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PubMedDate not supplied

Potential interactions of methylphenidate and atomoxetine with dextromethorphan.

OBJECTIVE: To examine the potential for drug-drug interactions to influence drug metabolism between the attention-deficit/hyperactivity disorder (ADHD) dl-methylphenidate and atomoxetine with dextromethorphan, a probe for interactions involving cytochrome P450 (CYP) 2D6 isoenzyme. DESIGN: In vitro and ex vivo analysis of changes in metabolism of study drugs. SETTING: Laboratory. PATIENTS: Not applicable. INTERVENTIONS: Pooled human liver microsomal fractions prepared at CEDRA Corporation (now CellzDirect, Austin, Tex.) by the standard differential centrifugation method (lot 821-1). Human liver microsomes were pooled from 15 donors. Recombinant CYP 2D6-containing microsomes (Supersomes; lots 20 and 24 BD Gentest; Woburn, Mass.) were prepared from a baculovirus-infected insect cell line that expressed only the human CYP 2D6 isoform. Dextromethorphan, with and without effector, was incubated with pooled human liver and recombinant CYP 2D6-containing microsomes. Atomoxetine and dl-methylphenidate were tested at 0.1x, 1x, and 10x their reported therapeutic concentrations. Paroxetine, a known inhibitor of CYP 2D6, was used as a reference agent, and quinidine was used as a positive control inhibitor of CYP 2D6. MAIN OUTCOME MEASURES: Changes in substrate metabolism indicative of CYP 2D6-mediated interactions. RESULTS: Atomoxetine and paroxetine inhibited the formation of dextrorphan by about 50% in human liver microsomes and by more than 80% in recombinant microsomes; the profiles of atomoxetine and the known 2D6 inhibitor paroxetine were similar. High concentrations of dextromethorphan reversed the inhibition of its metabolism, indicating a competitive mechanism of the interaction. Conversely, dextromethorphan and dextrorphan only modestly inhibited atomoxetine and paroxetine metabolism. dl-Methylphenidate did not inhibit dextrorphan formation in either microsome preparation, and dl-methylphenidate metabolism was unaffected by dextromethorphan or dextrorphan. CONCLUSION: These results demonstrate the potential for in vivo interactions between dextromethorphan and atomoxetine in patients with ADHD. However, they do not support the plausibility of an in vivo interaction between dextromethorphan and dl-methylphenidate.

Adrenergic Uptake Inhibitors↗
PubMed2005

Involvement of central serotonergic systems in dextromethorphan-induced behavioural syndrome in rats.

Dextromethorphan, a noncompetitive blocker of the N-methyl-D-aspartate (NMDA) type of glutamate receptor, at 45, 60 and 75 mg/kg, ip doses induced a behavioural syndrome characterised by reciprocal forepaw treading, lateral head-weaving, hind-limb abduction and flat body posture. Such type of behavioural syndrome is induced by 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT) by directly stimulating the central postsynaptic 5-hydroxytryptamine (5-HT, serotonin) receptors of the 5-HT1A type. Pretreatment with buspirone (5, 10 mg/kg, ip) and l-propranolol (10, 20 mg/kg, ip) antagonised the behavioural syndrome induced by 8-OH-DPAT and dextromethorphan. Pretreatment with p-chlorophenylalanine (100 mg/kg/day x 4 days) antagonised the behavioural syndrome induced by dextromethorphan and dexfenfluramine but had no significant effect on 8-OH-DPAT induced behavioural syndrome. This indicates that dextromethorphan induces the behavioural syndrome by releasing 5-HT from serotonergic neurons with resultant activation of the postsynaptic 5-HT1A receptors by the released 5-HT. Pretreatment with fluoxetine (10 mg/kg, ip) significantly potentiated the behavioural syndrome induced by dextromethorphan and 5-hydroxytryptophan but significantly antagonised dexfenfluramine induced behavioural syndrome. This indicates that dextromethorphan releases 5-HT by a mechanism which differs from that of dexfenfluramine. Dextromethorphan may be releasing 5-HT by blocking the NMDA receptors and thereby counteracting the inhibitory influence of l-glutamate on 5-HT release.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
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↗
PubMed1998

Novel single-point plasma or saliva dextromethorphan method for determining CYP2D6 activity.

