhibited by administration of all three NMDA antagonists (each 10 mg/kg). Morphine-tolerant mice receiving vehicle+morphine injections demonstrated an unchanged degree of antinociceptive tolerance. In these mice, the co-administration of memantine and MRZ 2/579, but not dextromethorphan, resulted in the reversal of morphine tolerance. In experiment 3, memantine and MRZ 2/579 (10 mg/kg) inhibited the acute antinociceptive effect of morphine, but dextromethorphan did not. These data indicate that low-affinity, clinically available and/or therapeutically promising NMDA receptor antagonists may be used to inhibit ongoing morphine tolerance.

Topics: Analgesics, Opioid; Animals; Cyclopentanes; Dextromethorphan; Drug Tolerance; Excitatory Amino Acid Antagonists; Male; Memantine; Mice; Morphine; Receptors, N-Methyl-D-Aspartate; Tail