dextromethorphan and caramiphen

Male Sprague-Dawley rats were trained to discriminate dextromethorphan (DM, 30 mg/kg, ip) from saline using a standard two-lever, fixed ratio 10, food reinforcement procedure. The DM-saline discrimination was acquired, and a range of doses of DM produced a dose-related generalization to the DM-lever choice. Stimulus generalization tests were conducted with dextrorphan, an active metabolite of DM, and with drugs selected from different pharmacological families. Dextrorphan induced a full generalization to DM, but only at a dose higher than the DM training dose. Morphine, a mu opiate receptors agonist, and U 50488, a kappa opiate receptors agonist, failed to substitute for DM. Cyclazocine, a benzomorphan derivative, with high affinity for sigma receptors, was able to produce a complete generalization to DM, without a change in the number of rats responding. Dizocilpine (MK 801), a phencyclidine-like drug, produced a complete generalization, but only at a dose that markedly reduced the number of rats responding. Carbetapentane and caramiphen, antitussive drugs with high affinity for the 'specific DM receptors', failed to substitute for DM. These results show that the discriminative stimulus of DM, did not result primarily from its metabolism to dextrorphan; and the discriminative stimulus properties of DM appear to more closely resemble those of cyclazocine than those of the other drugs tested. This suggests a role of sigma receptors in the mediation of the DM stimulus. These experimental data are discussed with reference to the cyclazocine-like subjective effects produced in man by large doses of DM.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antitussive Agents; Cyclazocine; Cyclopentanes; Dextromethorphan; Dextrorphan; Discrimination Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Morphine; Neuroprotective Agents; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Receptors, sigma

The effects of the non-opioid oral antitussives dextromethorphan (DM) and caramiphen (CP) were tested against the behavioural and EEG effects elicited by the N-methyl-D-aspartate (NMDA) antagonists dizocilpine (MK 801) and phencyclidine (PCP) in rats and mice. PCP (1.25-10 mg/kg i.p.) induced a dose-dependent increase/decrease of the locomotor/exploratory activity of mice. DM (25-50 mg/kg i.p.) and MK 801 (0.125-0.250 mg/kg i.p.) induced an increase of the locomotor/exploratory activity of mice, while CP (25-50 mg/kg i.p.) did not produce such an effect. CP (12.5 mg/kg i.p.) and DM (12.5 mg/kg i.p.) significantly potentiated the effects of PCP (1.25 mg/kg i.p.) and MK 801 (0.062 mg/kg i.p.) in the open field test in mice. In rats, PCP (1.25-10 mg/kg i.p.) induced three dose-dependent EEG stages: 1) increase of the cortical desynchronization periods; 2) increase of the amplitude of cortical background activity; 3) appearance of cortical slow wave-spike complexes. Even though DM (up to 100 mg/kg i.p.) only induced PCP-like EEG stage 1 by itself, and CP (up to 50 mg/kg i.p.) did not affect basal cortical EEG activity, these drugs, at the doses of 30-50 mg/kg i.p., potentiated all the EEG effects induced by PCP. These data support the view of an interaction between non-opioid antitussives and non-competitive NMDA antagonists.

Topics: Animals; Antitussive Agents; Behavior, Animal; Cyclopentanes; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Synergism; Electroencephalography; Ion Channels; Male; Mice; Phencyclidine; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

The allosteric modulation of sigma recognition sites by phenytoin (diphenylhydantoin) has been demonstrated by the ability of phenytoin to stimulate binding of various [3H] sigma ligands, as well as to slow dissociation from sigma sites and to shift sigma sites from a low- to a high-affinity state. Phenytoin stimulated the binding of the sigma 1- selective ligand [3H](+)pentazocine in a dose-dependent manner. Stimulation of binding at a final concentration of 250 microM phenytoin was associated with a decrease in the KD. The affinities of the sigma reference compounds caramiphen, dextromethorphan, dextrophan, (+)3-PPP and (+)SKF-10,047 were three- to eight-fold higher, while the affinities of benzetimide, BMY-14802, carbetapentane, DTG and haloperidol were unchanged in the presence of 250 microM phenytoin. The relative sensitivity of sigma compounds to allosteric modulation by phenytoin is not a property of all sigma ligands, and may provide an in vitro basis for distinguishing actions of sigma compounds and predicting sigma effects in vivo.

