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PubMed1985

Effects of morphine, naltrexone, and dextrorphan in untreated and morphine-treated pigeons.

Six pigeons, trained to peck a response key on a fixed-ratio 20 schedule of food reinforcement, were used to examine the effects of morphine, naltrexone, and dextrorphan, before, during, and after chronic treatment with increasing doses of morphine (10.0-100.0 mg/kg/day). Tolerance developed to the rate-decreasing effect of the daily maintenance doses of morphine within 2 days of each dose increase. A small amount of tolerance to morphine and supersensitivity to naltrexone was evident within the 1st week of morphine treatment (10.0 mg/kg/day). Continued administration of morphine (32.0-100.0 mg/kg/day) produced further tolerance to morphine and supersensitivity to naltrexone, as evidenced by a 5-fold increase in the dose of morphine, and 1,000-fold decrease in the dose of naltrexone, necessary to suppress responding. By the 4th week of treatment (100.0 mg/kg/day), a modest tolerance had also developed to the rate-decreasing effects of dextrorphan. Suppression of responding by naltrexone, but not morphine or destrorphan, was accompanied by a loss in body weight over the 1- to 2-h session in morphine-maintained pigeons; both weight loss and reduced response rates also occurred on termination of morphine treatment. Sensitivity to the rate-decreasing effects of morphine and naltrexone was near normal within 10 days following termination of morphine treatment. The dramatic changes in sensitivity to naltrexone and morphine produced by daily morphine injections, as well as the ability to generate complete dose-effect curves within a single session, indicate that this behavioral preparation may provide sensitive concurrent measures of narcotic tolerance and supersensitivity to antagonists in the pigeon.

Animals↗
PubMed1988

Dextromethorphan and dextrorphan as calcium channel antagonists.

Dextromethorphan and dextrorphan, which reduce excitatory amino acid-induced neurotoxicity, decreased K+ depolarization-evoked 45Ca2+ uptake into brain synaptosomes and cultured neural (PC12) cells. Half-maximal inhibition of synaptosomal 45Ca2+ uptake occurred with 48 microM dextromethorphan or 200 microM dextrorphan, which are similar to concentrations associated with protection from excitotoxicity. The ability to decrease Ca2+ flux through N-type (synaptosomal) and L-type (PC12) voltage-gated Ca2+ channels may therefore contribute to the neuroprotective effects of these compounds.

Animals↗
PubMed1996

Additive neuroprotective effects of dextrorphan and cycloheximide in rats subjected to transient focal cerebral ischemia.

Previous studies have implicated both excitotoxicity and apoptosis in the pathogenesis of cerebral infarction induced by focal ischemic insults. Here we tested the possibility that the NMDA antagonist, dextrorphan, and the protein synthesis inhibitor, cycloheximide, would produce additive protective effects in a rodent model of focal ischemia-reperfusion. Transient focal cerebral ischemia was induced by a 90 min period of ligation of the right middle cerebral artery and both common carotid arteries. Administration of either 30 mg/kg dextrorphan or 0.5 mg/kg cycloheximide, given i.p. 15 min before ischemia, reduced infarct volume by about 65%. When optimal concentrations of each drug were given together, infarct volume was reduced by 87% as measured 14 days later. These observations support the idea that both excitotoxicity, and apoptosis dependent on new protein synthesis, contribute to cerebral infarction after transient focal ischemia in the rat.

Animals↗
PubMed1985

Differential effects of dextrorphan and levorphanol on the excitation of rat spinal neurons by amino acids.

The effects of the stereoisomers dextrorphan and levorphanol on the excitation of spinal neurons by electrophoretically administered excitatory amino acids were studied in pentobarbitone-anaesthetised rats. Both isomers reduced responses to N-methyl-DL-aspartate (NMA), dextrorphan being both more selective and more potent than levorphanol in this respect. This observation supports the proposal that the NMA-blocking activity of a variety of drugs with psychotomimetic properties is subserved by actions at phencyclidine (PCP)/sigma opiate receptors.

