morphinans and Morphine-Dependence

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: 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

The effects of etorphine, a potent morphine-like drug, were qualitatively and quantitatively compared to those of morphine. In nondependent subjects, etorphine in doses of 0.025, 0.050, and 0.100 mg produced pupillary constriction and morphine-like subjective effects and euphoria. Etorphine was 500 times as potent as morphine, with a very rapid onset and short duration of action. In morphine-dependent subjects, etorphine suppressed abstinence but for a shorter period than morphine. These studies indicate that in man etorphine is a morphine-like drug with a high abuse potential.

Topics: Clinical Trials as Topic; Euphoria; Humans; Morphinans; Morphine Dependence; Narcotics; Pentanols; Personality Inventory; Placebos; Pupil; Structure-Activity Relationship; Substance Withdrawal Syndrome; Surveys and Questionnaires; Time Factors

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

Evidence suggests that the dopamine receptor rate-limiting enzyme, tyrosine hydroxylase (TH), and the glutamate receptor, N-methyl-D-aspartate receptor 2B (NR2B), contribute to morphine dependence. Previous studies show that chronic exposure to morphine changes the expression of opioid receptors. In this study, we focus on the effects of sinomenine on morphine-dependent mice and its related neural mechanisms. Conditioned place preference (CPP) mouse model was established using morphine (9 mg/kg, s.c.), and their expression levels of TH and NR2B were observed by immunohistochemistry. Moreover, their mu opioid receptor (MOR) and delta opioid receptor (DOR) contents were assessed using quantitative reverse transcription polymerase chain reaction. Results showed that high sinomenine dose (80 mg/kg) effectively attenuated the behavior of CPP mice and reversed increased expression levels of TH and NR2B induced by morphine. Moreover, compared with the morphine group, sinomenine up-regulated the content of MOR to a normal level but did not significantly affect the DOR expression. In summary, these data indicate that sinomenine can inhibit morphine dependence by increasing the expression levels of TH, NR2B, and MOR in the mouse brain; however, DOR may not contribute to this effect.

Topics: Animals; Brain; Mice; Morphinans; Morphine; Morphine Dependence; Neurons; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Tyrosine 3-Monooxygenase

A series of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3'-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1'- and/or 4'-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6'- and/or 7'-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca(2+) increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6'-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands.

Topics: Animals; CHO Cells; Cricetulus; Drug Design; Humans; Isoquinolines; Ligands; Mice; Molecular Dynamics Simulation; Morphinans; Morphine Dependence; Narcotic Antagonists; Receptors, Opioid, mu; Structure-Activity Relationship

to investigate the effects of ATPM-ET [(-)-3-N-Ethylaminothiazolo [5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] on physical dependence and behavioral sensitization to morphine in mice.. the pharmacological profile of ATPM-ET was characterized using competitive binding and GTPγS binding assays. We then examined the antinociceptive effects of ATPM-ET in the hot plate test. Morphine dependence assay and behavioral sensitization assay were used to determine the effect of ATPM-ET on physical dependence and behavior sensitization to morphine in mice.. the binding assay indicated that ATPM-ET ATPM-ET exhibited a high affinity to both κ- and μ-opioid receptors with K(i) values of 0.15 nmol/L and 4.7 nmol/L, respectively, indicating it was a full κ-opioid receptor agonist and a partial μ-opioid receptor agonist. In the hot plate test, ATPM-ET produced a dose-dependent antinociceptive effect, with an ED(50) value of 2.68 (2.34-3.07) mg/kg. Administration of ATPM-ET (1 and 2 mg/kg, sc) prior to naloxone (3.0 mg/kg, sc) injection significantly inhibited withdrawal jumping of mice. In addition, ATPM-ET (1 and 2 mg/kg, sc) also showed a trend toward decreasing morphine withdrawal-induced weight loss. ATPM-ET (1.5 and 3 mg/kg, sc) 15 min before the morphine challenge significantly inhibited the morphine-induced behavior sensitization (P<0.05).. ATPM-ET may have potential as a therapeutic agent for the treatment of drug abuse.

