levorphanol and Morphine-Dependence

Topics: Animals; Aspirin; Brain; Cyclazocine; Drug Tolerance; Fenclonine; Humans; Levorphanol; Male; Methadone; Mice; Morphinans; Morphine; Morphine Dependence; Nalorphine; Pargyline; Pentazocine; Phenylalanine; Physostigmine; Placebos; Serotonin; Substance Withdrawal Syndrome

Acute morphine dependence was compared in mice selectively-bred for high (HA) and low (LA) swim stress-induced analgesia and high (HAR) and low (LAR) levorphanol analgesia by counting the number of naloxone-precipitated jumps. Whereas LAR mice displayed greater acute morphine dependence than HAR mice, HA and LA mice did not differ. No genotypic differences were observed in non-dependent mice, discounting possible differences in basal naloxone sensitivity and/or opioid peptide levels. Thus, the two selection projects, while both producing lines exhibiting highly divergent sensitivity to morphine analgesia, have not had analogous effects on all opioid measures, supporting the notion of independent genetic mediation of opioid analgesia and dependence. Further, these data suggest that analgesic sensitivity may not predict sensitivity to morphine dependence.

Topics: Analgesia; Animals; Behavior, Animal; Disease Models, Animal; Exercise Test; Levorphanol; Male; Mice; Mice, Inbred Strains; Morphine; Morphine Dependence; Naloxone; Selection, Genetic

Topics: Animals; Choice Behavior; Disease Models, Animal; Dopamine; Drinking Behavior; Female; Fenclonine; Humans; Hydroxydopamines; Levorphanol; Morphine Dependence; Norepinephrine; Rats; Rats, Inbred Strains; Self Administration; Serotonin; Substance-Related Disorders; Sucrose; Sweetening Agents

Chlornaltrexamine (CNA) produces ultralong-lasting (3--6 days) narcotic antagonism in mice and persistent stereospecific binding to rat-brain homogenate. Protection studies in mice suggest that CNA mediates its narcotic antagonist effects by interacting with the same receptors that are occupied by naloxone. A single icv dose of CNA also has been found to inhibit the development of physical dependence in mice for at least 3 days. These studies suggest that CNA exerts its sustained effects by selective covalent association with opioid receptors.

Topics: Alkylating Agents; Analgesics; Animals; Humans; In Vitro Techniques; Male; Mice; Molecular Conformation; Morphine; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Nitrogen Mustard Compounds; Rats; Receptors, Opioid; Time Factors

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

1 Four benzomorphans which have potent antinociceptive activity in the hot-plate and writhing tests in the mouse but do not suppress or precipitate withdrawal symptoms in the morphine-dependent monkey, have been examined for their pharmacological actions in the guinea-pig ileum and mouse vas deferens. 2 In the guinea-pig ileum their agonist potencies are 1.5 to 400 times greater than that of normorphine of morphine whereas in the mouse vas deferens their potencies relative to morphine are 0.3 to 100. They exhibit no antagonist activity in either preparation. Benzomorphans which substitute for morphine in the morphine-dependent monkey do not show such differences between their relative potencies in the guinea-pig ileum and mouse vas diferens. 3 The relative potencies of the four benzomorphans to inhibit stereospecific [3H]-dihydromorphine binding by membrane fragments from rat brain, are more closely related to their relative agonist potencies in the mouse vas deferens than to those found in the guinea-pig ileum. 4 In order to antagonize the agonist actions of these benzomorphans, naloxone is required in concentrations which are 3 to 7 times higher than those needed for the antagonism of normorphine or morphine or of benzomorphans which suppress abstinence in morphine-dependent monkeys. 5 It may be possible to use the three assays, namely, ratio of relative agonist potency in mouse vas deferens to that in guinea-pig ileum, ratio of relative agonist potency to relative affinity to opiate receptors and the concentration of nalozone required for antagonism, for the prediction of the potential of new compounds to produce physical dependence.

Topics: Analgesics, Opioid; Animals; Benzomorphans; Binding, Competitive; Codeine; Electric Stimulation; Guinea Pigs; Haplorhini; Humans; Ileum; In Vitro Techniques; Levorphanol; Male; Mice; Morphinans; Morphine; Morphine Dependence; Muscle Contraction; Muscle, Smooth; Naloxone; Rats; Receptors, Drug; Synaptic Membranes; Vas Deferens

By subcutaneous implantation of 2 or 13 morphine pellets (75 mg morphine/pellet), rats were made tolerant to, and dependent on narcotic analgesics. Occipital cortex slices from dependent animals and placebo-implanted controls were incubated with (-)-3H-noradrenaline and subsequently superfused with physiological salt solution. The accumulation of 3H-noradrenaline was not changed by pretreatment with 2, but was slightly decreased by pretreatment with 13 morphine pellets. The overflow of tritium evoked by electrical field stimulation was higher in slices from morphine-implanted rats than in those from placebo controls. Morphine and levorphanol, added in vitro, inhibited the stimulation-induced overflow of tritium at similar concentrations and to a similar degree in slices from morphineand placebo-pretreated animals.--It is concluded that, during chronic treatment with morphine, an adaptation takes place in the brain to compensate for the acute effect of narcotic analgesics, i.e. inhibition of the release of noradrenaline by nerve impulses. The chain of events from the drug-receptor interaction to the depression of the release process can be escluded as substrate of this adaptation. During withdrawal, the compensatory changes provoke an enhanced increase of extracellular noradrenaline during nerve impulses.

Topics: Animals; Cerebral Cortex; Drug Implants; Drug Tolerance; Electric Stimulation; Humans; Levorphanol; Male; Morphine; Morphine Dependence; Naloxone; Neurons; Norepinephrine; Occipital Lobe; Rats; Substance Withdrawal Syndrome

Topics: Aminopyrine; Analgesics; Animals; Behavior, Animal; Humans; Isonipecotic Acids; Levorphanol; Male; Methadone; Mice; Morphinans; Morphine; Morphine Dependence; Motor Activity; Nalorphine; Naloxone; Narcotic Antagonists; Substance Withdrawal Syndrome

Topics: Analgesics; Animals; Chemical Phenomena; Chemistry; Codeine; Heroin; Humans; Hydromorphone; Levorphanol; Meperidine; Methadone; Morphinans; Morphine Dependence; Structure-Activity Relationship

Topics: 5-Hydroxytryptophan; Analgesia; Animals; Behavior, Animal; Brain Chemistry; Drug Tolerance; Fenclonine; Humans; Levorphanol; Male; Morphine Dependence; Phenylalanine; Rats; Serotonin; Tritium

Topics: Adrenal Glands; Animals; Body Weight; Brain; Drug Tolerance; Epinephrine; Female; Growth; Humans; Levorphanol; Methadone; Monoamine Oxidase Inhibitors; Morphine; Morphine Dependence; Norepinephrine; Organ Size; Rats; Stimulation, Chemical; Substance Withdrawal Syndrome; Substance-Related Disorders; Thebaine; Time Factors