nalorphine and Morphine-Dependence

Topics: Analgesics; Animals; Behavior, Animal; Benzomorphans; Cyclazocine; Discrimination Learning; Dogs; Dopamine; Drug Tolerance; Electroencephalography; Humans; Macaca mulatta; Mice; Morphine; Morphine Dependence; Motor Activity; Nalorphine; Pain; Rabbits; Rats; Receptors, Dopamine; Receptors, Opioid; Receptors, Opioid, kappa; Seizures; Temperature

When an opioid capable of forming active metabolites is administered, the total pharmacology is the result of interactions of the opioid and such metabolites, especially normetabolites. Normetabolites may affect the morphine-like characteristics of certain opioids and thus influence their reinforcement in animals and man. Most opioids, when administered in single doses, are positively reinforcing in addicts. Oral administration, as compared with parenteral, facilitates the formation of normetabolites. When chronically administered, many opioids, including acetylmethadol, meperidine, morphine, codeine, propoxyphene, and levorphanol, show evidence of a longer half-life for their normetabolites. Normetabolites may have aversive characteristics and thus impair positive reinforcement of the parent drug in animals and man. For example, addicts do not like chronic oral morphine or chronic oral codeine. Conversely, methadone, the normetabolites of which are inactive, is well accepted during chronic oral administration. Drugs which inhibit N-demethylation will increase the agonist potency of opioids having inactive normetabolites (e.g., methadone) but will decrease the agonist potency of opioids having more potent normetabolites than the parent (e.g., acetylmethadol). The divergent responses of addicts to single doses of opiates as compared with chronic doses indicate that chronic addiction tests in man are needed befored relative abuse liability can be predicted.

Topics: Animals; Dealkylation; Dextropropoxyphene; Dogs; Haplorhini; Heroin Dependence; Humans; Methadone; Methyltransferases; Morphine Dependence; Nalorphine; Narcotics; Pupil; Reinforcement, Psychology; Self Administration; Species Specificity; Time Factors

Topics: Animals; Behavior, Animal; Cyclazocine; Cyclopropanes; Dose-Response Relationship, Drug; Facial Expression; Handling, Psychological; Haplorhini; Humans; Morphinans; Morphine Dependence; Nalorphine; Naloxone; Narcotic Antagonists; Species Specificity; Structure-Activity Relationship; Substance Withdrawal Syndrome; Thebaine; Time Factors

Topics: Analysis of Variance; Cyclazocine; Drug Evaluation; Humans; Morphine; Morphine Dependence; Nalorphine; Naloxone; Narcotic Antagonists; Pupil; Substance Withdrawal Syndrome; Surveys and Questionnaires; Time Factors

Topics: Animals; Chlorpromazine; Codeine; Cyclazocine; Drug Combinations; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Lysergic Acid Diethylamide; Mice; Morphinans; Morphine; Morphine Dependence; Nalorphine; Naloxone; Narcotic Antagonists; Pentobarbital; Rats; Receptors, Drug; Species Specificity; Substance Withdrawal Syndrome; Substance-Related Disorders; Surveys and Questionnaires

Topics: Adolescent; Amphetamine; Amphetamines; Barbiturates; Cannabis; Codeine; Heroin; Humans; Hydromorphone; Jurisprudence; Meperidine; Mescaline; Methadone; Morphine Dependence; Nalorphine; Narcotic Antagonists; Psychotherapy; Statistics as Topic; Substance-Related Disorders

A randomized and blind experimental design was used to study the effects of naloxone and nalorphine on the development of morphine dependence in monkeys. The results suggest: (a) that significant dose-related differences existed for combined numbers of withdrawal symptoms times frequency of occurrences; (b) that naloxone and nalorphine were qualitatively similar; (c) antagonists are more effective as dependence develops; (d) naloxone is approximately 10 times more potent than nalorphine, and (e) vomiting was the only withdrawal sign with which ED50s could be calculated. Dependence on morphine still increases up to 9 months after the commonly accepted 90-day stabilization period as measured by the ED50 for vomiting for naloxone.

Topics: Animals; Dose-Response Relationship, Drug; Female; Haplorhini; Humans; Macaca mulatta; Male; Morphine; Morphine Dependence; Nalorphine; Naloxone; Substance Withdrawal Syndrome; Vomiting

Topics: Cyclopropanes; Heroin; Humans; Injections, Subcutaneous; Male; Morphinans; Morphine; Morphine Dependence; Nalorphine; Naloxone; Narcotic Antagonists; Prisons; Surveys and Questionnaires

Topics: Analysis of Variance; Codeine; Cyclazocine; Dextropropoxyphene; Dose-Response Relationship, Drug; Emotions; Humans; Levallorphan; Lysergic Acid Diethylamide; Morphine Dependence; Nalbuphine; Nalorphine; Narcotic Antagonists; Pentazocine; Placebos; Substance Withdrawal Syndrome; Surveys and Questionnaires

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

A sensitive taste conditioning test was used to measure the aversive effect of a single intraventricular (i.c.v.) or subcutaneous (s.c) injection of an opioid antagonist that readily crosses the blood brain barrier (naltrexone), and one of two that do not (methylnaltrexone and diallylnormorphinium). This was done in drug-naive rats and in rats implanted 5 days earlier with a pellet containing 75 mg morphine. It was found that the morphine exposure had no significant effect on the dose-response curve of the taste aversion produced by s.c. methylnaltrexone and s.c. diallynormorphinium but reduced the lowest effective dose for the other antagonist treatments from three to more than 100 times. Consideration of the data, together with the pharmacokinetic properties of the drugs and the routes of administration used, supported a conclusion that only those aversions involving central antagonist activity show the potentiation effect of chronic morphine treatment. The findings were also discussed with regard to the location of receptors important for aversions produced by opioid antagonists in naive rats.

