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PubMed1993

Dextromethorphan O-demethylation polymorphism in Jordanians.

The O-demethylation of dextromethorphan (DMT) to dextrorphan (DRP) was studied in 241 unrelated, healthy Jordanian volunteers (171 males, 70 females). Urine was collected for 8 h following a single oral dose of DMT bromhydrate 30 mg. A thin-layer chromatographic (TLC) technique was used to identify the metaboliser phenotype. The frequency of the poor metaboliser phenotype was found to be 2.9% (approximate 95% confidence interval 0.8-5.0%). Applying the Hardy-Weinberg Law, the frequency of the recessive autosomal gene controlling poor metabolism was 0.17 (95% confidence interval 0.108-0.232).

Adolescent↗
PubMed1977

Specific action of narcotics on reflex activation of rat alpha-motoneurones.

Specific effects of narcotics (opiates) were studied on rat extensor alpha-motoneurones. The animals were anaesthetized with halothane, artificially ventilated and immobilized with N,N'-diallyl nortoxiferinium-HCl. The alpha-motoneurones were activated by tetanic stimulation of the cut ipsilateral gastrocnemius-soleus (GS) nerve. Morphine (2 and 4 mg/kg) administered intravenously, significantly increased the frequency of reflex discharges. In most of the neurones tested, naloxone (0.25 mg/kg) given intravenously, abolished the effect of morphine. In some neurones, however, naloxone induced a further activation. The dose of naloxone employed was ineffective when given alone. The effect of morphine was mimicked by an intravenous injection of levorphanol (1 mg/kg), but not by an equimolar dose of the stereoisomer dextrorphan, which suggests that the activating effect on alpha-motoneurones is a specific one. An intraperitoneal injection of apomorphine (1 mg/kg) reduced the effect of morphine. The effect of narcotics on alpha-motoneurones parallels narcotic-induced catalepsy and muscular rigidity, with regard to dose-dependence as well as to the antagonism of naloxone and apomorphine, and suggests that both catalepsy and muscular rigidity are mainly due to an activation of extensor alpha-motoneurones. Since this activation can be inhibited by spinalization of the rats, it can be inhibited by spinalization of the rats, it can be concluded that the activation is due to a supraspinal action of morphine, resulting in a decreased dopaminergic neurotransmission in the brain.

Action Potentials↗
PubMed1986

Opiates induce long-term increases in prodynorphin-derived peptide levels in the guinea-pig myenteric plexus.

The subcutaneous administration of a single dose of an opiate agonist (levorphanol) or antagonist (naloxone) to guinea pigs results in an at least 3-fold elevation of dynorphin and alpha-neoendorphin-immunoreactivity in the longitudinal muscle myenteric plexus preparation. The effects are time- and dose-dependent, significant elevations first being observed 6 h after treatment and lasting for up to 24 h. Pretreatment levels of opioid peptides were observed after 8 days. Combined injection of the narcotic agonist and antagonist, at sufficiently high doses, resulted in an additive effect of the individual drugs. The respective stereoisomers dextrorphan and (+)-naloxone did not affect prodynorphin-derived peptide concentrations. An increase of endogenous opioids was also observed after administration of the nonopiate clonidine, a compound which, like opiates, alters the activity of the myenteric plexus. It is suggested that feedback mechanisms in the myenteric plexus are responsible for the elevation of endogenous opioid peptides following exposure to exogenous opiates. Using a monoclonal antibody (3-E7), which recognizes virtually all endogenous opioid peptides, it was found that levels of higher molecular material were also increased upon opiate challenge. This suggests that a single dose of an exogenous opiate results in an increase in peptide synthesis.

Animals↗
PubMedDate not supplied

Inhibition by opiate narcotics of rat flexor alpha-motoneurones.