Acetylcholine↗
PubMed1984

Behavioral effects of morphine, levorphanol, dextrorphan and naloxone in the frog Rana pipiens.

Systemic morphine induces explosive motor behavior and generalized muscular rigidity in frogs. Naloxone does not reverse either of these effects of morphine but at high doses causes muscular flaccidity and unresponsiveness to stimulation. Intraspinal morphine induces rigidity, but not explosive motor behavior, and this action is blocked by naloxone. Behavioral effects are seen rarely after intraspinal levorphanol (rigidity) and never after intraspinal dextrorphan or naloxone. In contrast to systemic morphine and naloxone, systemic levorphanol and dextrorphan are lethal to frogs at high doses.

Animals↗
PubMed1987

Dextrorphan and dextromethorphan attenuate hypoxic injury in neuronal culture.

The dextrorotatory opioid derivatives, dextrorphan and dextromethorphan, can attenuate hypoxic injury in cortical cell cultures. This effect is concentration-dependent in the micromolar range, and not strongly stereospecific, as it can also be demonstrated with the levorotatory enantiomer of dextrorphan, levorphanol. The possibility that these clinically available compounds may have therapeutic utility in hypoxic or ischemic encephalopathy warrants further investigation.

Animals↗
PubMed1997

Morphine and dextrorphan lose antinociceptive activity but exhibit an antispastic action in chronic spinal rats.

Within 3-4 weeks after spinal transection, morphine-induced antinociception, assessed with the tail flick reflex in rats, is profoundly reduced. The cause of this decrement is unknown. The present studies were conducted to determine whether this phenomenon reflects a general loss in opiate activity or a selective decline in opiate antinociception. This was accomplished by assessing the effect of morphine on two different responses, the tail flick reflex and the hindlimb spasticity that develops in chronic spinal rats. Because excitatory amino acid antagonists are also antinociceptive in acute spinal rats, the effect of one such drug, dextrorphan, on these two behaviors was also evaluated in chronic spinal animals. The antinociceptive and antispastic effect of subcutaneous (6 mg/kg) and intrathecal (5 micrograms) morphine injections were assessed in intact and chronic (21-28 days) spinal rats, whereas the effect of subcutaneous (25 and 40 mg/kg) and intrathecal (350 micrograms) dextrorphan was assessed in acute (1 day) and chronic spinal rats. The antinociceptive effect of both drugs was significantly reduced in chronic spinal animals, relative to saline controls. However, each drug treatment produced a significant antispastic effect in the same animals, indicating a selective decline in opiate action. This outcome also suggests that excitatory amino acid antagonists may be useful as adjunct antispastic agents.

Animals↗
PubMed1989

[Determination of dextromethorphan and its major metabolite dextrorphan by gas chromatography].

A gas chromatography assay has been developed for the determination of dextromethorphan and dextrorphan in human fluids. Drugs are extracted with chloroform-isopropanol-n-heptane (50/17/33, v/v) form alkalinized samples using cyclizine as an internal standard, analysed using a 3 p. cent OV-17 column, and detected by selective nitrogen detection. The lower detection limits are 0.4 and 0.7 micrograms/l for dextromethorphan and dextrorphan, respectively.

Chromatography, Gas↗
PubMed1998

Bioavailability of dextromethorphan (as dextrorphan) from sustained release formulations in the presence of guaifenesin in human volunteers.