Topics: Animals; Blood-Brain Barrier; Dose-Response Relationship, Drug; Drug Synergism; Infusions, Parenteral; Injections, Subcutaneous; Male; Morphine Dependence; Nalorphine; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Rats; Rats, Inbred Strains; Taste

1. Morphine induced a contractile response in the mouse colon which consisted of two phases or components. 2. The first component was dose-related and was inhibited by tetrodotoxin, atropine and naloxone, but was insensible to hexamethonium, propranolol, phentolamine, diphenhydramine and methysergide. 3. The second component of the contractile effect was not modified by atropine, hexamethonium, propranolol, phentolamine, guanethidine or diphenhydramine, but was antagonized by naloxone, tetrodotoxin and serotonin antagonists. 4. Tachyphylaxis was observed only for the first component of the morphine induced contractile response of the mouse colon.

Topics: Animals; Colon; In Vitro Techniques; Methadone; Mice; Morphine; Morphine Dependence; Muscle Contraction; Muscle, Smooth; Nalorphine; Naloxone; Neostigmine; Serotonin Antagonists

The effects of morphine, naloxone, and nalorphine on responding maintained under a variable-interval schedule of food presentation were assessed in rhesus monkeys before and after successive periods of daily morphine maintenance (15.0 mg/kg/day SC). Withdrawal from morphine dependence was accomplished gradually following the first two maintenance periods and abruptly following the third period. Schedule-controlled responding was disrupted when morphine maintenance was abruptly discontinued but not when the maintenance dosage was gradually reduced to zero. Tolerance to the acute effects of IV morphine on responding developed during morphine maintenance and dissipated after daily injections were discontinued. The effects of IV naloxone and IV nalorphine following each period of morphine maintenance were generally similar to their effects in initial determinations. These data indicate that tolerance-producing regimens of repeated daily injections with morphine do not necessarily produce enduring changes in the effects of opiate antagonists on schedule-controlled behavior. Additionally, gradual withdrawal from morphine maintenance can minimize the behavioral disruptions that attend abrupt abstinence.

Topics: Animals; Conditioning, Operant; Dose-Response Relationship, Drug; Female; Humans; Macaca mulatta; Male; Morphine; Morphine Dependence; Nalorphine; Naloxone; Reinforcement Schedule

The aim of this study was to eliminate endogenous stores of histamine before inducing the precipitated withdrawal syndrome. Results demonstrate that histamine plays a role in the emergence of some of the symptoms which characterize the precipitated abstinence syndrome in morphine-dependent dogs. Morphine-dependent dogs receiving 0.5 mg/kg n-allyl-normorphine exhibit the precipitated abstinence syndrome. Injection of compound 48/80, 0.5 mg/kg, a potent histamine liberator, produced, on the other hand, typical signs of the abstinence syndrome. A second injection of this compound 24 hours later, however, failed to induce these signs. An injection of n-allyl-normorphine also failed to induce these signs in dogs pretreated with compound 48/80 despite the fact that the dogs were still on their morphine regime. Control experiments on naive animals showed that injection of 0.5 mg/kg n-allyl-normorphine failed to produce signs of the abstinence syndrome. Injection of compound 48/80, a potent histamine liberator, on the other hand, did produce the typical signs of the abstinence syndrome. Animals pretreated with n-allyl-normorphine followed by compound 48/80 responded similarly to animals treated with compound 48/80 alone.

Topics: Animals; Dogs; Female; Humans; Male; Morphine Dependence; Nalorphine; p-Methoxy-N-methylphenethylamine; Substance Withdrawal Syndrome

Topics: Animals; Body Weight; Diarrhea; Female; Humans; Intestines; Morphine Dependence; Nalorphine; Naltrexone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

Series of N-(cyclopropylmethyl) (P series) or N-(cyclobutylmethyl) (B series) 3-methoxy (1) or 3-hydroxy (2) morphinan-6-ones with hydrogen (a), methyl (b), or ethyl (c) groups in the 8 beta position were converted to the 6-methylene compounds 3 or 4 by reaction with Ph3P = CH2. One member of this new series, N-(cyclobutylmethyl)-8 beta-methyl-6-methylenemorphinan-3-ol (4Bb), had potent mixed agonist-narcotic antagonist properties and, in contrast to the previously studied 6-oxo compound 2Bb, did not substitute for morphine in dependent rats or monkeys.

Topics: Analgesics; Animals; Chemical Phenomena; Chemistry; Haplorhini; Humans; Mice; Morphinans; Morphine Dependence; Narcotic Antagonists; Rats; Reaction Time; Substance Withdrawal Syndrome

A series of 8-alkyl-3-methoxy-17-methylmorphinan-6-ones (3C) and -isomorphinan-6-ones (3T) were prepared by conjugate addition of lithium dialkylcuprates to the corresponding 7,8-didehydro-6-ones 2C and 2T. These 17-methyl compounds were potent analgesics and were converted to mixed narcotic agonists-antagonists 7-10, by replacement of the 17-methyl groups with cycloalkylmethyl moieties. The 8 substituent modified the type of activity observed. One of these compounds, 17-(cyclobutylmethyl)-3-hydroxy-8 beta-methylmorphinan-6-one (10Ca), had an agonist-antagonist ratio of 0.1. Compound 10Ca did not support or cause dependence in rats. This compound, however, appeared to be a typical narcotic agent in morphine-dependent monkeys.