Specific effects of opiate narcotics on rat flexor alpha-motoneurones were studied in ventral roots of laminectomized rats under halothane anaesthesia. The alpha-motoneurones were activated by tetanic stimulation of the cut ipsilateral common peroneal nerve, exciting up to group II- but not group III- and C-afferents. Morphine (0.5--3.0 mg/kg i.v.) reduced or completely suppressed the discharge rate of flexor alpha-motoneurones in a dose-dependent manner. This effect was antagonized by naloxone (0.5 mg/kg i.v.) and mimicked by levorphanol (1.0 mg/kg i.v.), but not by an equal dose of its stereoisomer dextrorphan, suggesting that the effect described is a specific one. After spinalization, the inhibitory effect of morphine was abolished. Previous studies had shown that opiates (e.g. morphine, given in a dose of 2 or 4 mg/kg i.v.) excite rat extensor alpha-motoneurones, an effect opposite to the opiate narcotic action on flexor alpha-motoneurones. The action of opiates leading to an inhibition of flexor alpha-motoneurones may contribute to akinesia and catalepsy, and opioid-induced muscular rigidity. From the results presented it appears that morphine produces a reciprocal change in the activity evoked in extensor and flexor reflex pathways.

Animals↗
PubMed1989

Determination of dextromethorphan metabolizer phenotype in healthy volunteers.

The dextromethorphan metabolizer phenotype in 450 healthy volunteers (299 men, 151 women) was determined after oral administration of a 15 mg dose. In 8 h-postdose urine samples the ratio of dextrorphan (DOP) to dextromethorphan (DMP) was measured by HPLC. Urinary excretion of DMP and DOP within 8 h after the dose varied greatly between individuals, ranging from 0-11% and 0.04-100% of dose, respectively. In 143 test subjects the fraction of the dose of DMP in urine was below the detection limit. In the remaining 307 volunteers the metabolic ratio (MR) of DOP to DMP varied from 0.07 to 2906. In 404 test subjects the MR was greater than 10 and they were classified as extensive metabolizers (90% of the entire group). Of the entire group 5% had MRs of 1-10 and less than 1, respectively. Depending on the limit for classification of poor metabolizers, their frequency was 5-10% in the Caucasian population studied. The present data are in agreement with previous findings that the oxidative metabolic polymorphisms of debrisoquin and DMP co-segregate; the frequency of the PM phenotype of dextromethorphan in Caucasian populations varies between 5 and 10%.

Adolescent↗
PubMed1998

Blockade of glutamatergic transmission as treatment for dyskinesias and motor fluctuations in Parkinson's disease.

In animal models of Parkinson's disease (PD), glutamate antagonists diminish levodopa (LD)-associated motor fluctuations and dyskinesias. We sought to investigate if these preclinical observations can be extended to the human disease, by evaluating the effects of three non-competitive NMDA antagonists (dextrorphan, dextromethorphan and amantadine) on the motor response to LD in patients with advanced PD. In four separate trials, adjuvant therapy with these drugs reduced LD-induced dyskinesias and motor fluctuations. These findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptor can ameliorate LD associated motor response complications.

Amantadine↗
PubMedDate not supplied

Analysis of pharmacokinetic parameters for assessment of dextromethorphan metabolic phenotypes.

In this study, the metabolic ratios of dextromethorphan to dextrorphan (DM/DX) in plasma were calculated at steady state after administering 2 dosage forms (Medicon) and Detusiv) of DM with different release rates. The urinary metabolic ratio for each subject was also determined based on the total drug concentration in the urine. An analysis of pharmacokinetic parameters for determining the DM metabolic phenotype was conducted. Results demonstrate that double logarithmic correlations between the metabolic ratios based on pharmacokinetic parameters of either AUC(0-tau,ss), C(max,ss), C(min,ss), or C(ave,ss) for Medicon and Detusiv and the urinary metabolic ratios were all significant. Probit plots of the metabolic ratios based on these pharmacokinetic parameters revealed 2 clusters of distribution, representing extensive and intermediate metabolizers. An antimode of 2.0 for total drug based on these pharmacokinetic parameters was determined and correspondingly referred to an antimode of 0.02 for the urinary metabolic ratio to delineate extensive and intermediate metabolizers. This model was also verified to be appropriate when using total plasma concentrations of DM and DX at any time during the period of the dosing interval at steady state to calculate the metabolic ratio for identifying extensive and intermediate metabolizers. Therefore, the metabolic ratio based on the pharmacokinetic parameters of either AUC(0-tau,ss), C(max,ss), C(min,ss), or C(ave,ss) and plasma concentrations of DM and DX in a single blood sample at steady state are proposed as an alternative way to identify phenotypes of CYP2D6.

Administration, Oral↗
PubMed2002

Affinity and specificity of N-methyl- D-aspartate channel blockers affect their ability to disrupt prepulse inhibition of acoustic startle in rats.