A multiple dose bioavailability study with six healthy male human volunteers was conducted. The bioavailability of an experimental sustained release tablet containing dextromethorphan hydrobromide (DXP-HBr), was compared with a marketed sustained release DXP-HBr suspension in a three-way crossover study. Plasma samples, collected serially after oral drug administration, were analysed for the major metabolite of dextromethorphan (DXP), dextrorphan (DX), using a specific HPLC method with fluorescence detection. The bioavailability parameters; area under the concentration-time curve (AUC), maximum plasma concentration (Cmax), and time to peak (Tmax), were obtained from the plasma concentration-time data. Additionally, pharmacokinetic parameters such as mean residence time (MRT), accumulation factor (R), fluctuation index (Fi), total body clearance (Cl), and the average concentration (C) were estimated by using model independent kinetics approach. Analysis of variance of the data revealed that the presence of guaifenesin in the test formulation does not appear to have a statistically significant (p > 0.05) effect on the bioavailability of dextromethorphan as dextrorphan. The relative bioavailability of the tablet dosage form with respect to the suspension was found to be 113% on Day 1 and 110% on Day 6.

Adult↗
PubMed1993

Dextrorphan attenuates the behavioral consequences of ischemia and the biochemical consequences of anoxia: possible role of N-methyl-d-aspartate receptor antagonism and ATP replenishing action in its cerebroprotecting profile.

The acute anti-ischemic and anti-anoxic effects of dextrorphan (DX) were compared with those of dizocilpine (MK-801) in a variety of animal models, and in vivo and in vitro testings under anoxic conditions. DX reduced the incidence of death in ischemic mice and improved the rotarod performance of mice with brain ischemia. The ischemically-impaired memory of mice treated with DX markedly improved, as shown in the step-through type passive avoidance test, Morris water maze and in the habituation of exploratory behavior test. MK-801 likewise improved the water maze performance of the ischemically-impaired mice, but to a lesser extent. The step-through type passive avoidance performance of ischemic mice was not improved by MK-801. In the passive avoidance task with normal mice, DX, like MK-801, produced anterograde amnesia at doses higher than those needed to attenuate the behavioral effects of ischemia. DX, intravenously or centrally administered, markedly and dose-dependently reduced the incidence of death in mice receiving potassium cyanide (KCN). DX lessened the reduction in adenosine triphosphate (ATP) and increased lactate contents in mice dosed with KCN and also lessened the reduction in ATP in the TCA cycle and oxidative phosphorylation reactions caused by KCN (0.58 mmol/l), whereas MK-801 failed to show any effect on ATP formation pathways in vivo and in vitro, and failed to protect mice against KCN-induced lethal toxicity in vivo. In the in vitro studies, DX increased the adenylate kinase activity of the rat brain homogenate. DX was found to be a cerebroprotectant with anti-ischemic and anti-anoxic actions, the effects probably stemming from its N-methyl-d-aspartate receptor antagonistic property in cooperation with its ATP replenishing action.

Adenosine Triphosphate↗
PubMed1987

Dextrorphan and dextromethorphan attenuate glutamate neurotoxicity.

The dextrorotatory morphinan opioid, dextrorphan, which has recently been reported to block the excitation of cortical neurons by N-methyl-D-aspartate, was found at 10-100 microM concentrations to attenuate both morphological and chemical evidence of glutamate neurotoxicity in murine neocortical cell cultures; a similar effect was found with its methyl ester derivative, dextromethorphan. Given other data suggesting that glutamate neurotoxicity may participate in the pathogenesis of the central neuronal loss associated with certain human neurological diseases, the present observations raise the possibility that these clinically tested opioids, or related compounds, may eventually prove to have some clinical therapeutic utility.

Animals↗
PubMed1989

Pretreatment with the NMDA antagonist dextrorphan reduces cerebral injury following transient focal ischemia in rabbits.

We studied the efficacy of systemic pre-treatment with dextrorphan (DX), a clinically tested N-methyl-D-aspartate (NMDA) antagonist, in a rabbit model of transient focal cerebral ischemia. Rabbits were treated with either a 24 mg/kg i.v. loading dose followed by 12 mg/kg/h i.v. infusion of 0.48% DX in normal saline (NS), or with an equivalent volume of NS alone. One and 1/2 h after starting the drug or NS, the rabbits underwent a 1 h occlusion of the left internal carotid and anterior cerebral arteries, followed by 4 h of reperfusion. The DX-treated rabbits had significantly less neocortical ischemic neuronal damage (7.4%) than the normal saline group (31.6%) and demonstrated a significant decrease in ischemic cortical edema. DX may prove useful in the treatment of clinical cerebrovascular disease.