Topics: Acetates; Analgesics; Animals; Haplorhini; Humans; Mice; Morphinans; Morphine Dependence; Narcotic Antagonists; Rats; Reaction Time; Structure-Activity Relationship; Substance Withdrawal Syndrome; Substance-Related Disorders

3,6-Dimethoxy-7 beta, 17-dimethyl-4-hydroxy-5,6,8,14-tetradehydromorphinan (2) was converted to the 4-deoxy compound 4 and hydrolyzed to a mixture of the B/C-cis (C series) and B/C-trans (T series) isomers of 7,8-didehydromorphinan-6-one, 5. Hydrogenation of the separated isomers gave 7-methyl-6-oxo derivatives 6a. 7,8-Dimethyl-(6b) or 7-methyl-8-ethylmorphinan-6-one (6c) was prepared by reaction of 5 with lithium organocuprates. The analgesic N-methyl compounds 6 were converted to 17-(cyclopropylmethyl) or 17-(cyclobutylmethyl) derivatives 10--13. Some of these compounds had mixed profiles of narcotic agonist-antagonist effects. Studies with drug-dependent monkeys indicated that several of these compounds with an analgesic-antagonist ratio of less than 0.4 substitute for morphine.

Topics: Analgesics; Animals; Chemical Phenomena; Chemistry; Humans; Morphinans; Morphine Dependence; Narcotic Antagonists; Substance Withdrawal Syndrome

Topics: Animals; Central Nervous System Depressants; Codeine; Drug Evaluation, Preclinical; Haplorhini; Humans; Macaca; Macaca mulatta; Morphine Dependence; Nalorphine; Naloxone; Narcotic Antagonists; Narcotics; Self Administration; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

Groups of naive rats were offered morphine sulfate for self-admininstration in doses of 0.0032-10 mg/kg for 6 days. On day 7 saline was substituted for morphine. Loss of weight was taken as physiological evidence of dependence. Rats that did not lose weight formed a single population whose mean injection rate did not differ from control rats receiving only saline injections. Injection rates for rats losing weight were log-normally distributed, and the mean of the logarithms of the injection rates was linearly related to the logarithm of the dose. Mean daily injection rates averaged 12 for controls, 23 at 10 mg/kg, and 411 at 0.01 mg/kg. A transient increase in morphine intake after an injection of nalorphine was taken as behavioral evidence of dependence. Nalorphine increased morphine intake when rats were self-injecting 0.32 and 1.0 mg/kg of morphine, but not 0.032 or 0.1 mg/kg. The reinforcing property of morphine may occur without behavioral evidence of dependence.

Topics: Animals; Body Weight; Conditioning, Operant; Dose-Response Relationship, Drug; Extinction, Psychological; Female; Humans; Morphine; Morphine Dependence; Nalorphine; Rats; Self Administration; Time Factors

Intracerebral administration of copper sulfate potentiated morphine analgesia in morphine-tolerant and -dependent mice, but copper failed to affect other abstinence signs. When abstinence was precipitated with a partial antagonist, nalorphine, stereotyped jumping was not inhibited by either calcium or copper. These modifications of narcotic effects by copper were produced without alterations in the brain disposition of morphine. Total radioactivity in the brain following radioactive naloxone administration was also not altered.

Topics: Analgesia; Animals; Calcium; Cations, Divalent; Copper; Humans; Male; Mice; Morphine; Morphine Dependence; Nalorphine; Naloxone; Substance Withdrawal Syndrome

Topics: Analgesics, Opioid; Animals; Benzimidazoles; Cerebral Cortex; Conditioning, Classical; Conditioning, Operant; Conditioning, Psychological; Cues; Diethylamines; Drug Tolerance; Emotions; Environment; Euphoria; Humans; Morphine; Morphine Dependence; Nalorphine; Reinforcement, Psychology; Retrospective Studies; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Clonidine; Cyproheptadine; Humans; Male; Morphine Dependence; Nalorphine; Rats; Substance Withdrawal Syndrome; Time Factors

Rhesus monkeys were trained to self-administer morphine intravenously at dose levels sufficient to develop physical dependence. The monkeys were then trained to press a lever to escape a continuous infusion of the morphine antagonist, nalorphine. When saline was substituted for the nalorphine, escape responding extinguished. After morphine self-administration was eliminated, responding to escape from nalorphine was maintained in the postdependent monkeys, showing no difference from escape responding during morphine dependence. Finally, perphenazine was substituted for the nalorphine and the monkeys reliably escaped continuous infusions of this phenothiazine. The escape procedure appears useful for analyzing the aversive properties of drugs.

Topics: Animals; Escape Reaction; Haplorhini; Humans; Macaca mulatta; Morphine; Morphine Dependence; Nalorphine; Perphenazine; Reaction Time; Self Administration; Time Factors

Rats previously trained to a fixed-interval schedule (FI 2 min) were treated twice daily with saline or morphine hydrochloride (final dose 40 mg/kg i.p.) for 44 days. On day 45 an abstinence state was induced by withdrawing morphine or by giving nalorphine (1 mg/kg i.p.). Operant behavior was recorded on alternate days during the period of chronic treatment and during the withdrawal phase (21 days). It was found that the number of lever presses decreased significantly during the first days of morphine administration but increased later over the control values. The quarter-life was not changed during this period. Morphine withdrawal and nalorphine treatment both caused a further increase in lever presses that lasted about 11 days. Again quarter-life was not changed. These results indicate that the effects of morphine on FI behavior in rats not only undergo tolerance but are actually reversed during the chronic treatment. The data obtained during the withdrawal phase are discussed in relation to the secondary abstinence syndrome described by Martin et al. (1963).