RATIONALE: Phencyclidine (PCP) binds with high affinity to a site located within the ionophore of N-methyl- D-aspartate (NMDA) receptors. Previous studies have demonstrated that PCP and other high-affinity NMDA channel blockers reliably disrupt prepulse inhibition (PPI) of acoustic startle, an animal model of sensorimotor gating used to study attentional deficits associated with schizophrenia. Recently, a number of low-affinity NMDA channel blockers that exhibit minimal PCP-like effects in humans at therapeutic doses have been developed. OBJECTIVES: The purpose of this study was to evaluate the effects on PPI of NMDA channel blockers with varying affinities for the channel site as well as different specificities for NMDA receptors. METHODS: Sprague-Dawley rats were presented with multiple stimulus presentation trials, including pulse-alone and PPI trials. RESULTS: As expected, the high-affinity ligands dizocilpine and dextrorphan disrupted PPI at doses that did not affect the response during pulse-alone trials. Low-affinity drugs produced a mixed pattern of results. Whereas dextromethorphan and memantine disrupted PPI, orphenadrine, amantadine, desipramine, and alaproclate did not affect this response. Ibogaine also disrupted PPI, but only within a dose range that severely decreased the startle response during pulse-alone trials. CONCLUSIONS: These results suggest that not all NMDA channel blockers share PCP's effect of PPI disruption. In addition, they suggest caution in the use of supratherapeutic doses of these compounds and in their use in vulnerable populations (e.g., schizophrenic patients).

Acoustic Stimulation↗
PubMed2003

Discriminative stimulus effects of acute morphine followed by naltrexone in the squirrel monkey.

RATIONALE: The discriminative stimulus effects of a combination of acute morphine followed by naltrexone have been described in rats. OBJECTIVE. The purpose of this study was to extend observations to a non-human primate. METHODS: Eight squirrel monkeys were trained in a discrete-trial avoidance/escape procedure to discriminate morphine (1.7 mg/kg, IM, 4 h) followed by naltrexone (0.1 mg/kg, IM, 0.25 h) (MOR-->NTX) versus saline (1.0 ml/kg, IM, 4 h) followed by naltrexone (0.1 mg/kg, IM, 0.25 h) (SAL-->NTX). RESULTS: Seven subjects acquired the discrimination in an average of 108+/-14 sessions. MOR-->NTX-appropriate responding increased as an orderly function of increasing dose of morphine (0.56-1.7 mg/kg) and of naltrexone (0.01-10 mg/kg). The discrimination was also dependent upon interval between morphine and naltrexone administration. The MOR-->NTX cue was fully generalized to the combination of levorphanol (0.3 mg/kg) followed by naltrexone, but not to the non-opioid stereoisomer of levorphanol, dextrorphan (0.3 and 3.0 mg/kg) or the kappa-opioid-receptor-selective agonist U69,593 (0.3 mg/kg) followed by naltrexone. Naltrexone administered 15 min before morphine dose-dependently blocked MOR-->NTX-appropriate responding. CONCLUSIONS: This is the first non-rodent study of the discriminative effects of MOR-->NTX. MOR-->NTX produces a unique interoceptive stimulus that is pharmacologically selective, requires occupation of opioid receptors, presumably mu, for some minimum period of time, and is reversible. This discrimination procedure might provide new insights into the early drug-receptor interactions that underlie the development of physical dependence upon morphine-like drugs.

Animals↗
PubMed1976

Actions of opiates upon single unit activity in the cortex of naive and tolerant rats.

The effect of microelectrophoretically and systemically applied opiates on neuronal discharge activity in the sensorimotor cortex of naive and morphine tolerant/dependent rats has been studied. In naive rats depression of spontaneous discharge activity was the predominant effect of low doses of phoretically applied morphine. Higher doses and repeated application frequently converted this effect into excitation. Only the depressant effect was antagonised by naloxone. Naloxone itself had no effect on spontaneous discharge activity when applied at dose-levels sufficient to antagonise the depressant effect of morphine. Levorphanol mimicked the action of morphine whereas dextrorphan was inactive. Morphine depressed the excitatory action of L-glutamate and of acetylcholine by a naloxone-antagonisable mechanism. Systemic application of Fentanyl mimicked the inhibitory effect of phoretically applied morphine upon transcallosally evoked discharge activity. The late response was markedly depressed whereas the primary response was little affected. Phoretically applied naloxone antagonised the effects of systemically applied Fentanyl. In chronically morphinised rats the depressant effect of microelectrophoretically administered morphine was almost lacking and a naloxone-resistant excitation became the predominant effect. In these animals the excitant effect of naloxone was also increased and the anti-glutamate effect and the anti-acetylcholine effect of morphine was abolished. The present data speak in favour of a postsynaptically located stereospecific receptor which mediates the inhibitory effects of opiates and which may be involved in the development of acute and chronic tolerance to these drugs.