Topics: Animals; Behavior, Animal; Dose-Response Relationship, Drug; Hot Temperature; Male; Mice; Morphinans; Morphine; Morphine Dependence; Motor Activity; Naloxone; Narcotic Antagonists; Narcotics; Pain Measurement; Receptors, Opioid, kappa; Receptors, Opioid, mu

To observe the effect of alcohol extracts from orientivne and its effective component sinomenine on withdrawal syndromes and neurotransmitter of morphine-abstinent mice and on intracellular calcium level in morphine-dependent neuronal-cells line. To study the detoxification of alcohol extracts from orientvine and sinomenine on morphine-dependent animal and explore the mechanism of its effect.. The effect of alcohol extracts from orientivne and sinomenineon on abstinent syndromes was observed by experiment study on morphine-dependent ex vivo ileum from guinea pigs and morphine-dependent mice. The morphine-dependent model mice were established by injection on dosage increasing by degrees. The hypothalamic monomine neurotransmitters such as NA, DA, 5-HT were tested by fluorospectrophotometry. Morphine-dependent cell line was established by administering morphine at different doses into the culture medium. The cells were stained with fluo-3 and the intracellular calcium level was measured by flow cytometry.. Alcohol extracts from orientvine and sinomenine could alleviate withdrawal contractile response of morphine-dependent ex vivo ileum from guinea pigs and withdrawal syndromes of morphine-dependent mice, decrease the concentration of the neurotransmitters, and elevate the intracellular calcium level and inhibit the decreasing of Ca2+ induced by naloxone.. Alcohol extracts from orientvine and sinomenine have some effects on withdrawal syndromes which may be related to inhibiting neurotransmitters and the regulation of intracellular calcium concentration.

Topics: Animals; Calcium; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Ethanol; Female; Guinea Pigs; Ileum; Male; Mice; Morphinans; Morphine; Morphine Dependence; Muscle Contraction; Neurons; Norepinephrine; Random Allocation; Rats; Rats, Sprague-Dawley; Sinomenium; Substance Withdrawal Syndrome

It has been proposed that on chronic morphine treatment the micro-opioid receptor becomes constitutively active, and as a consequence, the opioid withdrawal response arises from a reduction in the level of this constitutively active receptor. In support of this, the putative micro-opioid receptor inverse agonist naltrexone has been shown to precipitate more severe withdrawal behavior in mice than the putative neutral receptor antagonist 6 beta-naltrexol. In the present study naltrexone and 6 beta-naltrexol were compared in NIH Swiss mice to test the hypothesis that their differential ability to precipitate withdrawal is due to differences in their in vivo opioid receptor antagonist potencies caused by differential access to micro-opioid receptors in the central nervous system and not necessarily by intrinsic differences in their opioid receptor activity. In naïve mice both compounds had similar potencies to antagonize morphine-induced antinociception in the hot plate and warm-water tail-withdrawal assays when measured under equilibrium conditions and afforded similar calculated apparent in vivo micro-opioid receptor affinities. In morphine-dependent mice both compounds precipitated withdrawal jumping but naltrexone was between 10- and 100-fold more potent than 6 beta-naltrexol. A similar potency difference was seen for other withdrawal behaviors. Both naltrexone and 6 beta-naltrexol at 1 mg/kg reversed antinociception induced by the long-lasting micro-opioid receptor agonist BU72 in the warm-water tail-withdrawal assay, but antagonism by naltrexone was 6-fold more rapid in onset at equal doses. Since the compounds have similar affinity for the micro-opioid receptor in vivo, the results suggest that the differences observed between the ability of naltrexone and 6 beta-naltrexol to precipitate withdrawal in the mouse may be explained by differential onset of receptor antagonist action.