Topics: Animals; Body Weight; Conditioning, Operant; Drug Tolerance; Humans; Male; Morphine; Morphine Dependence; Nalorphine; Rats; Reinforcement Schedule; Substance Withdrawal Syndrome; Time Factors

In morphine-dependent rats the withdrawal precipitating properties of various morphine antagonists and partial agonists were studied by quantitatively evaluating a variety of different withdrawal signs. A comparison of the dose response curves of the various substances obtained for the different signs revealed marked differences in respect to the lowest effective doses (EDs) necessary to precipitate the withdrawal signs as well as in the maximum frequencies of the signs induced. The "pure" antagonist, naloxone, which was judged very potent according to the ED, precipitated the lowest levels of jumping, whereas certain partial agonists of the benzomorphane type, which were less potent according to the ED, induced very high levels of this sign. These latter compounds, however, failed to precipitate "complete" withdrawal, as evidenced by the nearly complete absence of some of the withdrawal signs. The jumping precipitating potency of the antagonists as judged from the ED was found to be highly correlated to the stereospecific binding of these substances to rat brain homogenate. On the other hand, the ability of the substances to precipitate high levels of jumping was seen to increase, at least within a certain range, with increasing degree of agonistic properties, as indicated by the ratio of stereospecific binding in the presence and absence of sodium.

Topics: Benzomorphans; Binding Sites; Brain; Humans; Levallorphan; Morphine Dependence; Nalorphine; Naloxone; Naltrexone; Narcotic Antagonists; Pentazocine; Receptors, Drug; Sodium; Stereoisomerism; Subcellular Fractions; Substance Withdrawal Syndrome

Three different syndromes produced by congeners of morphine have been identified in the nondependent chronic spinal dog. These syndromes have been attributed to interaction of agonists with three distinguishable receptors (mu, kappa and sigma). Morphine is the prototype agonist for the mu receptor, ketocyclazocine for the kappa receptor and SKF-10,047 for the sigma receptor. The morphine syndrome (mu) in the dog is characterized by miosis, bradycardia, hypothermia, a general depression of the nociceptive responses and indifference to environmental stimuli. Ketocyclazocine (kappa) constricts pupils, depresses the flexor reflex and produces sedation but does not markedly alter pulse rate or the skin twitch reflex. SKF-10,047 (sigma), in contrast to morphine and ketocyclazocine, causes mydriasis, tachypnea, tachycardia and mania. The effects of these three drugs can be antagonized by the pure antagonist naltrexone, indicating that they are agonists. Further, chronic administration of morphine, ketocyclazocine and SKF-10,047 induces tolerance to their agonistic effects. Morphine suppresses abstinence in morphine-dependent dogs while ketocyclazocine does not. Ketocyclazocine at best precipitated only a liminal abstinence syndrome in the morphine-dependent dog, indicating that it had little affinity for the morphine receptor. Ketocyclazocine thus appears to be a selective agonist at the kappa receptor. Further, it has been shown that buprenorphine is a partial agonist of the mu type which both suppressed and precipitated abstinence in the morphine-dependent dog while morphine and propoxyphene are stronger agonists. Apomorphine and SKF-10,047 produce similar pharmacologic effects suggesting that sigma activity may involve a dopaminergic mechanism.

Topics: Animals; Apomorphine; Cyclazocine; Cyclopropanes; Dextropropoxyphene; Dogs; Ethylketocyclazocine; Humans; Morphinans; Morphine; Morphine Dependence; Nalorphine; Naltrexone; Phenazocine; Spinal Cord

A series of morphine-like and nalorphine-like drugs were studied in the nondependent, morphine-dependent and cyclazocine-dependent chronic spinal dog. In the nondependent dog, three profiles of activity were found which could be utilized to distinguish between morphine, WIN 35, 197-2 and cyclazocine. Propiram, a prototypic partial agonist of the morphine type, produced morphine-like effects in nondependent dogs and both precipitated and suppressed abstinence in cyclazocine-dependent dogs as was needed to precipitate abstinence in morphine-dependent dogs. WIN 35, 197-2, a strong agonist in the guinea-pig ileum which has been shown to be resistant to antagonism by naloxone, neither precipitated nor suppressed morphine abstinence but suppressed cyclazocine abstinence. In the nondependent dog, it depressed the flexor reflex but not skin twitch reflex. Cyclazocine altered reflex activity much like WIN 35, 197-2 but produced tachycardia, tachypnea, mydriasis and canine delirum. The morphine and cyclazocine precipitated and withdrawal abstinence syndromes were qualitatively different. Twenty times as much naltrexone was needed to precipitate abstinence in morphine-dependent dogs. Nalorphine both precipitated and suppressed cyclazocine abstinence and appeared to be a partial agonist of the nalorphine-type. Morphine suppressed the cyclazocine abstinence syndrome. Cross-tolerance was not observed in ketocyclazocine-dependent dogs. These data are consistent with the hypothesis that there are strong and partial agonists of the mu and kappa types, and further, that physical dependence on morphine and cyclazocine is mediated through different receptors. WIN 35, 197-2 appears to be a pure strong agonist of the kappa type. Cyclazocine is a mu antagonist and mixed kappa and sigma agonist.

