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PubMed1994

Dextrorphan and dextromethorphan: comparative antitussive effects on guinea pigs.

Dextromethorphan, after administration, is rapidly and extensively transformed into dextrorphan. The aim of this study was to compare the cough-suppressing activity of 6, 12, 24, 48 mg/kg, i.p., of dextrorphan (dextro rotatory isomer of racemorphan) with that of dextromethorphan, using the model of citric acid-induced coughing in the unanaesthetized, unrestrained guinea pig. A significant dose-effect relationship of dextrorphan in reducing citric acid-induced cough was observed. This effect was comparable with that of dextromethorphan. However, at 48 mg/kg, i.p., dextromethorphan had a toxic effect while dextrorphan did not. Because dextrorphan is the major metabolite of dextromethorphan and has antitussive activity comparable to that of dextromethorphan, clinical use of dextrorphan is suggested.

Animals↗
PubMed1997

Behavioural pharmacology of the non-competitive NMDA antagonists dextrorphan and ADCI: relations between locomotor stimulation, anticataleptic potential and forebrain dopamine metabolism.

The effects of systemic administration of the non-competitive N-methyl-D-aspartate (NMDA) antagonists dextrorphan (10-40 mg/kg, i.p.) and [+/-]-5-aminocarbony-10,11-dihydro-5H-dibenzo[a,d]cycloheptan++ +-5,10-imine (ADCI) (25-70 mg/kg, i.p.) on basal ganglia-mediated behaviour and on forebrain dopamine metabolism were investigated in rats. Dextrorphan increased locomotor activity but did not induce stereotyped sniffing. ADCI failed to produce any significant motor stimulant and motor depressant actions. Both dextrorphan and ADCI dose-dependently antagonized catalepsy induced by the D-1 dopamine receptor antagonist SCH 23390 or the D-2 dopamine receptor antagonist haloperidol. Only the highest doses of dextrorphan and ADCI increased dopamine metabolism in the prefrontal cortex and/or in the nucleus accumbens, but not in the dorsal striatum. Our results show that dextrorphan and ADCI produce some of the behavioural effects (antagonism of experimentally induced catalepsy) and neurochemical actions (regionally selective stimulation of dopamine metabolism) that have previously been observed in the prototypical non-competitive NMDA antagonist, dizocilpine. The failure of ADCI to induce hyperlocomotion and stereotypy suggests that anticataleptic doses of ADCI may be devoid of the psychotomimetic actions commonly associated with non-competitive blockade of NMDA receptor function.

Animals↗
PubMed1990

Identification and initial characterization of high-affinity [3H]dextrorphan binding sites in rat brain.

We have identified specific high-affinity [3H]dextrorphan binding sites in rat forebrain. [3H]Dextrorphan binds saturably and reversibly to an apparently homogenous class of sites characterized by a Bmax of 2.62 +/- 0.06 pmol/mg protein and KD of 60 +/- 4 nM. Glycine and glutamate independently increase [3H]dextrorphan binding in a concentration-dependent manner. The pharmacological profiles of [3H]dextrorphan binding characterized by equilibrium competition experiments together with these data suggest that [3H]dextrorphan labels a site at or near the N-methyl-D-aspartate receptor.

Animals↗
PubMed2006

Comparative effects of dextromethorphan and dextrorphan on nicotine discrimination in rats.