O-Demethylation of dextromethorphan co-segregates with 4-hydroxylation of debrisoquin and is used for CYP2D6 phenotyping. In most previous studies, 8-h urinary samples were collected for determining the dextromethorphan metabolic ratio (dextromethorphan/dextrorphan molar ratio). In addition, a salivary sampling at 3 h had been suggested for the phenotyping. To evaluate the repeatability and validity of previously reported and other potential phenotyping methods, we determined the metabolic ratios from urine samples (for various intervals), or from plasma or saliva (at varying time points) after repetitive single doses of immediate-release or repetitive multiple doses of controlled-release dextromethorphan preparations. For the single-dose study, each of 12 subjects received 15 mg of immediate-release dextromethorphan in period I and period II, respectively, with a 1-week washout period. For the multiple-dose study, each of 16 subjects received 60 mg controlled-release dextromethorphan twice daily for 5 days in period I and period II, respectively, with a 2-week washout period. Dextromethorphan and dextrorphan were assayed by high-performance liquid chromatography. In the single-dose study, most metabolic ratios revealed good repeatabilities for the two periods (paired t test). The metabolic ratio from urine collected for 4 h, 6 h, 8 h or 12 h from plasma at any time between 1 h and 5 h or at 8 h, or from saliva at 2 h or 6 h, could reflect that from 0- to 24-h urine or AUCinfinity. In the multiple-dose study, all metabolic ratios revealed good repeatabilities. The plasma metabolic ratio at any time between 0.5 h and 10 h or the saliva metabolic ratio at any time between 3 h and 12 h, but not the urine metabolic ratio from any interval, could predict the metabolic ratio from ACUSStau. The 2 h, 3 h, 4 h or 5 h plasma metabolic ratio and 6 h saliva metabolic ratios after a single dose correlated significantly with their corresponding multiple-dose metabolic ratio (r > 0.8, P < .05). In conclusion, the plasma sample at 2 h, 3 h, 4 h or 5 h or the saliva sample at 6 h in either the single immediate-release (15 mg) or the multiple controlled-release dose (60 mg) procedure could be used for determining the dextromethorphan metabolic ratio.

Adult↗
PubMed1998

Preoperative dextromethorphan reduces intraoperative but not postoperative morphine requirements after laparotomy.

UNLABELLED: N-methyl-D-aspartate (NMDA) antagonists combined with opioids are thought to be effective in the control of pain states. We evaluated morphine use and analgesia in 37 patients postlaparotomy. Patients received 60 mg of oral dextromethorphan or placebo the night before and again 1 h before surgery. Morphine was titrated intraoperatively to maintain blood pressure and heart rate within 20% of baseline and postoperatively via patient-controlled analgesia (PCA). The dextromethorphan and placebo groups were compared for morphine use intraoperatively, in recovery, via PCA in the first 4 and 24 h, and total use over the study period. Pain scores at rest and on activity for the first 4 and 24 h were also compared. Intraoperatively, the dextromethorphan group required less morphine: 13.1+/-4.3 vs 17.6+/-6.0 mg (P = 0.012). Postoperatively, there was no significant difference between the dextromethorphan and placebo groups for morphine use: in the recovery room 10.9+/-7.7 vs 12.1+/-7.7 mg; the first 4 h of PCA 15.9+/-9.3 vs 12.7+/-5.1 mg; the first 24 h of PCA 76.4+/-44.7 vs 61.8+/-27.5 mg; or in total morphine use 100.4+/-49.5 vs 91.5+/-3.1 mg. Pain scores for the two groups were not statistically different throughout the study period. We conclude that 60 mg of oral dextromethorphan given the night before and repeated an hour before surgery does not provide a postoperative morphine-sparing effect or improve analgesia after laparotomy. IMPLICATIONS: Patients given dextromethorphan before surgery had significantly reduced intraoperative morphine requirements. However, postoperative morphine requirements were unaltered. Dextromethorphan may need to be continued postoperatively to improve postoperative analgesia.

Abdomen↗
PubMed2001

Epidemiologic analysis of prenatal exposure to cough medicines containing dextromethorphan: no evidence of human teratogenicity.