Acetylcholine↗
PubMed1976

The mechanism of inhibition of neuronal activity by opiates in the spinal cord of cat.

Extra- and intracellular recordings from motoneurones, interneurones and dorsal horn neurones (laminae 4 and 5) were obtained from the lumbar segments (L6-L7) of spinalised (Th 9/10) or pentobarbital-anaesthetised and anaemically decorticated cats. In the majority of spinal neurones microelectrophoretically applied morphine and levorphanol reversibly depressed spontaneous as well as stimulus-evoked and L-glutamate- or acetylcholine-induced activity. There is evidence that opiates block L-glutamate-induced depolarisations by impairing the Na+-influx triggered at the postsynaptic membrane. These depressant effects of opiates could be antagonised by naloxone, and, except in a few cases, were not associated with hyperpolarisation of the cell. Dextrorphan, the D+ enantiomer of levorphanol, displayed no such depressant actions, indicating that stereospecific receptors mediate the depressant effects of opiates. Phoretically applied atropine, procaine and Ca2+ ions have anti-glutamate and anti-acetylcholine actions similar to opiates, but these actions were not antagonised by naloxone. The hyperpolarising effect of glycine was not influenced at dose levels of opiates sufficient to suppress depolarisation induced by L-glutamate or acetylcholine. Microelectrophoretically administered morphine and levorphanol slowed the rate of rise of mono- and polysynaptic EPSPs by a naloxone-antagonisable mechanism at dose levels where almost no alteration in spike shape was detectable. Increased doses of morphine and levorphanol reduced the amplitude of IPSPs and completely blocked or reduced the amplitude of both direct- and antidromically-evoked spikes. These effects of increased doses of opiates were not antagonised by naloxone. Intravenous injection of 2 mg/kg of morphine or 20 mug/kg of Fentanyl mimicked the suppression of spontaneous and evoked neuronal activity observed after phoretic administration. This depressant action of systemically applied opiates could be transiently antagonised by phoretic administration of naloxone. The results are discussed with respect to a stereospecific action of opiates at a postsynaptic receptive site in the spinal cord.

Acetylcholine↗
PubMed1976

Effects of morphine and naloxone on Renshaw cells and spinal interneurones in morphine dependent and non-dependent rats.

The effects of microelectrophoretically administered morphine, naloxone, levorphanol and dextrorphan have been investigated on Renshaw cells and interneurones in the spinal cord of morphine-dependent and non-dependent anaesthetized rats. Morphine excited cholinoceptive neurones and enhanced the excitatory actins of acetylcholine and L-glutamate. This action of morphine appeared to be stereospecific and was antagonized by naloxone. Naloxone also antagonized acetylcholine-induced excitation but not L-glutamate-induced excitation. In dependent rats morphine was a more effective excitant of cholinoceptive neurones and naloxone was more effective as an antagonist of acetylcholine-induced excitations. These observations were interpreted as indicating that cholinergic mechanisms may be involved in morphine dependence and naloxone-precipitated abstinence.

Acetylcholine↗
PubMed1977

Iontophoretic application of opiates to the locus coeruleus.

The vast majority of morphine-sensitive single units in the area examined were localized to the locus coeruleus. This corresponds well with the known distribution of the highest densities of opiate receptor sites in this region of the midbrain. The effect of iontophoretically applied morphine was a marked and prolonged depression of spontaneous activity. Levorphanol, an opiate agonist, produced an effect similar to that of morphine while comparable doses of dextrorphan, it's clinically inactive stereoisomer, did not. Naloxone and levallorphan prevented as well as reversed the depression due to application of agonists. While the units were depressed following the application of opiate agonists, the cells were still excited by the neurotransmitter acetylcholine. We conclude that (1) neuronal sensitivity to opiates has a high positive correlation with autoradiographically determined opiate receptor sites, and (2) this sensitivity to opiates is blocked by opiate antagonists and is stereospecific in nature.