While the role of dextrorphan and dextromethorphan as N-methyl-d-aspartate (NMDA) receptor antagonists has received considerable research attention, their effects on nicotinic acetylcholine receptors (nAChR) has been less well characterized. Recent in vitro and in vivo research has suggested that these drugs noncompetitively block alpha3beta4*, alpha4beta2, and alpha7 nAChR subtypes and antagonize nicotine's antinociceptive and reinforcing effects. Both drugs were most potent at blocking alpha3beta4* AChR. This study investigated the effects of dextrorphan and dextromethorphan on nicotine's discriminative stimulus effects. Three groups of rats were trained in a two-lever drug discrimination procedure to discriminate 0.4 mg/kg s.c. nicotine from saline. Nicotine dose-dependently substituted for itself in all three groups. In contrast, when dextrorphan (group 1) or dextromethorphan (group 2) were injected i.p., neither substitution for nor antagonism of nicotine was observed for either drug. Since i.p. administration allows substantial metabolism of dextromethorphan to its parent compound dextrorphan, the two drugs were also tested following s.c. administration (group 3). Discrimination results were similar across both routes of administration, in that neither substitution nor antagonism occurred, however, s.c. administration reduced response rates to a much greater extent than did i.p. administration. Previous work suggests that beta2 subunits are crucial for mediation of nicotine's discriminative stimulus effects and may play a role in its reinforcing effects, albeit other research suggests a role for alpha3beta4* nicotinic receptors in the latter. Our results suggest that alpha3beta4* nicotinic receptors do not play a major role in nicotine's discriminative stimulus effects. Further, they suggest that the role of cholinergic mediation of the behavioral effects of dextrorphan and dextromethorphan related to the abuse properties of nicotine may be minimal.

Animals↗
PubMed1981

Stereospecific dextrorphan tolerance in rats.

1 Levorphanol was 20 times more potent than dextrorphan in decreasing food-reinforced fixed ratio 15 responding in male Sprague Dawley rats. 2 Chronic dextrorphan (100 mg/kg, i.p.; every 8 h) resulted in the development of dextrorphan tolerance. The dextrorphan dose-effect curve was shifted to the right three fold. 3 In contrast to dextrorphan, nontolerance developed to the effects of levorphanol. 4 These data support the hypothesis that (+)-isomers of opioids produce pharmacologically distinct CNS effects.

Animals↗
PubMed1993

Comparative pharmacokinetics of oral dextromethorphan and dextrorphan in the rabbit.

The pharmacokinetics of dextromethorphan (CAS 125-71-3) and its metabolite dextrorphan (CAS 125-73-5) was compared. The drugs were administered orally at the same molar dose of 0.085 mmol/kg. Plasma levels of dextromethorphan, dextrorphan, and metabolites 3-hydroxymorphinan and 3-methoxymorphinan were determined by HPLC with fluorimetric detection. Dextromethorphan was rapidly and extensively metabolized and the plasma profiles of dextrorphan, administered directly or as metabolite of dextromethorphan, were similar. The concentrations of 3-hydroxymorphinan were higher after dextromethorphan than dextrorphan. 3-Methoxymorphinan was detectable only 60 and 120 min after dextromethorphan. This work proposes the therapeutic use of dextrorphan instead of its precursor dextromethorphan.

Administration, Oral↗
PubMed1993

Intrathecal treatment with dextrorphan or ketamine potently reduces pain-related behaviors in a rat model of peripheral mononeuropathy.

The therapeutic effects of dextrorphan and ketamine, two non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, on neuropathic pain-related behaviors were examined in rats with peripheral mononeuropathy induced by loose ligation of the common sciatic nerve (chronic constrictive injury, CCI). Four daily intrathecal treatments (beginning 1 h after nerve ligation) with dextrorphan or ketamine (12.5-100 nmol) reliably attenuated hyperalgesia to radiant heat and spontaneous pain-related behaviors in CCI rats. Thermal hyperalgesia also was reduced in CCI rats receiving a single intrathecal treatment with either dextrorphan or ketamine (50 and 100 nmol for each compound) on day 3 after nerve ligation when thermal hyperalgesia was well developed. Since both dextrorphan and ketamine are currently utilized in other clinical applications, the results suggest a new therapeutic utility of these 'old' compounds in treatment of neuropathic pain syndromes resulting from peripheral nerve injury.

Animals↗
PubMed1995

Potentiation of morphine-induced antinociception in acute spinal rats by the NMDA antagonist dextrorphan.