BACKGROUND: In a recent experimental study on chick embryos, Andaloro et al. (1998, Pediatr. Res. 43:1-7) observed a relationship between neural crest/neural tube defects (NTDs) and prenatal exposure to dextromethorphan. These authors made an extrapolation of their results to the human embryo, indicating that this drug could produce NTDs in humans. Rosenquist (1999, Teratology 60:58-60) based on the results of the epidemiologic study performed by Ferencz et al. (1997, Perspect. Pediatr. Cardiol. 5:50-162), concluded that dextromethorphan could cause congenital heart defects in humans. Because this drug is an over-the-counter drug, the suggestion of those authors has led to great controversy and public concern about the possible teratogenic effect of this drug on the human embryo. METHODS: We present the results of a case-control study by using logistic regression analyses on the effect of prenatal exposure to drugs containing dextromethorphan only, or in combination with other drugs, on human development. We mostly analyzed dextromethorphan. The study was designed in part as hypothesis confirmation for NTDs and congenital heart defects and, in part, as hypotheses generation by testing the association with many other congenital defects. RESULTS: The results do not show a relation between the occurrence of NTDs and heart defects or other defects with exposure to drugs containing dextromethorphan. CONCLUSIONS: The usual use of dextromethorphan in cough medications during pregnancy does not increase the risk for congenital defects.

Antitussive Agents↗
PubMed1978

Effect of salicylamide and acetaminophen on dextromethorphan hydrobromide metabolism: possible pharmacological implications.

The effect of salicylamide and acetaminophen on the metabolic fate of dextrorphan, the primary metabolite of dextromethorphan, was studied in vivo in the rat. Plasma dextrorphan levels were measured at 5-min intervals up to 20 min and at longer intervals up to 2 hr after dextromethorphan hydrobromide was administered orally either alone or in combination with salicylamide and acetaminophen. The combination gave rise to higher plasma dextrorphan levels than did dextromethorphan hydrobromide alone at most sampling times. Conjugation of dextrorphan was inhibited almost quantitatively by salicylamide and acetaminophen at the 5-min sampling time. Salicylamide alone increased the plasma dextrorphan levels when it was coadministered with dextromethorphan, but the differences were not statistically significant. The antitussive activity of dextromethorphan hydrobromide in the unanesthetized dog was faster in onset, greater in intensity, and longer in duration when it was coadministered with salicylamide and acetaminophen. It is suggested that salicylamide and acetaminophen may inhibit the metabolic inactivation of dextrorphan, thereby improving the coughinhibiting potential of dextromethorphan hydrobromide.

Acetaminophen↗
PubMed1990

Effect of orally administered dextromethorphan on theophylline- and pentylenetetrazol-induced seizures in rats.

Dextromethorphan, widely used as an antitussive, has recently been shown to protect animals against maximal electroshock and excitatory amino acid (N-methyl-D-aspartate)-induced convulsions. Its protective efficacy against theophylline-induced seizures was determined in this investigation in view of the limited effectiveness of presently available anticonvulsants against this manifestation of serious theophylline intoxication. Rats were pretreated with an oral dose of dextromethorphan (50 mg/kg) or saline solution. Fifteen minutes later, the rats were infused intravenously with theophylline [approximately 11 mg/(kg.min)] until the onset of maximal seizures. Pretreatment with dextromethorphan was associated with a significant decrease in the concentrations of theophylline in the cerebrospinal fluid and serum at the pharmacologic endpoint. To further explore this unanticipated effect, a similar experiment was performed with the convulsant pentylenetetrazol (PTZ), which was infused at a rate of approximately 3.4 mg/(kg.min) until the onset of maximal seizures. Dextromethorphan-pretreated animals required a significantly larger dose of PTZ than did controls to produce the first myoclonic jerk, but a significantly smaller dose of the convulsant to produce maximal seizures. Serum and cerebrospinal fluid concentrations of PTZ at onset of maximal seizures were significantly lower in dextromethorphan-treated than in control animals. The proconvulsant activity of dextromethorphan with respect to theophylline-induced maximal seizures is similar to that of phenytoin, and is consistent with other pharmacologic evidence of such similarity.

Administration, Oral↗
PubMed1995

Cytochrome P-450IID6 phenotyping in cancer patients: debrisoquin and dextromethorphan as probes.

The usefulness of substituting dextromethorphan for debrisoquin as a probe for cytochrome P-450IID6 deficiency was investigated in 20 male cancer patients. Each patient was studied on two occasions. An oral dose of dextromethorphan (60 mg) was administered to 13 patients and are week later an oral dose of debrisoquin (10 mg) was administered to each patient. The order was reversed for the other 7 patients. An 8-h urine sample was collected after administration of each test drug and assayed for parent drug and metabolites. Five poor metabolizers (PMs) and 15 extensive metabolizers (EMs) of debrisoquin were tested. The debrisoquin metabolic ratio (DMR), calculated as [parent drug]/[metabolite], correlated with the metabolic ratio of dextromethorphan (R2 = 0.58, P = 0.0001). All PMs of debrisoquin (metabolic ratio > 12.0) were easily identified as being PMs of dextromethorphan (metabolic ratio > 0.30). Within the EM group, there was a significant correlation between the metabolic ratios of debrisoquin and dextromethorphan (R2 = 0.82, P < 0.0001). There was not as clear a correlation in the PM group (R2 = 0.32, P = 0.32). These findings suggest that dextromethorphan can be substituted for debrisoquin in establishing the debrisoquin phenotype in a patient population with metastatic cancer.