Topics: Animals; Behavior, Animal; Cyclazocine; Dogs; Drug Interactions; Female; Humans; Morphine; Morphine Dependence; Nalorphine; Spinal Cord; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

In rats made dependent on morphine by implantation of morphine pellets, withdrawal, as precipitated by intraventricular injection of morphine antagonists, was compared to withdrawal as precipitated by systemic antagonist application. The results, most clearly those obtained with a hydrophilic compound, diallyl-nor-morphinium-bromide, point to periventricularly located sites of action for the release of most withdrawal signs by antagonists. Jumping, reaching only low levels after i.ventr. injection of levallorphan and nalorphine, was very pronounced when the benzomorphane derivative SH 254, was used. In the case of writhing and diarrhea, the situation is more complicated. Possibly, central as well as peripheral mechanisms are involved in the expression of these signs.

Topics: Animals; Cerebral Ventricles; Humans; Injections, Intraperitoneal; Injections, Intraventricular; Levallorphan; Male; Morphinans; Morphine; Morphine Dependence; Nalorphine; Narcotic Antagonists; Rats; Receptors, Drug; Substance Withdrawal Syndrome

Single doses of serine (250 mg/kg i.p.) failed to elevate central glycine in mice (1 h after injection), or to compensate for losses caused by implantation of morphine base (70 mg/animal), and reduced the jumping response to nalorphine (100 mg/kg i.p.). In contrast, sustained treatment with 250-mg/kg doses of serine at 24-hour intervals produced increases in brain and medullar glycine (1 h after 4th injection: 46-50% in normal, 39-75% in morphine-dependent mice, and enhanced the jumping response (40% over controls).

Topics: Animals; Brain; Drug Tolerance; Glycine; Humans; Male; Mice; Morphine Dependence; Nalorphine; Serine; Strychnine; Substance Withdrawal Syndrome

Topics: Animals; Behavior, Animal; Drug Administration Schedule; Haplorhini; Humans; Injections, Intravenous; Macaca mulatta; Male; Morphine Dependence; Nalorphine; Reinforcement Schedule; Substance Withdrawal Syndrome; Time Factors

A pattern of lever pressing and schedule-induced polydipsia was maintained in rats by a fixed-interval 90-second of food presentation. The effects of acute morphine, methadone, nalorphine, naloxone, pentazocine and cyclazocine were studied in control rats (morphine-free rats) and rats maintained on 200 mg/kg daily oral infections of morphine (morphine-maintained rats). The effects of morphine, nalorphine and naloxone also were studied in rats that were drinking a 0.5 mg/ml of morphine solution (morphine-drinking rats) in the experimental apparatus. All six drugs decreased drinking in the morphine-free rats. Pentazocine and naloxone increased lever-pressing rates in the morphine-free rats, while morphine, methadone, nalorphine and cyclazocine only decreased lever-pressing rates. In the morphine-maintained rats, the dose-effect curves for both lever-pressing and drinking measures were shifted to the left for naloxone, nalorphine, pentazocine and cyclazocine, indicating an increased sensitivity to the antagonists, while the dose-effect curves for morphine and methadone were shifted to the right, indicating that the morphine-maintenance regimen had produced tolerance to these drugs. Morphine and methadone injections increased drinking in the morphone-maintained rats, but none of the drugs increased lever-pressing rates in the morphine-maintained rats. In the morphine-drinking rats, morphine decreased lever pressing at doses that left licking rates unaffected. Since the effects of morphine in the morphine-drinking rats differed from those in the morphine-free rats or the morphine-maintained rats, the effects of morphine on the self-ingestion of morphine in the experimental setting cannot be attributed entirely to the schedule of pellet delivery or to the effect of chronic morphine dosing.

Topics: Animals; Cyclazocine; Drinking Behavior; Humans; Methadone; Morphine; Morphine Dependence; Nalorphine; Naloxone; Narcotic Antagonists; Narcotics; Pentazocine; Rats; Reinforcement Schedule

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: Animals; Behavior, Animal; Body Weight; Codeine; Dose-Response Relationship, Drug; Humans; Infusions, Parenteral; Injections, Intraperitoneal; Male; Meperidine; Methadone; Morphine; Morphine Dependence; Nalorphine; Naloxone; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors; Vocalization, Animal

Topics: Aggression; Animals; Disease Models, Animal; Drug Synergism; Glycine; Humans; Mice; Morphine Dependence; Nalorphine; Substance P; Substance Withdrawal Syndrome

1 The spontaneous release of acetylcholine (ACh) from the cerebral cortex of control and morphine-dependent rats was investigated. The rate of resting output of ACh in morphine-dependent animals was lower than that in the control animals.2 Administration of naloxone and nalorphine to morphine-dependent rats was followed by a significant rise in the release of cortical ACh. In control rats no such increase in the release of ACh occurred after similar injections of narcotic antagonists.3 Injections of morphine produced a consistent decrease in the rate of spontaneous release of cortical ACh in the control rats, but similar injections in the dependent rats did not produce a decrease in the rate of cortical ACh release.4 The relevance of these results with regard to development of the narcotic abstinence syndrome is discussed.