Neurophysiologic and behavioral evidence indicates that excitatory amino acid (EAA) antagonists may provide a new class of selective analgesics for opiate resistant, neuropathic pain syndromes. Therapeutic applications have been limited because of unacceptable side effects of most EAA blockers. However, dextrorphan, a metabolite of the antitussive drug, dextromethorphan, is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of EAA receptor with few side effects and a moderate analgesic effect in animals with peripheral neuropathy. It may therefore, have clinical benefit, either alone or in combination with opiates, for neuropathic pain. In this study a subeffective dose of dextrorphan (15 mg/kg) was combined with several doses of morphine (1.5, 3.0 and 6.0 mg/kg) and assessed in an animal model of central injury, the tail flick response of the acute spinal rat. At doses which were individually ineffective, the combination of dextrorphan and morphine (15 and 1.5 mg/kg, respectively) produced a significant antinociceptive response. The same dose of dextrorphan also increased the antinociceptive response to 3.0 and 6.0 mg/kg of morphine. Coadministration of low doses of an NMDA antagonist and an opiate, might have clinical benefit for the relief of pain with reduced risk of undesirable side effects.

Animals↗
PubMed1987

Dextrorphan: an antagonist for phencyclidine receptors.

Radio-binding assay, bioassay and HPLC detection were used to observe the antagonistic effects of dextrorphan on PCP's actions. Dextrorphan displayed high affinity to PCP receptor in the rabbit mesenteric blood vessels. It had weak PCP-like bioactivity, but could antagonize PCP's action dose-dependently in vitro study with the rabbit ear artery preparation and shifted the dose-response curve of PCP to the right. After PCP administration, the content of norepinephrine in the vascular bath medium was increased, which was reversed by dextrorphan. Thus suggests that dextrorphan is an antagonist with very mild agonistic action for PCP receptors.

Animals↗
PubMed1989

The N-methyl-D-aspartate (NMDA) receptor antagonist, dextrorphan, prevents the neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA) in rats.

Using the systemically active, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dextrorphan, we explored the role of the NMDA receptor-calcium channel complex in the toxic mechanism of action of 3,4-methylenedioxymethamphetamine (MDMA). Rats were treated with MDMA, dextrorphan, or the combination of MDMA and increasing doses of dextrorphan, and then killed 10 days later for the assay of serotonin and dopamine in the striatum, hippocampus, and cortex. Dextrorphan totally prevented the serotonin-depleting effects of MDMA in the straitum, with a lessened but still significant blockade noted in the hippocampus and cortex. These findings may provide a clue to the molecular events underlying MDMA-induced neurotoxicity.

3,4-Methylenedioxyamphetamine↗
PubMed2006

Dextromethorphan, 3-methoxymorphinan, and dextrorphan have local anaesthetic effect on sciatic nerve blockade in rats.

Dextromethorphan has been used as an antitussive for more than 40 years and is considered a drug with a good margin of safety. The aim of the study was to evaluate whether dextromethorphan and its metabolites--3-methoxymorphinan and dextrorphan--had local anaesthetic effects. Using a method of sciatic nerve blockade in rats, the potencies and durations of actions of dextromethorphan and its metabolites on sciatic nerve blockades of motor function, proprioception, and nociception were evaluated. Lidocaine was used as control. We found that dextromethorphan and its metabolites produced dose-related local anaesthetic effects on sciatic nerve blockades of motor function, proprioception, and nociception. The ranks of potencies were lidocaine>dextromethorphan>3-methoxymorphinan>dextrorphan (P<0.01 for each comparison). Under an equi-potent basis, dextrorphan and 3-methoxymorphinan had durations of actions longer than that of lidocaine (P<0.05 for each comparison). Co-administration of dextromethorphan or its metabolites with lidocaine produced an additive effect on sciatic nerve blockades. In conclusion, dextromethorphan and its metabolites - 3-methoxymorphinan and dextrorphan- had a local anaesthetic effect on sciatic nerve blockades of motor function, proprioception and nociception with durations of actions longer than that of lidocaine. Co-administration of dextromethorphan and its metabolites produced an additive effect on sciatic nerve blockades.

Anesthetics, Local↗
PubMed1997

Dextrorphan, but not dextromethorphan, exerts weak antidystonic effects in mutant dystonic hamsters.

