levorphanol and Seizures

The antitussive, dextromethorphan (DM), and its metabolite, dextrorphan (DX), were evaluated for antiepileptic properties in vitro. Interictal bursts and prolonged ictal epileptiform afterdischarges, induced by perfusion of guinea pig neocortical brain slices with Mg2+-free solution, were blocked by DX (1-250 microM) or DM (100 microM). Intracellular records showed that these agents blocked N-methyl-D-aspartate (NMDA)-induced depolarizations without altering intrinsic membrane properties. DX blocked NMDA but not quisqualate-evoked multi-unit excitatory responses. DM is a widely available, orally effective drug with low toxicity in antitussive doses, which has antiepileptic and NMDA-antagonist properties in vitro. Its toxicity and effectiveness as an anticonvulsant should be expeditiously examined in clinical trials.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Antitussive Agents; Aspartic Acid; Cerebral Cortex; Dextromethorphan; Dextrorphan; Evoked Potentials; Guinea Pigs; In Vitro Techniques; Levorphanol; Morphinans; N-Methylaspartate; Seizures; Valine

Dextromethorphan, its metabolite dextrorphan, phencyclidine, ketamine, MK-801, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid and DL-2-amino-7-phosphonoheptanoic acid were evaluated for potency to antagonize N-methyl-D-aspartate-induced convulsions following intraperitoneal administration using male CF-1 mice. Whereas reference anticonvulsants (e.g., phenytoin) were ineffective in this model, dextromethorphan and all competitive and noncompetitive N-methyl-D-aspartate antagonists blocked seizures. The results are consistent with the interpretation that dextromethorphan elicits some of its pharmacological responses via an interaction with receptors for excitatory amino acids.

Topics: Animals; Anticonvulsants; Aspartic Acid; Dextromethorphan; Dibenzocycloheptenes; Dizocilpine Maleate; Levorphanol; Male; Mice; N-Methylaspartate; Psychomotor Performance; Seizures

Dextromethorphan (DM), a non-prescription antitussive, has anticonvulsant properties and antagonizes N-methyl-D-aspartate (NMDA) receptor-mediated responses in rat spinal and cortical neurons. The effects of daily intraperitoneal injections of DM on amygdala-kindled seizures were examined. DM was found both to prevent the development of full kindling in rats and to decrease seizure intensity in previously fully kindled animals. The findings of this study, combined with the ready availability of DM and its apparent safety in antitussive doses suggest that clinical testing of this drug as an anticonvulsant is warranted.

Topics: Amygdala; Animals; Antitussive Agents; Dextromethorphan; Kindling, Neurologic; Levorphanol; Male; Rats; Rats, Inbred Strains; Seizures

The non-opioid antitussives dextromethorphan and carbetapentane, the active ingredients of several over-the-counter cough suppressants, provide a dose-related protection against maximal electroshock seizures in rats. Both drugs, which bind with high affinity to the same site in the brain, potentiated the effects of the prototypic antiepileptic drug diphenylhydantoin. We propose that these novel anticonvulsant drugs may represent potentially useful therapeutic agents for the treatment of some forms of epilepsy, either alone or in combination with existing antiepileptic drugs.

Topics: Animals; Anticonvulsants; Antitussive Agents; Cyclopentanes; Dextromethorphan; Drug Synergism; Electroshock; Levorphanol; Male; Phenytoin; Rats; Rats, Inbred Strains; Seizures

After a series of seven electroconvulsive shocks, mice (C57BL/6J) showed a marked change in their response to opiates. Although very large doses of mu agonists induce convulsions in normal control mice, our evidence indicated that this was accomplished through nonopiate mechanisms: they could not be blocked by naltrexone and the pattern of drug potencies (codeine greater than morphine greater than levorphanol) was not consistent with an opiate response. In contrast, after electroconvulsive shock small doses of mu agonists induced convulsions that could be blocked by naltrexone and the pattern of drug potency (levorphanol greater than morphine greater than codeine) was consistent with an opiate mechanism. Kappa drugs, on the other hand, produced convulsions in both control and ECS animals, although there was an enhanced responsiveness in the latter. Furthermore, the convulsions produced by kappa drugs were blocked by naltrexone and showed stereoselectivity in both control and ECS animals. The changes in responsiveness to mu and kappa opiates cannot be explained on the basis of a general increase in seizure susceptibility, as sensitivity to the nonopiate convulsant, strychnine, was not enhanced after electroconvulsive shock. The results point to a qualitative change in response to mu agonists after electroconvulsive shock, but only a change in sensitivity to kappa agonists.

Topics: Animals; Codeine; Dose-Response Relationship, Drug; Electroshock; Levorphanol; Mice; Mice, Inbred C57BL; Morphine; Naltrexone; Narcotics; Receptors, Opioid; Seizures

Intracerebroventricular (ICV) injection of both enkephalin (100 micrograms) and morphine (200 micrograms produces characteristic electrographic seizures. Injection of low doses of either morphine or levorphanol into the lateral ventricle of the brain prior to the administration of epileptogenic doses of enkephalin can block the induction of such seizures. A similar trend was observed when either opiate preceded ICV morphine. Microinjections of both morphine (30 micrograms) or levorphanol (40 micrograms) into the periaqueductal gray area (PAG) or into the nucleus accumbens resulted in potent analgesia. However, only morphine injected into the nucleus accumbens was effective in blocking electrographic seizures induced by ICV enkephalin. On the basis of this and other previous findings we propose that the excitatory-epileptic and the inhibitory-antiepileptic action of opiates and opioids are mediated by two different systems. Furthermore, we propose that such systems may differ both in their anatomical distribution and in the classes of opiate receptors underlying their action.

Topics: Animals; Anticonvulsants; Drug Interactions; Enkephalin, Leucine; Injections, Intraventricular; Levorphanol; Male; Morphine; Nucleus Accumbens; Periaqueductal Gray; Rats; Rats, Inbred Strains; Seizures

Opiate alkaloid and opioid peptide actions on spontaneous neuronal activity and postsynaptic amino acid responsiveness were assessed using intracellular recording techniques applied to murine spinal cord neurons in primary dissociated cell culture. Application of opiates was by superfusion and amino acids by iontophoresis. Glycine and GABA but not glutamate responses were antagonized by the opiate alkaloids. Since opiate effects on glycine and GABA responses were not naloxone-reversible, only weakly stereospecific, and not produced by the opioid peptide [D-Ala2]-Met-enkephalinamide, it is unlikely that these effects were mediated by opiate receptors. Opiate depression of glycine inhibition was correlated with the induction of paroxysmal depolarizations in cultured spinal cord neurons, suggesting that antagonism of inhibitory amino acid transmission may underlie the convulsant actions of high concentrations of the opiate alkaloids.

Topics: Animals; Cells, Cultured; Dextrorphan; Enkephalin, Methionine; Enkephalins; Evoked Potentials; gamma-Aminobutyric Acid; Glycine; Levorphanol; Mice; Morphine; Naloxone; Narcotics; Neural Inhibition; Neurons; Seizures; Spinal Cord; Synapses

Topics: Analgesics; Animals; Codeine; Dextropropoxyphene; Dose-Response Relationship, Drug; Drug Interactions; Hot Temperature; Levorphanol; Male; Meperidine; Methadone; Mice; Mice, Inbred Strains; Naloxone; Pentazocine; Physical Stimulation; Reaction Time; Seizures; Time Factors; Tremor