Topics: Animals; Binding, Competitive; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred ICR; Morphinans; Morphine; Morphine Dependence; Naltrexone; Narcotic Antagonists; Narcotics; Pain Measurement; Pyrroles; Receptors, Opioid, mu; Substance Withdrawal Syndrome

Topics: Animals; Brain; Male; Mice; Mice, Inbred Strains; Morphinans; Morphine Dependence; Nitric Oxide Synthase Type I

To evaluate the effects of Caulis Sinomenii and sinomenine on conditioned place preference (CPP) induced by morphine and brain histamine level in mice.. Sixty mice were randomized into 6 equal groups and morphine (Mor) was injected subcutaneously (9 mg/kg) for 6 consecutive days to induce CPP using a shuttle box. Since the 4th day of training, the mice in 5 of the groups were treated for 3 consecutive days with Caulis Sinomenii (10 g/kg), sinomenine (60 mg/kg), diphenhydramine (30 mg/kg), CP48/80 (5 mg/kg) and L-histidine (750 mg/kg) in addition to morphine (9 mg/kg) treatment, respectively, leaving the other group with exclusive morphine treatment. Another 10 mice received saline injection to serve as saline control group. The content of histamine (HA) in the mouse brain was measured by fluorospectrophotometry.. In morphine group, the mice showed significantly extended stay in morphine-paired compartment whose HA content in the brain was markedly increased (P<0.01). Treatment with Caulis Sinomenii and sinomenine resulted in significantly reduced time of stay in morphine-paired compartment and brain HA level (P<0.01).. CPP induced by morphine in mice is associated with increased HA level in the brain. Caulis Sinomenii and sinomenine can suppress the acquisition of place preference induced by morphine and modulate HA level in the central nervous system in morphine-dependent mice.

Topics: Animals; Arginine; Brain; Conditioning, Operant; Diphenhydramine; Histamine; Male; Mice; Morphinans; Morphine; Morphine Dependence; Motor Activity; Random Allocation; Sinomenium

To explore the effects of long-term morphine exposure on cAMP and cGMP levels in primary cultured tuberomammillary nucleus (TM) neurons of neonatal rats and the effects of sinomenine on morphine-dependent TM cells.. TM neurons after a 7-day primary culture were further cultured in the medium containing 100 micromol/L morphine for 48 h to prepare the cell model of morphine dependence. Serial doses of histamine or sinomenine were administered 30 min naloxone treatment, the cAMP and cGMP levels of the TM cells were determined by enzyme immunoassay. cAMP and cGMP levels were also determined in normal TM cells treated by histamine or sinomenine.. After treatment with 100 micromol/L morphine for 48 h, cAMP and cGMP levels in the TM neurons were increased markedly. Treatment with 100 micromol/L naloxone added in the culture media caused an overshoot of cellular cAMP and a marked declination of cGMP, resulting in significantly increased cAMP/cGMP ratio. Sinomenine at 30 and 100 micromol/L and histamine at 40 micromol/L failed to obviously affect cAMP and cGMP levels in normal TM neurons, but sinomenine at 300 micromol/L and histamine at 80 micromol/L significantly increased the intracellular cAMP level. After pre-treatment with sinomenine at the above 3 doses or histamine at 40 micromol/L, the TM neurons with morphine dependence exhibited significant reduction in intracellular cAMP level but increment in cGMP level after naloxone treatment, with significantly reduced cAMP/cGMP ratio.. Long-term morphine (100 micromol/L) exposure for 48 h can induce marked changes of cAMP and cGMP levels in the TM neurons. The central histaminergic nervous system may be responsible for the development of morphine dependence and withdrawal. Sinomenine can significantly reduce the cAMP level and enhance cGMP level of morphine-dependent TM neurons precipitated by naloxone, which results in a near-normal ratio of cAMP and cGMP.