Topics: Allosteric Regulation; Animals; Binding Sites; Cyclopentanes; Dextromethorphan; Dextrorphan; Guinea Pigs; Ligands; Male; Pentazocine; Phenazocine; Phenytoin; Piperidines; Radioligand Assay; Receptors, sigma; Tritium

The ability of dextromethorphan (DXM) and phencyclidine (PCP) receptor ligands to attenuate increases in cytosolic free Ca2+ concentration ([Ca2+]i) evoked by N-methyl-D-aspartate (NMDA) and high extracellular [K+] was examined using the fluorescent dye Fura 2 in cultured rat hippocampal pyramidal neurons. The DXM receptor ligand caramiphen (40 microM) reduced K(+)-evoked rises in [Ca2+]i to a greater extent than NMDA-evoked rises; the reverse was true for the PCP receptor ligands ketamine (10-40 microM) and dextrorphan (10 microM). DXM itself, which has affinity for both DXM and PCP receptors, reduced both K(+)- and NMDA-evoked increases in [Ca2+]i in a concentration-dependent manner. The results suggest that DXM receptor ligands may at least in part exert their known anticonvulsant and neuroprotective effects by reducing Ca2+ influx through voltage-activated Ca2+ channels.

Topics: Animals; Calcium; Cyclopentanes; Cytosol; Dextromethorphan; Female; Fura-2; Hippocampus; Ketamine; Ligands; N-Methylaspartate; Parasympatholytics; Potassium; Pregnancy; Pyramidal Tracts; Rats; Receptors, Neurotransmitter; Receptors, Phencyclidine

The non-opioid antitussive drugs, dextromethorphan, caramiphen and carbetapentane, are also anticonvulsant. The effects of these antitussives on potassium-stimulated release of endogenous amino acids from rabbit hippocampal slices was tested. All 3 drugs significantly reduced the release of glutamate, with carbetapentane being the most potent (IC50 approximately 40 microM). We suggest that the anticonvulsant action may be due to their ability to decrease glutamate release.

Topics: Animals; Antitussive Agents; Aspartic Acid; Cyclopentanes; Depression, Chemical; Dextromethorphan; Female; gamma-Aminobutyric Acid; Glutamates; Glutamic Acid; Glycine; Hippocampus; In Vitro Techniques; Male; Potassium; Rabbits

Three commonly used antitussive compounds were tested for their ability to block epileptiform activity recorded extracellularly from hippocampal and olfactory cortex slices maintained in vitro. Antitussives were bath-applied to brain slices either before or after epileptiform activity was induced. Dextromethorphan (DM) prevented electrically evoked epileptiform afterdischarges and arrested spontaneous bursting induced by exposure to added NMDA or to Mg2(+)-free medium. In contrast, caramiphen (CM) and carbetapentane (CB) were effective against epileptiform activity induced by Mg2(+)-free medium, but not by NMDA. Atropine was not effective in blocking epileptiform activity at concentrations 10 times the effective concentration of CM, which has known cholinolytic activity. Our results suggest that all these antitussives exert their anticonvulsant action at the DM binding site. Neither cholinolytic activity nor antagonism of the NMDA receptor-channel complex appears to be necessary for antitussives to prevent or arrest epileptiform activity. DM appears to have a separate NMDA-antagonist property in addition to its actions at the DM site. Our neurophysiological evidence supports the hypothesis that these antitussives have anticonvulsant properties independent of any action at the NMDA receptor-channel complex.