The effects of dextromethorphan and its metabolite dextrorphan on severity of dystonia were examined in mutant dystonic hamsters, an animal model of idiopathic paroxysmal dystonia, in which recent examinations have shown antidystonic effects of selective N-methyl-D-aspartate (NMDA) receptor antagonists. Dextromethorphan and dextrorphan are non-competitive NMDA receptor antagonists which additionally exhibit affinity for sigma receptors. Dextrorphan (20 and 40 mg/kg i.p.) significantly retarded the progression of dystonia at the higher dose, whereas dextromethorphan (20, 40, 60 mg/kg i.p.) failed to exert any antidystonic effects even at high doses which caused severe effects. The lack of antidystonic efficacy of dextromethorphan may be related to its higher affinity to sigma receptors compared with dextrorphan.

Animals↗
PubMed1997

Protection of rat spinal cord from ischemia with dextrorphan and cycloheximide: effects on necrosis and apoptosis.

OBJECTIVE: We examined the characteristics of neuronal cell death after transient spinal cord ischemia in the rat and the effects of an N-methyl-D-aspartate antagonist, dextrorphan, and a protein synthesis inhibitor, cycloheximide. METHODS: Spinal cord ischemia was induced for 15 minutes in Long-Evans rats with use of a 2F Fogarty catheter, which was passed through the left carotid artery and occluded the descending aorta, combined with a blood volume reduction distal to the occlusion. The rats were killed after 1, 2, and 7 days. Other groups of rats were pretreated with dextrorphan (30 mg/kg, intraperitoneally, n = 7), cycloheximide (30 mg, intrathecally, n = 7), or vehicle (saline solution, n = 12) and killed after 2 days. RESULTS: This model reliably produced paraplegia and histopathologically distinct morphologic changes consistent with necrosis or apoptosis by light and electron microscopic criteria in different neuronal populations in the lumbar cord. Scattered necrotic neurons were seen in the intermediate gray matter (laminae 3 to 7) after 1, 2, and 7 days, whereas apoptotic neurons were seen in the dorsal horn laminae 1 to 3 after 1 and 2 days. Deoxyribonucleic acid extracted from lumbar cord showed internucleosomal fragmentation (laddering) on gel electrophoresis indicative of apoptosis. The severity of paraplegia in the rats treated with dextrorphan and cycloheximide was attenuated 1 day and 2 days after ischemia. The numbers of both necrotic and apoptotic neurons were markedly reduced in both dextrorphan- and cycloheximide-treated rats. CONCLUSIONS: The results suggest that both N-methyl-D-aspartate receptor-mediated excitotoxicity and apoptosis contribute to spinal cord neuronal death after ischemia and that pharmacologic treatments directed at blocking both of these processes may have therapeutic utility in reducing spinal cord ischemic injury.

Animals↗
PubMed1999

Analysis of dextrorphan, a metabolite of dextromethorphan, using gas chromatography with electron-capture detection.

Dextromethorphan, a constituent of many over-the-counter cough syrups, is used as a probe drug for phenotyping subjects for their cytochrome P450 2D6 (CYP2D6) enzyme activity and for measuring CYP2D6 activity of preparations such as microsomes. In such studies, formation of the metabolite dextrorphan is used as indicator of the activity of this CYP enzyme. The present report describes an electron-capture gas chromatographic procedure developed for detection and quantification of dextrorphan in human liver microsomal preparations in vitro. After basification of the incubation mixture, dextrorphan was derivatized with pentafluorobenzoyl chloride under aqueous conditions prior to analysis on a gas chromatograph equipped with a capillary column, an electron capture detector, and a printer-integrator. Para-hydroxymephenytoin was carried through the procedure as internal standard. The procedure, which involves the derivatization of dextrorphan under aqueous conditions, is rapid and involves the use of the relatively economical procedure of electron-capture gas chromatography. The derivative is stable and possesses excellent chromatographic properties.

Benzoates↗
PubMed1990

Dextrorphan binds to opioid receptors in guinea-pig brain membranes and is an antagonist at opioid receptors in myenteric plexus.