Topics: Animals; Animals, Newborn; Cells, Cultured; Cyclic AMP; Cyclic GMP; Female; Histamine; Hypothalamus; Morphinans; Morphine; Morphine Dependence; Neurons; Rats; Rats, Sprague-Dawley

To investigate the effects of sinomenine on morphine withdrawal response and acetylchline (Ach)-induced contracture in isolated guinea pig ileum.. The withdrawal contracture was elicited by subjecting isolated ileum incubated with morphine (3 micromol/L) at 37.5 degrees Celsius for 4 h to naloxone (1 micromol/L) treatment. Sinomenine (10, 50, 250 micromol/L) and nimodipine (Nim, 0.1 micromol/L) were administered 1 min before and after naloxone in morphine-dependent ilea bathed in Krebs solution containing morphine, to observe the changes in the withdrawal contracture of the ileum. The effect of sinomenine (10, 50, 250 micromol/L) on the contracture of untreated ileum in Krebs solution elicited by acetylcholine was also observed.. Naloxone-induced withdrawal contracture or acetylcholine-induced contracture of the ileum was significantly decreased in a dose-dependent manner, indicating that sinomenine can inhibit morphine withdrawal symptoms in guinea pigs.

Topics: Animals; Guinea Pigs; Ileum; Morphinans; Morphine; Morphine Dependence; Muscle Contraction; Naloxone; Nimodipine; Substance Withdrawal Syndrome

Exercise stimulates the release of endogenous opioid peptides and increases nociceptive (i.e. pain) thresholds in both human and animal subjects. During chronic, long-term exercise, sensitivity to the effects of morphine and other mu opioids decreases, leading some investigators to propose that exercise may lead to the development of cross tolerance to exogenously administered opioid agonists.. The purpose of the present investigation was to examine the effects of chronic exercise on sensitivity to mu opioids, and to determine whether these effects can be attributed to the development of opioid tolerance and dependence.. Rats were obtained at weaning and housed singly in standard polycarbonate cages (sedentary) or modified cages equipped with exercise wheels (exercise). After 6 weeks under these conditions, opioids possessing a range of relative efficacy at the mu receptor (morphine, levorphanol, buprenorphine, butorphanol, nalbuphine) were examined in a warm-water tail-withdrawal procedure.. Morphine, levorphanol and buprenorphine produced maximal levels of antinociception in both groups of rats, but all were more potent in sedentary rats than in exercising rats. Butorphanol and nalbuphine produced maximal levels of antinociception in sedentary rats under some conditions in which they failed to produce antinociception in exercising rats. Sensitivity to the effects of buprenorphine was decreased in sedentary rats that were transferred to cages equipped with exercise wheels, and increased in exercising rats that were transferred to sedentary housing conditions. In the latter group, exercise output prior to housing reassignment was positively correlated with increases in sensitivity to buprenorphine following housing reassignment. Naloxone administration precipitated a mild withdrawal syndrome in exercising rats that was not readily apparent in sedentary rats.. These data suggest that chronic exercise leads to the development of mu-opioid tolerance and physical dependence, and that these effects are similar to those produced by chronic opioid administration.

Topics: Animals; Injections, Intraperitoneal; Male; Morphinans; Morphine Dependence; Motor Activity; Narcotics; Nociceptors; Pain Measurement; Rats; Rats, Long-Evans; Receptors, Opioid, mu; Running

To study on the detoxification effect of sinamine in morphine-dependent rats.. Morphine-dependent rats were induced by injecting morphine on dosage increasing by degrees, then treated with medication. The withdrawal symptoms, body weight and NE, DA, 5-HT in the brain were tested.. Sinamine could alleviate withdrawal symptom, reablement body weight, inhibit neurotransmitter in the brain.. Sinamine have effects on morphine-dependent rats which may relate to modulating neurotransmitter.