Aged↗
PubMed1993

Dextromethorphan attenuates the effects of ischemia on rabbit electroretinographic oscillatory potentials.

Dextromethorphan has been shown to protect against ischemic tissue damage. We investigated the effects of dextromethorphan on electroretinographic oscillatory potentials in retinal ischemia. Retinal ischemia was induced in rabbits by increasing intraocular pressure to 120 mm Hg for 30, 60 or 90 minutes. Dextromethorphan was intravenously administered before ischemia and maintained throughout the whole period of experiments. Oscillatory potentials were recorded before and during ischemia as well as 4 hours of recirculation after ischemia. As expected, all oscillatory potentials were decreased after 60 and 90 minutes of ischemia. However, after 30 minutes of ischemia followed by 4 hours of recirculation, amplitudes of P2 were elevated whereas those of P3 and P4 were decreased with normal P1 amplitudes. Dextromethorphan administration diminished the effects of 30 minutes of ischemia on oscillatory potentials and partially attenuated the effects of 60 minutes of ischemia, whereas the effects of 90 minutes of ischemia could not be reversed by dextromethorphan treatment. These results indicate that electroretinographic oscillatory potentials could be useful indicators to evaluate retinal function in the ischemic condition and that dextromethorphan can attenuate the effects of relatively short periods of ischemia on rabbit electroretinographic oscillatory potentials.

Acute Disease↗
PubMed1989

An electrophysiological study on the common antitussive drug dextromethorphan in hippocampal slices in the rat.

Dextromethorphan, a common antitussive drug derived from the opioid class of morphinans, has been reported to have antiepileptic properties in some experimental tests. The effects of dextromethorphan were tested on the synaptic responses of the interconnections between Schaffer collaterals and CA1 pyramidal cells in hippocampal slices of the rat. Dextromethorphan, up to 100-200 microM, did not affect the basal field potentials resulting from electrical stimulation of the radiatum (0.1 Hz, 100-200 microA, 75 mu sec) of CA1 pyramidal cells. Larger concentrations of the drug (300-400 microM) depressed the amplitude and increased the duration of the CA1 basal population spikes. Dextromethorphan, up to 200-300 microM, affected neither the duration nor the incidence of the additional population spikes of the epileptiform bursting, resulting from perfusion of the slice with 1 mM penicillin or in the absence of magnesium ions. The data indicate that: (1) dextromethorphan has an influence on CA1 pyramidal cells, different from that of other opioids; (2) the reported antiepileptic effects of dextromethorphan do not involve the hippocampal area.

Animals↗
PubMed1995

A radiometric TLC assay of liver microsomal dextromethorphan O-demethylation.

A simple and sensitive assay for in vitro analysis of dextromethorphan O-demethylation, a marker for P450 2D deficiency in both humans (2D6) and rats (2D1), has been devised. Commercially available [N-methyl-3H]-dextromethorphan was used to develop a radiometric TLC assay for dextromethorphan O-demethylation. Hexane-triethylamine efficiently extracted dextromethorphan and metabolites from rat liver microsomes, and a solvent system of cyclohexane-toluene-diethylamine (65:15:20, v/v/v) provided sufficient separation (approximately 2 cm) between the two radioactive bands, dextromethorphan and dextrorphan, and no interference from the unlabeled N-demethylation products, 3-methoxymorphinan and 3-hydroxymorphinan. The recovery of dextrorphan from TLC plates increases with microsomal protein and incubation time. An eight-fold decrease in activity was noted in female Dark Agouti relative to the male Sprague-Dawley rats, respective models for poor and extensive P450 2D metabolizers. The assay, even with an approximately 100-fold dilution of radiolabeled substrate, had an approximate limit of detection of 100 pmol. Within- and between-run imprecision was 12.4% and 7.2%, respectively. The radiometric TLC assay for dextromethorphan O-demethylation was sensitive and easy, and used readily available equipment.

Animals↗
PubMed2004

Morphine potentiates dextromethorphan-induced vasodilation in rat superior mesenteric artery.