Topics: Acetylcholine; Animals; Brain; Humans; Morphine; Morphine Dependence; Nalorphine; Naloxone; Rats

Topics: Animals; Behavior, Animal; Body Weight; Flurothyl; Humans; Male; Morphine Dependence; Nalorphine; Rats; Seizures; Substance Withdrawal Syndrome; Time Factors

Topics: Amygdala; Animals; Cerebral Cortex; Depression, Chemical; Drug Interactions; Electrophysiology; Humans; Hypothalamus; Methadone; Morphine; Morphine Dependence; Nalorphine; Naloxone; Neurons; Rats; Substance Withdrawal Syndrome; Time Factors

Topics: Analgesics; Animals; Bridged-Ring Compounds; Cyclazocine; Dose-Response Relationship, Drug; Electroshock; Haplorhini; Humans; Macaca; Mice; Morphine; Morphine Dependence; Nalorphine; Naloxone; Naphthalenes; Narcotic Antagonists; Pentazocine; Postural Balance; Rats; Reaction Time; Reflex; Substance Withdrawal Syndrome; Tail

Topics: Analgesics; Animals; Cyclazocine; Female; Haplorhini; Humans; Male; Mice; Morphinans; Morphine; Morphine Dependence; Nalorphine; Naloxone; Narcotic Antagonists; Pentazocine; Stereotyped Behavior; Substance Withdrawal Syndrome; Substance-Related Disorders; Thebaine; Time Factors

Topics: Animals; Avoidance Learning; Codeine; Cyclazocine; Electric Stimulation; Electrodes, Implanted; Female; Haplorhini; Heroin; Humans; Light; Macaca; Male; Morphine; Morphine Dependence; Nalorphine; Narcotic Antagonists; Narcotics; Pentazocine; Reinforcement Schedule; Reinforcement, Psychology

Topics: Aminopyrine; Animals; Azepines; Body Weight; Codeine; Cyproheptadine; Dextropropoxyphene; Humans; Male; Meperidine; Meprobamate; Methods; Morphine Dependence; Nalorphine; Pentazocine; Pentobarbital; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

Topics: Administration, Oral; Animals; Body Weight; Diet; Drinking Behavior; Feeding Behavior; Humans; Injections; Male; Morphine; Morphine Dependence; Nalorphine; Rats; Substance Withdrawal Syndrome; Time Factors

Topics: Conditioning, Classical; Conditioning, Operant; Conditioning, Psychological; Euphoria; Extinction, Psychological; Humans; Morphine Dependence; Nalorphine; Narcotic Antagonists; Psychotherapy; Recurrence; Reinforcement, Psychology; Self Medication; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Acetylcholine; Animals; Brain; Brain Chemistry; Hemicholinium 3; Humans; Male; Morphine Dependence; Nalorphine; Rats; Substance Withdrawal Syndrome; Time Factors

1. The effects of morphine, nalorphine, acetazolamide, and 10% CO(2) on brain metabolite concentrations of 24h-starved rats were studied. 2. A single dose of morphine (20mg/kg body wt.) caused an increase in brain glucose concentration (42%) and decreased concentrations of lactate (24%), pyruvate (29%), citrate (20%), alpha-oxoglutarate (16%), malate (14%) and creatine phosphate (10%) after 30min. No changes were found in adenine nucleotide concentrations. 3. The same dose of morphine increased arterial CO(2) from 5.07 to 7.60 kN/m(2) (38 to 57 Torr), decreased the pH from 7.41 to 7.31 and decreased O(2) from 14.1 to 10.8kN/m(2) (106 to 81 Torr) at 30min. 4. Rats injected with morphine three times daily (20mg/kg body wt.) for 2 weeks had no changes in brain metabolite concentrations or in blood gases 30min after their last injection. 5. Nalorphine (an antagonist of morphine) caused essentially no changes in brain metabolite concentrations in normal rats. When nalorphine (20mg/kg) was administered to rats previously treated with morphine three times daily for 2 weeks, there was an increase in brain glucose (100%), lactate (23%), pyruvate (18%) and citrate (10%) concentrations. 6. Acetazolamide (an inhibitor of carbonic anhydrase) and 10% CO(2) increased the arterial CO(2) from 4.79 to 6.78kN/m(2) (36 to 51 Torr) and from 5.32 to 10.8kN/m(2) (40 to 81 Torr) respectively. 7. Both acetazolamide and 10% CO(2) caused changes in brain metabolite concentrations similar to those for acutely administered morphine. Thus 10% CO(2) caused increased brain glucose concentration (123%) and decreased brain lactate (46%), pyruvate (34%), citrate (26%), alpha-oxoglutarate (33%), malate (45%) and creatine phosphate (7%) concentrations. No changes in adenine nucleotide concentrations were found. 8. The results indicate that the effect of morphine on brain metabolite concentrations may be accounted for by the increased [CO(2)]. 9. These findings constitute a consistent pattern of metabolic changes after acute morphine administration, morphine addiction, and withdrawal from morphine addiction.