Topics: Animals; Antitussive Agents; Cyclopentanes; Dextromethorphan; Electric Stimulation; Epilepsy; Evoked Potentials; Guinea Pigs; Hippocampus; In Vitro Techniques; Magnesium; N-Methylaspartate; Olfactory Bulb

The antitussives dextromethorphan (DM), carbetapentane (CBP), and caramiphen (CM) are known to have anti-convulsant properties. They were given individually to guinea pigs prior to poisoning with 2 x LD50 soman to test their efficacy against organophosphorus-induced convulsions, brain damage, and lethality. All subjects received an injection of pyridostigmine coincident with the antitussive, and were treated with atropine methylnitrate and pralidoxime chloride 30 sec after soman administration. CM, in a dose-dependent manner, protected against lethality and either prevented or reduced the intensity of convulsions, electrographic seizure activity (EGSA), and brain damage. CBP delayed the onset of EGSA and reduced its intensity. DM prevented EGSA at higher doses, but neither DM nor CBP protected against the lethal effects of soman. CM is known to possess relatively stronger anticholinergic properties than the other antitussives used in this experiment, which may have contributed to its relatively superior efficacy against soman.

Topics: Animals; Anticonvulsants; Antitussive Agents; Cyclopentanes; Dextromethorphan; Guinea Pigs; Male; Necrosis; Nervous System Diseases; Neurons; Soman

The antitussive properties of caramiphen edisylate were studied in the decerebrate cat in which cough was elicited by direct electrical stimulation of the cough center. In this preparation dextromethorphan hydrobromide was compared to caramiphen as an antitussive agent. Dextromethorphan was somewhat more potent when given i.v. as well as when given directly into the left vertebral artery (i.a.). Both agents were far more effective when given i.a. than when given i.v. The effective dose ratios of i.v./i.a. were about 12 and 14 for caramiphen and 11 and 7 for dextromethorphan (actual and cumulative doses). These ratios indicate that both agents have a central rather than a peripheral site of antitussive action. Both drugs had antitussive effects in i.a. doses which did not alter arterial blood pressure or respiration greatly. However, after i.v. administration transient changes in both arterial blood pressure and respiration were observed with both agents. It was concluded that the antitussive action of both caramiphen and dextromethorphan is due to a selective effect on the cough center in the brainstem of the cat. On a milligram per kilogram basis, caramiphen required a 3 to 4 times larger dose than dextromethorphan for equieffective antitussive effects.

Topics: Animals; Antitussive Agents; Brain Stem; Cats; Cough; Cyclopentanes; Decerebrate State; Dextromethorphan; Female

Several antitussive agents were assessed for their cough-suppressant activity. Cough responses were obtained by electrically stimulating the lower brainstem, in cats lightly anesthetized with sodium pentobarbital or in unanesthetized midcollicular decerebrate preparations. Cough sounds were recorded with the aid of a microphone. The cough reactive region was concentrated in an area dorsomedial to the trigeminal tract and nucleus. The potency of these antitussive agents (dextromethorphan, RO 21-4790-001, codeine, clonazepam, diazepam and caramiphen) were determined by studying their effect on the centrally induced cough responses. Each of these agents was administered in graded doses intravenously to determine the minimal effective doses for suppressing the cough responses. They are 0.57, 2.55, 1.71, 0.048, 0.28 and 3.18 mg/kg for the above listed drugs. The results indicate that clonazepam was found to be the most potent antitussive among these agents, the mean effective dose being about 1/35 of that of codeine. The antitussive potency of benzodiazepines is not well correlated with their muscle relaxant activity. For instance, clonazepam and diazepam have the same potency in depressing polysynaptic spinal reflexes, whereas the former is six times more potent than diazepam as an antitussive. This finding indicates that clonazepam has a high specificity as an antitussive.

Topics: Animals; Antitussive Agents; Cats; Clonazepam; Codeine; Cough; Cyclopentanes; Dextromethorphan; Diazepam; Ethylamines; Injections, Intravenous