Topics: Animals; Biogenic Monoamines; Body Weight; Brain; Dopamine; Male; Morphinans; Morphine Dependence; Norepinephrine; Rats; Serotonin; Substance Withdrawal Syndrome

The effects of a novel kappa-opioid receptor agonist, TRK-820, on the development of physical dependence on morphine were investigated in mice in comparison with those of U-50,488H. A marked body weight loss and several withdrawal signs were observed following naloxone challenge in morphine-dependent mice. Co-injection of TRK-820 (0.003-0.03 mg/kg, s.c.) but not U-50,488H (1-10 mg/kg, s.c.) during chronic morphine treatment dose-dependently suppressed the naloxone-precipitated body weight loss, jumping, wet dog shakes and diarrhea. These results suggest that TRK-820-sensitive kappa-opioid receptor subtypes may play a significant role in modulating the development of physical dependence on morphine.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Male; Mice; Morphinans; Morphine Dependence; Receptors, Opioid, kappa; Spiro Compounds

The possible involvement of delta 2 opioid receptors in the development of morphine dependence was investigated using selective delta 2 receptor antagonists, naltriben (NTB) and naltrindole 5'-isothiocyanate (5'-NTII). The degree of morphine dependence was estimated by the ED50 values of naloxone (s.c.) required to precipitate withdrawal jumping and diarrhea 72 hr after morphine pellet implantation. NTB administered s.c. as well as naloxone precipitated jumping and diarrhea in morphine-dependent mice. Chronic treatment with 5'-NTII (both i.c.v. and i.t. routes, 24 hr before, just before, 24 and 48 hr after morphine pellet implantation) increased the ED50 values of naloxone for jumping and diarrhea. These results suggest that both supraspinal and spinal delta 2 opioid receptors are involved in the development of physical dependence on systemically administered morphine. However, chronic treatment with NTB (s.c. route, 30 min before, 24 and 48 hr after morphine pellet implantation) failed to affect the ED50 values of naloxone for both withdrawal signs. These seemingly discrepant results suggest that continuous blockade of delta 2 opioid receptors (by a nonequilibrium and long-lasting antagonist, 5'-NTII) rather than intermittent blockade of delta 2 opioid receptors (by an equilibrium and relatively short-acting antagonist, NTB) is necessary to inhibit the development of morphine dependence.

Topics: Animals; Enkephalin, Leucine; Isothiocyanates; Male; Mice; Morphinans; Morphine Dependence; Naloxone; Naltrexone; Receptors, Opioid, delta; Substance Withdrawal Syndrome; Thiocyanates

Topics: Analgesics; Animals; Indoles; Male; Morphinans; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Weight Loss

Topics: Humans; Morphinans; Morphine; Morphine Dependence; Pain; Receptors, Opioid

Butorphanol precipitated a withdrawal syndrome in rats receiving continuous intracerebroventricular infusions of morphine for three days. However, the potency of butorphanol to induce defecation, urination, teeth chattering and escape behavior was one to two orders of magnitude less on a molar basis than that of naloxone. Wet shake behavior, a prominent feature of naloxone precipitated withdrawal, was absent in morphine dependent animals challenged with butorphanol. These data indicate qualitative as well as quantitative differences in the withdrawal syndromes induced by butorphanol and naloxone.

Topics: Animals; Butorphanol; Dose-Response Relationship, Drug; Male; Morphinans; Morphine Dependence; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

2,5-Dimethyl-2'-hydroxy-9 alpha-(3-methylbutyl)-6,7-benzomorphan, the 9 beta-analogue, and 9 alpha-N-substituted (N-ethyl, propyl, butyl, pentyl, hexyl, phenylethyl, allyl, and cyclopropylmethyl) compounds were synthesized and evaluated biochemically and pharmacologically. The 9 beta N-methyl compound was found to be as potent as morphine in the mouse hot plate assay and had one-seventh the affinity of morphine for the opioid receptor. The N-alkyl and N-phenethyl 9 alpha-substituted compounds were either inactive or relatively ineffective as antinociceptive agents. None of the examined compounds substituted for morphine in single-dose suppression studies in the rhesus monkey. The N-cyclopropylmethyl compound in the 9 alpha series had half the narcotic antagonist potency of nalorphine and one-eighth of its affinity for the opioid receptor. The 9 alpha-(3-methylbutyl) moiety, unlike bulky substituents in the 9 beta position of 6,7-benzomorphans, generally lowers affinity for the mu opioid receptor and diminishes their in vivo activity as agonists or antagonists.