Animals↗
PubMed1989

Effect of MK-801, kynurenate, glycine, dextrorphan and 4-acetylpyridine on striatal toxicity of quinolinate.

Measurements of striatal choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) activities indicated that systemic administration of 4-8 mg/kg of MK-801 to rats completely blocked neuronal damage due to intrastriatal injections of 75-150 nmol of quinolinic acid. Similar experiments with 0-2 mg/kg MK-801 suggested the ED50 might be between 1 and 1.5 mg/kg for protection against 50 nmol of intrastriatal quinolinic acid, and between 2 and 3 mg/kg for 75 nmol. Repeated pretreatment with kynurenate (3 x 300 mg/kg) gave significant but not complete protection against similar doses of quinolinic acid, with the protective effect being greater for GAD than for ChAT. Glycine appeared to potentiate the effect of high doses of quinolinic acid on ChAT and the other pretreatments tested (dextrorphan, dextromethorphan, 4-acetylpyridine) had no significant effect.

Animals↗
PubMedDate not supplied

Levorphanol but not dextrorphan suppresses the foot-lifting response to an aversive thermal stimulus in the terrestrial snail, Cepaea nemoralis.

The terrestrial snail, Cepaea nemoralis, when placed on a surface heated at 40 degrees C lifts the anterior portion of its foot from the source of heat. This stereotyped response, which suggests aversion, can be inhibited by injections of small doses of morphine and levorphanol, but is not affected by similar or larger doses of dextrorphan. It is suggested that the "analgesic" effect of the opiates in these animals involves interaction with stereochemically specific opiate receptors that may be fundamentally similar to those occurring in mammals.

Animals↗
PubMed1991

Induction of phencyclidine-like behavior in rats by dextrorphan but not dextromethorphan.

The behavioral effects of dextromethorphan (DM), dextrorphan (DO) and phencyclidine (PCP) were compared in rats. DO (15-120 mg/kg) was similar to PCP (1.25-20 mg/kg) in inducing dose-dependent locomotor hyperactivity, stereotypy and ataxia. DM (15-120 mg/kg) induced moderate hyperactivity only at the higher doses about 45 min after treatment. DM and DO modified the locomotor facilitation induced by 10 mg/kg PCP in opposite directions. Pretreatment with DO facilitated, whereas DM dose-dependently inhibited PCP-elicited hyperactivity. Although the metabolism of DM in rats is unknown, the recently reported abuse of DM in humans may occur by its conversion to DO in the organism, i.e., to a metabolite which produces PCP-like effects.

Animals↗
PubMed1988

Dextrorphan and dextromethorphan, common antitussives, are antiepileptic and antagonize N-methyl-D-aspartate in brain slices.

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.

2-Amino-5-phosphonovalerate↗
PubMed1988

Delayed treatment with dextromethorphan and dextrorphan reduces cerebral damage after transient focal ischemia.

The N-methyl-D-aspartate (NMDA) antagonists dextromethorphan (DM) and dextrorphan (DX) were found to reduce significantly neocortical severe ischemic neuronal damage (SIND) when administered in a delayed fashion after the ischemic insult. Rabbits underwent occlusion of the left internal carotid artery and anterior cerebral artery for 1 h, followed by 4 h of reperfusion. Immediately after the completion of the 1 h arterial occlusion, animals were blindly treated intravenously with 20 mg/kg loading dose followed by 10 mg/kg/h of DM, 15 mg/kg loading dose followed by 15 mg/kg/h of DX, or an equivalent volume of normal saline (NS) alone. The area of neocortical SIND was 3.7% in the DM group, 4.4% in the DX group, and 41.3% in the normal saline controls. These drugs may have considerable therapeutic potential in clinical stroke.

Animals↗