dextrorphan and Morphine-Dependence

Consistent with their antagonistic actions at N-methyl-D-aspartate type glutamate receptors, dextromethorphan (DXM) and its metabolite, dextrorphan (DXT) decrease the intensity of opioid withdrawal syndrome. Since quinidine (QND) affects CYP2D6-mediated metabolism and P-glycoprotein governed transport, we sought to determine whether co-treatment with QND would affect brain levels of DXM and DXT as well as the effect of these compounds on opioid withdrawal syndrome in mice. We found that DXM dose dependently inhibited the intensity of opioid withdrawal syndrome and that there was a tendency for a further decrease when QND was co-administered with DXM. Administration of 30 mg/kg of DXM resulted in higher brain levels of DXM and DXT than administration of 10 mg/kg of DXM, but much lower DXT levels than that produced by 30 mg/kg of DXT. Co-treatment with QND resulted in higher brain levels of DXM (but not DXT) suggesting that QND produces an increase in the brain availability of DXM. In summary, brain levels of DXM were inversely correlated with the intensity of opioid withdrawal syndrome. QND induced increased brain levels of DXM tend to attenuate the intensity of opioid withdrawal syndrome. We suggest that it is DXM, rather than DXT, that is responsible for the attenuating effect on the intensity of opioid withdrawal syndrome, and that the beneficial action of QND on the effect of DXM should be more pronounced in humans.

Topics: Animals; Brain; Dextromethorphan; Dextrorphan; Dose-Response Relationship, Drug; Drug Synergism; Male; Mastication; Mice; Mice, Inbred C57BL; Morphine; Morphine Dependence; Motor Activity; Naloxone; Narcotic Antagonists; Quinidine; Stereotyped Behavior; Substance Withdrawal Syndrome

Topics: Analgesics; Animals; Corpus Striatum; Dextrorphan; Drug Implants; Humans; Levorphanol; Male; Mice; Morphine; Morphine Dependence; Naloxone; Rats; Reaction Time; Receptors, Opioid; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Brain; Central Nervous System Depressants; Cyclazocine; Cyclic GMP; Dextrorphan; Dose-Response Relationship, Drug; Humans; Levorphanol; Male; Morphine Dependence; Narcotics; Pentazocine; Rats; Stress, Psychological; Time Factors

The effect of morphine on the uptake of 45Ca++ was studied in synaptosomes from mouse brain using two procedures, centrifugation and filtration. The addition of morphine (1.7 x 10(-7) or 3.4 x 10(-7) M) reduced 45CA++ uptake by either technique, although the basal 45Ca++ uptake by the filtration method was approximately 7-fold higher than that by the centrifugation procedure. Similar effects were obtained after acute morphine treatment with 10 mg/kg s.c. Previous naloxone in vitro treatment (1.9 x 10(-8) M) or in vivo administration (2 mg/kg s.c.) reversed the morphine inhibition of the 45Ca++ uptake. On the other hand, after the animal was rendered tolerant and dependent by morphine pellet implantation, an enhancement of the synaptosomal 45Ca++ uptake was observed. It is concluded that changes in Ca++ fluxes in synaptosomes observed after acute and chronic morphine treatment may be involved with morphine pharmacological action related with analgesia, tolerance and physical dependence.

Topics: Animals; Brain; Calcium; Dextrorphan; Drug Tolerance; Humans; In Vitro Techniques; Levorphanol; Male; Mice; Morphine; Morphine Dependence; Osmolar Concentration; Synaptosomes

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.

Topics: Acetylcholine; Animals; Dextrorphan; Evoked Potentials; gamma-Aminobutyric Acid; Glutamates; Glycine; Humans; Interneurons; Levorphanol; Male; Morphine; Morphine Dependence; Naloxone; Neurons; Rats; Reaction Time; Spinal Cord; Synapses

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.

Topics: Acetylcholine; Action Potentials; Animals; Dextrorphan; Drug Tolerance; Evoked Potentials; Fentanyl; Glutamates; Humans; Levorphanol; Male; Morphine; Morphine Dependence; Naloxone; Narcotics; Neurons; Rats; Somatosensory Cortex