Dextrorphan (+)-tartrate, purified by repeated crystallization to remove all traces of the enantiomer levorphanol, binds to mu, delta, and kappa sites on guinea-pig brain membranes with lower affinities (by a factor of 400-3200) than levorphanol. In the guinea-pig ileum myenteric plexus longitudinal muscle preparation (GPI), dextrorphan, at 100-200 microM, inhibits the electrically stimulated twitch, but this action is not blocked or reversed by naloxone; both (+)- and (-)-naloxone produce similar non-opioid twitch inhibition at comparable concentrations. At 10-20 microM, dextrorphan blocks and reverses the twitch inhibition due to mu and kappa agonists, but the blockade can be overcome only partially by increasing the agonist concentration. We conclude that dextrorphan is an opioid ligand with low affinity and with antagonist effect on opioid receptors in the GPI.

Animals↗
PubMed1977

Prenatal administration of levorphanol or dextrorphan to the rat: analgesic effect of morphine in the offspring.

We have recently demonstrated that prenatal administration of morphine to the rat results in tolerance to the analgesic effects of morphine in the offspring at 3 to 11 weeks of age. To extend these findings, levorphanol or dextrorphan was administered to female CFE rats during days 5 to 12 of gestation. Control animals were injected with 0.9% saline on the same schedule. At 5 weeks of age all offspring were tested with graded doses of morphine in the hot-plate test for analgesia. Morphine produced a dose-related increase in analgesia in all offspring, but the effect of morphine in the offspring of levorphanol-treated females was significantly reduced compared to the offspring of saline-treated females; the analgesic effect of morphine did not differ between the offspring of the dextrorphan- and saline-treated females. The analgesic effect of morphine remained reduced in 9-week old offspring of levorphanol-treated females compared to the corresponding offspring of females that had received saline. Diminished analgesic activity of morphine in the offspring of levorphanol-treated females compared to the offspring of females that had received dextrorphan or saline was still observed even when the offspring were rendered tolerant to morphine by daily drug injections over a period of 5 days. Thus, the protracted tolerance to the analgesic effects of morphine can also be produced by a morphine congener (levorphanol), but not by its analgesically inactive (+) isomer (dextrorphan).

Analgesics, Opioid↗
PubMed1986

Dextrorphan: an antagonist for phencyclidine receptor.

Radio-binding assay, bioassay and HPLC detection were used to observe the antagonistic effects of dextrorphan on PCP's actions. Dextrorphan displayed high affinity to PCP receptors and it had weak PCP-like bioactivity, but could antagonize PCP's action dose-dependently in vitro and shift the dose-response curve to the right. PCP increased the contents of norepinephrine in bath medium, which was reversed by dextrorphan. Thus, the results suggest that dextrorphan is a partial antagonist for PCP receptors.

Animals↗
PubMed1986

Comparative antitussive effects of dextrorphan, dextromethorphan and phencyclidine.

The possible antitussive effects of dextrorphan (the (+) isomer of levorphanol) and phencyclidine (PCP) were compared to well known antitussive properties of dextromethorphan in the post-halothane anesthetized decerebrate cat in which cough was elicited by direct electrical stimulation of the cough center. Dextrorphan, when injected i.a. (0.05-0.32 mg kg-1) or i.v. (1 to 3 mg kg-1), PCP i.a. (0.1-0.32 mg kg-1) or i.v. (1.0 mg kg-1) had no effect on electrically elicited cough. After i.v. administration, dextrorphan caused a variable effect on respiration but did not have any respiratory effect with i.a. administration of the drug. PCP injection i.a. at 0.32 mg kg-1 severely inhibited respiration though coughing could still be elicited. But i.v. administration of 1.0 mg/kg-1 suppressed both cough and respiration for several hours. Dextromethorphan inhibited cough upon both i.a. and i.v. injection. The mean effective i.a. dose was 0.063 mg kg-1. A ten times higher dose was necessary (0.65 mg kg-1) for cough suppression by the i.v. route. It is concluded from the i.a./i.v. ratio that dextromethorphan has specific central antitussive activity not possessed by dextrorphan and PCP.

Animals↗