The combined action of morphine and dextromethorphan on the superior mesenteric artery was investigated in this study. The artery was cut into rings, placed in a muscle bath and mounted to a force transducer for recording tension. Rings preconstricted with 1 microM phenylephrine produced a dose-dependent relaxation to graded doses of dextromethorphan but showed no response to morphine. An equimolar combination of morphine and dextromethorphan exhibited a marked synergism quantitated by a factor of 3.7 (1.8-7.7, 95% CI). Naloxone, which had no effect on the dextromethorphan dose-response relation, abolished the synergism. Removal of the endothelium produced a slight attenuation of the morphine-dextromethorphan synergism, but the magnitude of this attenuation was the same when dextromethorphan alone was examined in the denuded preparation. In contrast to the marked synergism seen in the mesenteric artery preparation, similar experiments on the carotid artery and the aorta produced only additive interactions.

Animals↗
PubMed1996

Dextromethorphan reduces functional deficits and neuronal damage after global ischemia in rats.

Glutamate antagonists have been shown to be neuroprotective in animal models of cerebral ischemia. Global cerebral ischemia in rats leads to selective neuronal damage in the hippocampus and striatum. Following ischemia a transient locomotor hyperactivity and a deficit in spatial learning and memory occurs. The aim of the present study was to investigate the potential neuroprotective effect of dextromethorphan, an antagonist at the N-methyl-D-aspartate receptor, with behavioural and histological measures of global ischemia in rats. Global ischemia was induced by four-vessel occlusion (4VO) for 20 min in rats. Dextromethorphan was administered 20 min before induction of ischemia at a dose of 10 or 50 mg/kg. Before and on day 1, 3 and 5 after operation the spontaneous locomotor activity was measured. One week after surgery spatial learning was tested in the Morris water maze. After behavioural testing the animals were sacrificed and the neuronal damage was assessed. Treatment with 50 mg/kg of dextromethorphan reduced the increase in locomotor activity observed on day 1 and 3 after ischemia. In the water maze dextromethorphan reduced the increase in escape latency and in swim distance induced by 4VO. Furthermore, the ischemia-induced reduction in time spent in the quadrant of the former platform position during the probe trial was increased by treatment with dextromethorphan. Neuronal damage in the CA1 sector of the hippocampus and in the dorsolateral striatum produced by 4VO was significantly attenuated by dextromethorphan. The present results demonstrate that protective effects on neuronal damage may be related to an attenuation of deficits in spatial leaning and memory following global ischemia.

Animals↗
PubMed1996

Assessment of individual CYP2D6 activity in extensive metabolizers with renal failure: comparison of sparteine and dextromethorphan.

OBJECTIVES: To examine whether the variability of CYP2D6 activity in patients with chronic renal failure can be assessed, particularly among subjects with the extensive metabolizer phenotype, by use of standard in vivo indexes of CYP2D6 activity derived from oral administration of dextromethorphan and sparteine. METHODS: A single 100 mg oral dose of sparteine and a single 40 mg oral dose of dextromethorphan were administered on two occasions to 12 patients with chronic renal failure (creatinine clearance ranging from 20 to 70 ml/min) and 12 age- and sex-matched healthy subjects. Sparteine clearances, sparteine metabolic ratio, and urinary recovery of dextrorphan were calculated. Patients and healthy control subjects were not selected on the basis of their CYP2D6 phenotypes. RESULTS: Chronic renal failure was associated with a decrease in sparteine partial metabolic clearance to dehydrosparteine (median of 322 ml/min and range of 62 to 670 ml/min in patients with renal failure versus median of 635 ml/min and range of 77 to 1276 ml/min in normal subjects; p < 0.02). Sparteine apparent oral clearance (p < 0.03) and renal clearance (p < 0.001) decreased in patients with renal failure. However, sparteine metabolic ratio was not significantly altered in patients with renal failure and showed that all patients were extensive metabolizers of sparteine. Although fractional urinary excretion of dextrorphan decreased in patients with renal failure (median, 24.4%; range, 9.7% to 55.9%) compared with control (median, 47.5%; range, 24.1% to 72.1%) (p = 0.02), it also showed that all subjects were extensive metabolizers of dextromethorphan. The amount of dextromethorphan excreted in urine correlated with creatinine clearance independently from CYP2D6 activity measured as sparteine partial metabolic clearance. However, it did not correlate with sparteine metabolic ratio or with fractional urinary excretion of dehydrosparteine. CONCLUSION: Assessment of CYP2D6 activity by use of dextromethorphan and sparteine is possible in extensive metabolizer patients with chronic renal failure. However, in these subjects, dextromethorphan and sparteine do not reflect CYP2D6 activity in the same way.