Topics: Analgesics; Animals; Benzomorphans; Brain; Female; In Vitro Techniques; Macaca mulatta; Male; Mice; Morphinans; Morphine Dependence; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, mu

Topics: Animals; Butorphanol; Drug Synergism; Mice; Morphinans; Morphine Dependence; Motor Activity; Nalbuphine; Pentazocine; Tripelennamine

Topics: Animals; Haplorhini; Models, Molecular; Molecular Conformation; Morphinans; Morphine Dependence; Stereoisomerism; Structure-Activity Relationship

The mixed agonist-antagonist analgesics buprenorphine, butorphanol, nalbuphine, pentazocine and picenadol were compared to the prototype mu and kappa agonists morphine and Mr 2033, respectively, in the following tests in rhesus monkeys: overt behavioral effects upon acute administration in drug-naive animals; discriminative stimulus properties in monkeys trained to respond to either etorphine or ethylketazocine; self-administration of the test agent relative to codeine; single dose suppression and precipitation in withdrawn and non-withdrawn morphine-dependent monkeys, respectively; and primary addiction studies in drug-naive animals. Whereas both buprenorphine and nalbuphine precipitate withdrawal in morphine-dependent monkeys, withdrawal following chronic administration of buprenorphine resulted in no observable signs of abstinence, while nalbuphine withdrawal was similar to that seen in morphine-dependent monkeys. Butorphanol, pentazocine and picenadol all produced mild dependence of the kappa-type; that is, natural withdrawal behavior similar to that seen following chronic Mr 2033 administration.

Topics: Animals; Behavior, Animal; Benzomorphans; Buprenorphine; Butorphanol; Codeine; Discrimination, Psychological; Humans; Macaca mulatta; Morphinans; Morphine; Morphine Dependence; Nalbuphine; Narcotic Antagonists; Pentazocine; Piperidines; Substance Withdrawal Syndrome

Opioid agonist and antagonist properties of diastereoisomeric N-Tetrahydrofurfurylnoroxymorphones, Mr 2096 and Mr 2097 were examined in mice using the hot plate and tail flick tests and on acute dependence. Subcutaneous administrations of Mr 2096, the agonist diastereoisomer and Mr 2097, the antagonist diastereoisomer respectively produced analgesia and hyperalgesia in these tests, confirming the involvement of stereoselective opioid receptors in the regulation of thermonociception. Intracerebroventricular injection of Mr 2096 prolonged the tail flick latency, but that of Mr 2097 was without effect. The analgesic effect of Mr 2096 might be due to mimicking the descending inhibition of nociception and suppression of nociceptive reflexes at the level of spinal cord. The absence of hyperalgesia in the tail flick test following the central administration of Mr 2097 might arise from a rapid fall in concentration at relevant receptor sites and/or absence of a significant effect on the spinal reflex. In mice acutely dependent on morphine, Mr 2096 did not precipitate withdrawal. Mr 2097 behaved as an antagonist, precipitating withdrawal. These experiments indicate that stereoselective opioid receptors are involved in acute withdrawal syndrome. This study further confirms the importance of the steric properties of N-substituted moieties in Tetrahydrofurfurylnoroxymorphones.

Topics: Animals; Behavior, Animal; Humans; Injections, Intraventricular; Male; Mice; Morphinans; Morphine Dependence; Narcotic Antagonists; Narcotics; Reaction Time; Stereoisomerism; Substance Withdrawal Syndrome