Topics: Acetazolamide; Adenosine Diphosphate; Adenosine Triphosphate; Ammonia; Animals; Arteries; Aspartic Acid; Brain; Carbon Dioxide; Citrates; Glucose; Glutarates; Humans; Hydrogen-Ion Concentration; Lactates; Malates; Male; Morphine; Morphine Dependence; Nalorphine; Phosphocreatine; Pyruvates; Rats; Substance Withdrawal Syndrome

Topics: Animals; Arrhythmias, Cardiac; Bradycardia; Cerebral Aqueduct; Cerebral Ventricles; Fever; Humans; Injections, Spinal; Medulla Oblongata; Morphine; Morphine Dependence; Nalorphine; Pons; Rabbits; Seizures; Substance Withdrawal Syndrome

Topics: Adolescent; Diazepam; Humans; Injections, Intravenous; Levallorphan; Morphine Dependence; Nalorphine; Psychoses, Substance-Induced; Psychotherapy; Sleep; Substance-Related Disorders

Topics: Chromatography, Gas; Chromatography, Paper; Chromatography, Thin Layer; False Negative Reactions; False Positive Reactions; Humans; Medical History Taking; Morphine Dependence; Nalorphine; Phenothiazines; Substance-Related Disorders

Topics: Animals; Binding Sites; Biological Transport, Active; Centrifugation, Density Gradient; Cerebral Cortex; Cytoplasmic Granules; Drug Tolerance; Humans; Hydromorphone; In Vitro Techniques; Male; Morphine Dependence; Nalorphine; Nerve Endings; Norepinephrine; Osmosis; Rats; Synapses; Synaptic Vesicles; Tritium

Topics: Animals; Body Temperature; Brain; Carbon Isotopes; Fenclonine; Humans; Male; Mathematics; Morphine Dependence; Nalorphine; Norepinephrine; Rats; Serotonin; Substance Withdrawal Syndrome; Tritium; Tryptophan; Tyrosine

Topics: Animals; Female; Humans; Injections, Subcutaneous; Mice; Morphine; Morphine Dependence; Motor Activity; Nalorphine; Substance Withdrawal Syndrome

Topics: Animals; Behavior, Animal; Conditioning, Operant; Drug Synergism; Female; Haplorhini; Humans; Male; Morphinans; Morphine; Morphine Dependence; Nalorphine; Reinforcement, Psychology

Topics: Animals; Atropine; Body Temperature Regulation; Cholinesterase Inhibitors; Female; Haplorhini; Humans; Macaca; Male; Morphine; Morphine Dependence; Nalorphine; Neostigmine; Parasympathomimetics; Physostigmine; Substance Withdrawal Syndrome; Time Factors; Tropanes

Injection of small quantities of morphine into the cerebral ventricular system of awake, relatively unrestrained, monkeys depressed or abolished operant food-reinforced lever pressing. After repeated injections progressively higher doses of morphine were needed to depress responding. Also, dependence could be demonstrated in these animals by precipitating specific abstinence signs with an antagonist.

Topics: Animals; Behavior, Animal; Cerebral Ventricles; Conditioning, Psychological; Drug Tolerance; Feeding Behavior; Haplorhini; Humans; Injections; Macaca; Morphine; Morphine Dependence; Nalorphine; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Avoidance Learning; Conditioning, Classical; Escape Reaction; Female; Haplorhini; Humans; Male; Morphinans; Morphine; Morphine Dependence; Nalorphine; Naloxone; Narcotic Antagonists; Time Factors

Topics: Animals; Cycloheximide; Drug Tolerance; Female; Humans; Male; Mice; Morphine; Morphine Dependence; Nalorphine; Time Factors

Topics: Codeine; Heroin; Humans; Levallorphan; Meperidine; Methadone; Morphine; Morphine Dependence; Nalorphine; Narcotic Antagonists; Stereoisomerism; Substance-Related Disorders

Every tenth lever-press of three morphine-dependent rhesus monkeys was reinforced with food. A red light, initially a neutral stimulus, was presented every third or fourth session for 5 min before and 5 min after an intravenous injection of nalorphine, a morphine antagonist that produces an immediate abstinence syndrome in morphine-dependent monkeys. After several pairings, conditioned suppression of lever pressing, heart-rate decrease, vomiting, and excessive salivation were observed during the red-light period before nalorphine injection. No conditioned electrocardiogram, respiration or temperature changes occurred. After 10 red light-nalorphine pairings, morphine administration was completely discontinued and monkeys were then tested monthly for persistence of the conditioned responses. The red light paired with saline injection continued to suppress lever pressing and to produce heart-rate decreases after 60 to 120 days of complete abstinence from morphine. Subsequently, daily presentations of the red light-saline injection complex rapidly extinguished these conditioned responses. Nevertheless, they could be rapidly reinstated by additional nalorphine injections.

Topics: Animals; Behavior, Animal; Brain; Conditioning, Psychological; Feeding Behavior; Female; Haplorhini; Heart Rate; Humans; Injections, Intravenous; Male; Morphine Dependence; Nalorphine; Respiratory Function Tests; Reward; Salivation; Substance Withdrawal Syndrome; Temperature; Vomiting

Three rhesus monkeys Macaca mulatta, formerly dependent on morphine, had increased sensitivity to nalorphine's effect of suppressing operant responding for food, as compared with two monkeys with no history of morphine exposure. Within the dose range employed, nalorphine injections produced emesis, salivation, and hyperirritability in formerly morphine-dependent monkeys but not in controls.