Administration, Oral↗
PubMed2002

Dextromethorphan attenuates morphine withdrawal syndrome in neonatal rats passively exposed to morphine.

We had previously found that co-injection of dextromethorphan, an antitussive drug and a non-competitive NMDA receptor antagonist, with morphine into dam rats throughout the pregnancy period could attenuate the naloxone-precipitated morphine withdrawal syndrome in their offspring. In the present study, we further tested whether postnatal injection of dextromethorphan into the neonatal rats or a 3-day co-injection of dextromethorphan with morphine into the dam rats before delivery is also effective. Female Sprague-Dawley rats were bi-daily injected with escalating doses of morphine from a week before mating till the first postnatal week. Withdrawal syndrome of morphine in the offspring, manifested mainly as abdominal stretching, was generated by injection of naloxone on postnatal day 5. Direct injection of dextromethorphan into the offspring effectively reduced the severity of naloxone-precipitated abdominal stretching in a dose-dependent manner. A 3-day co-treatment with dextromethorphan given to the dam rat before delivery also had a similar attenuating effect, but the efficacy was lower than that produced by postnatal injection. Thus, the results from the present study support that dextromethorphan is of potential in treating or preventing neonatal morphine withdrawal syndrome.

Animals↗
PubMed2001

Co-administration of dextromethorphan during pregnancy and throughout lactation significantly decreases the adverse effects associated with chronic morphine administration in rat offspring.

In this study, we have focused our investigation of the facts whether co-administration of a NMDA antagonist dextromethorphan (DM) with morphine during pregnancy and throughout lactation could prevent the adverse effects associated with chronic morphine administration in rat offspring. Adult female Sprague-Dawley rats were randomly separated into four groups and were received subcutaneous injection of either saline, morphine, morphine + dextromethorphan or dextromethorphan twice a day and progressively increased 1 mg/kg at 7-day intervals from a beginning dose of 2 mg/kg for both morphine and dextromethorphan. The rats were mated between days 7 and 8. Administration of drugs was continued during pregnancy. After rat offspring were born, the doses of morphine or dextromethorphan injected into the maternal rats were increased by 1 mg/kg every two weeks till the offspring were 30 day old. The results showed that mortality of morphine group is much higher than control group. The offspring of morphine group weighed significantly less than control group on postnatal day 14 (p14), p30 or p60. The antinociceptive effect of morphine on p14 rats was reduced in the morphine group and indicated the development of morphine tolerance. The hippocampal NMDA receptor densities have been shown decreased on p14 rats. The precipitated withdrawal symptoms were assessed on p7 rats. Rats in morphine group showed greater frequency of abdominal stretch and wet dog shake in 2 hr than control group. On the other hand, co-administration of DM with morphine effectively prevented all these adverse effects of morphine to the offspring rats. DM co-administered with morphine also partially prevented the development of morphine tolerance in maternal rats. If this effect of dextromethorphan is applied to clinical pregnant patients with morphine addiction or chronic pain, it will have a great value for the benefit of their children.

Analgesics, Opioid↗
PubMed2003

Effects of dextromethorphan on dopamine release in the nucleus accumbens: Interactions with morphine.

Dextromethorphan has been reported to decrease the self-administration of several drugs of abuse, including morphine, methamphetamine, cocaine, and nicotine. Most drugs of abuse increase extracellular levels of dopamine (DA) in the shell of the nucleus accumbens. The effects of dextromethorphan on DA release in the nucleus accumbens of nai;ve rats and of rats treated acutely and chronically with morphine were studied using in vivo microdialysis. DA dialysate levels were evaluated by high-performance liquid chromatography with electrochemical detection. Acute morphine (5 mg/kg i.p.) treatment increased the levels of DA in the nucleus accumbens to approximately 175% of basal levels. Chronic morphine (20 mg/kg i.p. daily for 5 days) increased DA release in the nucleus accumbens to 250% of basal levels. Acute treatment with dextromethorphan (20 or 30 mg/kg s.c.) alone did not alter nucleus accumbens DA levels. Pretreatment with dextromethorphan (20 mg/kg s.c., 20 min prior) potentiated the effects of acute morphine, while attenuating the effects of chronic morphine on nucleus accumbens DA levels. These results with dextromethorphan suggest that the mechanism mediating the effects of dextromethorphan on drug self-administration involves modulation of the dopaminergic mesolimbic pathway.

Animals↗