The ability of four opiate partial agonists (buprenorphine, xorphanol, nalbuphine and butorphanol) to produce antinociception and morphine-like physical dependence was examined in the rat. For comparative purposes, morphine was also tested. Dose-response curves were constructed using the rat tail pressure test for analgesia which indicated a rank order of potency of buprenorphine much greater than morphine greater than butorphanol greater than xorphanol = nalbuphine. Assessment of primary physical dependence liability was made using the technique of chronic intraperitoneal infusion followed by precipitation of abstinence with the opiate antagonist, naloxone. The results clearly indicate that buprenorphine was not only the most potent antinociceptive agent, but also possessed the lowest incidence of physical dependence as indicated by precipitated abstinence signs. The other opiates were very much weaker as antinociceptive agents and all produced clear signs of physical dependence.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Butorphanol; Humans; Male; Morphinans; Morphine; Morphine Dependence; Nalbuphine; Nociceptors; Rats; Rats, Inbred Strains

Topics: Analgesics; Animals; Etorphine; Female; Humans; Macaca mulatta; Male; Mice; Morphinans; Morphine Dependence; Opioid-Related Disorders; Substance Withdrawal Syndrome

The purpose of the study was to define possible self-administration of nalbuphine, butorphanol and pentazocine by morphine post-addict rats. Rats were prepared with permanent EEG and EMG electrodes and indwelling IV cannulae, made tolerant to and physically dependent on morphine, then trained to lever press for morphine IV self-injections on a fixed ratio (FR) 20 schedule of reinforcement. Rats were then spontaneously withdrawn from morphine. When these morphine post-addict rats were returned to the experimental cages three to four weeks later, they were found to reestablish self-administration of morphine as well as to establish self-administration of nalbuphine, butorphanol and pentazocine. Suppression of REM sleep for at least 30 min was apparent following self-injections of these agents. After the stabilization of self-injection patterns, withdrawal from nalbuphine and pentazocine was found to be associated with intense abstinence symptoms. However, withdrawal from morphine and butorphanol was not. It can be concluded that while drug-seeking behavior for the above narcotics in morphine post-addict rats was analogous as measured by self-administration, nalbuphine and butorphanol appeared to produce lower levels of physical dependence.

Topics: Animals; Butorphanol; Female; Humans; Morphinans; Morphine; Morphine Dependence; Nalbuphine; Pentazocine; Rats; Rats, Inbred Strains; Self Administration; Sleep, REM; 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

Topics: Buprenorphine; Cyclazocine; Humans; Methadone; Morphinans; Morphine Dependence; Naltrexone

N-Ethyl-, N-(2-fluoroethyl)-, N-(2,2-difluoroethyl)-, and N-(2,2,2-trifluoroethyl)-substituted normeperidine (1b-e) and normetazocine (2b-e) derivatives were prepared. The analgesic activities of the compounds were determined in mice. Opiate receptor binding studies, in the presence and absence of sodium ion, were carried out. The antagonist activities of normetazocine derivatives were studied in monkeys. These were further examined in the isolated guinea pig ileum for relative agonist activity. The pKa values were measured; in vivo agonist acitivty was lost with weakly basic derivatives. For the normetazocine derivatives, opiate receptor binding data were consistent with guinea pig ileum agonist potency and mouse vas deferens antagonist potency but not with in vivo data. Opiate receptor binding was reduced for the less basic normetazocine derivatives. In the normeperidine series, there was no apparent direct relationship between pKa and opiate receptor binding. However, a relationship involving the hydrophobic character of the N-substituent is discussed. The N-(2-fluoroethyl) derivatives in both series were found to cause convulsions in rats at doses of 40-45 mg/kg ip. Elevated serum citrate levels were found in these rats, implicating in vivo oxidative deamination of the N-(fluoroalkyl) substituent to fluoroacetate.

Topics: Analgesics, Opioid; Animals; Benzomorphans; Guinea Pigs; Haplorhini; Humans; Male; Meperidine; Mice; Morphinans; Morphine Dependence; Narcotic Antagonists; Rats; Receptors, Opioid; Seizures; Structure-Activity Relationship; 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

The N-(2-cyanoethyl)-9alpha-ethyl-5-methyl-6,7-benzomorphan (1c) is a more potent antinociceptive and has stronger receptor binding affinity than its N-methyl analogue 1b. The N-(2-cyanoethyl)-4-phenylpiperidine compounds 2b and 3b were almost inactive compared to their N-methyl congeners 2a and 3a, respectively. It appears that the pharmacological effect of the N-(2-cyanoethyl) moiety is dependent on the opioid on which it is substituted.