Acetylcholine↗
PubMed1978

Differential excitatory and inhibitory effects of opiates on non-nociceptive and nociceptive neurones in the spinal cord of the cat.

Morphine, levorphanol, dextrorphan and naloxone were applied microelectrophoretically to cells identified as either having nociceptive inputs or non-nociceptive inputs in the dorsal horn of the cat. Morphine excited non-nociceptive cells and depressed nociceptive cells. Naloxone reversed morphine excitations on non-nociceptive cells, but only reversed about one-third of morphine depressions on nociceptive cells. Levorphanol depressed nociceptive cells, whilst dextrophan ejected with similar currents caused less depression or had no effect. It is concluded that excitation of non-nociceptive cells may constitute a spinal action relevant to the analgesic action of opiates, acting synergistically with a depressant effect on nociceptive neurones.

Animals↗
PubMed1979

Specific versus non-specific actions of opioids on hippocampal neurones in the rat brain.

An investigation has been made into the pharmacological specificity of the actions of microelectrophoretically applied opioids on neurones in the rat hippocampus, a structure containing a low concentration of specific receptors for these substances. The majority of hippocampal neurones remained unaffected by morphine or enkephalin. Some neurones, however, displayed either inhibitory or excitatory responses to the opioids. Of the inhibitory effects, a few appeared to be specific, in that they could be antagonized by naloxone, but most of the other inhibitory responses were found to be potentiated by this drug. Similarly, naloxone not only failed to antagonize, but frequently potentiated the excitatory responses to the opioids. Further evidence for the predominantly non-specific nature of the responses of hippocampal neurones to opioids was provided by experiments with the stereoisomers levorphanol and dextrorphan. Neurones could be found which were either inhibited or excited by both enantiomers. Stereospecific responses, when observed, were inhibitory. Although non-specific, the excitatory effects of enkephalin and morphine on hippocampal neurones were greatly reduced in morphine tolerant/dependent rats. Indeed, in the hippocampus of these animals, the opioids had predominantly inhibitory effects which were potentiated, not antagonized, by naloxone. It is concluded that the low concentration of opiate receptors in the rat hippocampus renders neurones within this structure sensitive to a variety of nonspecific opioid actions.

Action Potentials↗
PubMed1988

Morphinans attenuate cortical neuronal injury induced by glucose deprivation in vitro.

The non-narcotic dextrorotatory morphinan, dextrorphan, as well as its levorotatory opioid enantiomer, levorphanol, and its O-methyl derivative, dextromethorphan, have recently been shown to antagonize N-methyl-D-aspartate receptor-mediated neurotoxicity. Consistent with in vivo data suggesting that this neurotoxicity contributes to the neuronal damage associated with hypoglycemia, micromolar concentrations of these morphinans markedly attenuated the injury of cultured mouse cortical neurons produced by acute glucose deprivation. These observations lend specific support to the possibility that morphinan compounds may prove to have clinical therapeutic utility in hypoglycemic encephalopathy.

Animals↗
PubMed1992

N-methyl-D-aspartate (NMDA) and opioid receptors mediate dynorphin-induced spinal cord injury: behavioral and histological studies.

Both N-methyl-D-aspartate (NMDA) and opioid receptors have been implicated in the pathophysiology of traumatic spinal cord injury and dynorphin-induced paralysis. The present studies compared the effects of the non-competitive NMDA antagonist dextrorphan (Dex) and the kappa-selective opioid antagonist nor-binaltorphimine (nor-BNI) on the acute motor deficits and chronic neuropathological alterations caused by intrathecally administered dynorphin A-(1-17) (Dyn A). Infusion of Dyn A into the rat lower thoracic spinal subarachnoid space produced acute, reversible hindlimb paresis. Histological evaluations of spinal cord sections from these animals at 2 weeks post-infusion revealed ventral grey matter necrosis, neuronal loss and gliosis as well as axonal loss in adjacent white matter; however, there was minimal alteration in serotonin immunocytochemistry caudal to the injury zone. Dex or non-BNI pretreatment each significantly (P less than 0.05) reduced, and to a similar degree, the acute motor deficits and certain histological changes associated with Dyn A administration. These findings further support the hypothesis that dynorphin-induced spinal cord injury involves both NMDA receptors and opioid receptors.

Animals↗