Topics: Animals; Behavior, Animal; Conditioning, Operant; Macaca mulatta; Morphine Dependence; Nalorphine; Narcotic Antagonists; Reinforcement, Psychology; Salivation; Vomiting

Topics: Analgesics; Animals; Azocines; Chemical Phenomena; Chemistry; Dogs; Haplorhini; Humans; Morphine; Morphine Dependence; Nalorphine; Rats; Substance-Related Disorders

Topics: Animals; Humans; Meperidine; Methadone; Methods; Mice; Morphine Dependence; Motor Activity; Nalorphine; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Cats; Drug Tolerance; Female; Humans; Male; Morphine; Morphine Dependence; Nalorphine; Paralysis; Pupil; Skin Absorption

Topics: Animals; Body Temperature; Dogs; Drug Tolerance; Homeostasis; Humans; Morphine; Morphine Dependence; Nalorphine; Partial Pressure; Pulse; Reflex; Respiration; Substance Withdrawal Syndrome; Time Factors

Topics: Adrenal Medulla; Animals; Behavior, Animal; Body Temperature; Brain Chemistry; Brain Stem; Cats; Depression, Chemical; Dogs; Drug Tolerance; Epinephrine; Humans; Injections, Intraperitoneal; Monoamine Oxidase Inhibitors; Morphine; Morphine Dependence; Nalorphine; Norepinephrine; Phenobarbital; Rabbits; Rats; Substance Withdrawal Syndrome

Three rhesus monkeys, physically dependent on morphine, were trained to press a lever for food on a fixed ratio of 10 responses. A tone, initially a neutral stimulus, was aperiodically presented every third or fourth session, 5 min before and after the intravenous injection of nalorphine, a morphine antagonist which produces an immediate withdrawal syndrome in morphine-dependent monkeys. After several sessions, conditioned suppression of food-lever response rate was observed. Conditioned bradycardia, emesis, and excessive salivation also occurred. In 40 to 45 sessions the conditioned suppression of food-lever response rate and the conditioned autonomic changes were extinguished by presenting pairings of a tone and saline injection. The monkeys were then reconditioned by presenting the tone aperiodically, every third or fourth session, 5 min before and after the intravenous injection of nalorphine. Results were similar to the initial conditioning sessions. Two rhesus monkeys not dependent on morphine were stabilized on a food schedule similar to that used for the first three monkeys. These monkeys showed no change in food-lever response rate during or after nalorphine injections.

Topics: Animals; Bradycardia; Conditioning, Operant; Extinction, Psychological; Female; Food; Haplorhini; Humans; Male; Morphine Dependence; Nalorphine; Reaction Time; Salivation; Sound; Substance Withdrawal Syndrome; Vomiting

Topics: Animals; Autonomic Nervous System; Behavior, Animal; Central Nervous System; Guinea Pigs; Humans; Morphine; Morphine Dependence; Nalorphine; Pharmacology; Research; Substance Withdrawal Syndrome; Toxicology; Urine

Topics: Animals; Autonomic Nervous System; Behavior, Animal; Central Nervous System; Codeine; Guinea Pigs; Humans; Morphine Dependence; Nalorphine; Pharmacology; Research; Substance Withdrawal Syndrome; Toxicology

Topics: Animals; Drug Tolerance; Ethylamines; Humans; Levallorphan; Meperidine; Mice; Morphine Dependence; Nalorphine; Narcotic Antagonists; Narcotics; Proadifen; Substance Withdrawal Syndrome

Topics: Amines; Animals; Antihypertensive Agents; Central Nervous System; Humans; Mice; Monoamine Oxidase Inhibitors; Morphine Dependence; Nalorphine; Substance Withdrawal Syndrome

Topics: Animals; Codeine; Conditioning, Psychological; Equipment and Supplies; Haplorhini; Injections, Intravenous; Meperidine; Methadone; Morphine Dependence; Nalorphine; Opioid-Related Disorders; Rats; Substance-Related Disorders

Topics: Drug Tolerance; Intestine, Small; Intestines; Morphine; Morphine Dependence; Muscle Cramp; Nalorphine; Pharmacology; Rats; Research

Topics: Body Temperature; Cordotomy; Dogs; Drug Tolerance; Heart Rate; Morphine Dependence; Nalorphine; Neurophysiology; Pharmacology; Physiology; Pulse; Pupil; Reflex; Reflex, Stretch; Research; Respiration; Spinal Cord; Substance Withdrawal Syndrome; Tendons; Toxicology

Topics: Animals; Behavior, Animal; Benzimidazoles; Codeine; Drug Tolerance; Humans; Infusions, Parenteral; Meperidine; Morphine; Morphine Dependence; Nalorphine; Rats; Substance Withdrawal Syndrome

Topics: Behavior, Animal; Behaviorism; Morphine; Morphine Dependence; Nalorphine; Pharmacology; Rats; Research; Toxicology

Topics: Animals; Drug Implants; Mice; Morphine; Morphine Dependence; Nalorphine; Research

Topics: Animals; Drug Tolerance; Immune Tolerance; Levallorphan; Mice; Morphine; Morphine Dependence; Nalorphine; Narcotic Antagonists; Research

2-Dimethylallyl- 5,9-dimethyl-2'-hydroxybenzomorphan (Win 20,228) was found to be a weak antagonist of morphine and meperidine, whereas 2-allyl-5-ethyl-2'- hydroxy-9-methyl-6,7-benzomorphan (Win 19,362) and 2-allyl-2'-hydroxy-5,9- dimethyl-6,7-benzomorphan (Win 19,631) were about three times as potent as nalorphine. Preliminary clinical trials indicate that Win 19,362 is about twice as potent as morphine as an analgesic but, like nalorphine, is capable of producing severe psychic side effects. Win 20,228 is estimated to be about half as active as morphine as an analgesic, but no bizarre psychic effects were reported at any dose tested. Studies of addiction liability with Win 20,228 in monkeys suggest that this compound will not support morphine addiction.

Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Meperidine; Morphine; Morphine Dependence; Nalorphine; Narcotic Antagonists

Topics: Behavior, Addictive; Methadone; Morphine; Morphine Dependence; Nalorphine; Substance-Related Disorders

Topics: Animals; Dogs; Hindlimb; Morphine Dependence; Nalorphine; Reflex