Topics: Analgesics; Animals; Benzomorphans; Binding, Competitive; Brain; Dihydromorphine; Haplorhini; Humans; In Vitro Techniques; Macaca mulatta; Meperidine; Mice; Morphinans; Morphine Dependence; Nitriles; Piperidines; Rats; Structure-Activity Relationship

Topics: Analgesics; Animals; Brain; Drug Tolerance; Etorphine; Humans; Male; Morphinans; Morphine Dependence; Opioid-Related Disorders; Rats; Sulfobromophthalein; Time Factors; Tissue Distribution

1. Buprenorphine is a highly lipophilic derivative of oripavine. In rodent antinociceptive assays (writhing, tail pressure), buprenorphine had an action which was rapid in onset and of long duration; it was 25-40 times more potent than morphine after parenteral injection and 7-10 times more potent after oral administration. 2. The log dose-response relationship for buprenorphine was curvilinear in mouse and rat tail flick tests with the antinociceptive effect decreasing at higher, non-toxic doses. 3. Tolerance developed to the antinociceptive activity of buprenorphine in mice. 4. No signs of abstinence were observed on naloxone challenge or after abrupt withdrawal in monkeys receiving buprenorphine chronically for one month. 5. Buprenorphine antagonized the antinociceptive actions of morphine in mouse and rat tail flick tests but was an ineffective antagonist in the rat tail pressure test. 6. Buprenorphine precipitated signs of abstinence in morphine-dependent mice and monkeys but not in morphine-dependent rats. 7. Buprenorphine produced Straub tails in mice. This effect was not antagonized when the animals were pretreated with naloxone. However, in the rat tail pressure test high doses of diprenorphine antagonized established antinociceptive effects of buprenorphine. 8. It is concluded that buprenorphine represents a definite advance in the search for a narcotic antagonist analgesic of low physical dependence potential.

Topics: Analgesics; Animals; Catalepsy; Drug Tolerance; Erythrocebus patas; Haplorhini; Humans; Male; Mice; Mice, Inbred Strains; Morphinans; Morphine Dependence; Narcotic Antagonists; Papio; Rats; Reaction Time; Substance-Related Disorders

2,9alpha-Dimethyl-2'-hydroxy-6,7-benzomorphan (14) has been synthesized in six to seven steps from trans-3,4-dihydro-4-(2-dimethylaminoethyl)-6-methoxy-3-methyl-1(2H)-naphthalenone (1). The key reaction of the sequence was mercuric acetate cyclization of trans-1,2-dihydro-1-(2-methylaminoethyl)-7-methoxy-2-methylnaphthalene (8) which gave a mixture of 9alpha-methyl-8alpha-hydroxy-6,7-benzomorphan (9, 49%), the corresponding acetate (10, 13%), and the 9beta-methyl-8alpha-hydroxy-6,7-benzomorphan (11, 5%). In the presence of Et3N, the yields were 16, 37, and 0%, respectively. Structural assignments are based on ir, NMR, and mass spectral data and on chemical conversions.

Topics: Analgesics; Animals; Benzomorphans; Haplorhini; Humans; Male; Mice; Molecular Conformation; Morphinans; Morphine Dependence; Reaction Time; Stereoisomerism; Structure-Activity Relationship; Substance Withdrawal Syndrome

The levo and dextro isomers of 2,5-dimethyl-2'-hydroxy-9alpha- and -9beta-propyl-6,7-benzomorphans have been prepared. The analgesic potency and physical dependence capacity of the optical isomers and their racemic parents were determined. The 9alpha-propyl levo isomer was analgesically equipotent with morphine; the 9beta-propyl levo isomer was considerably more potent subcutaneously and equipotent orally. None of the optical isomers suppressed the withdrawal syndrome; the 9beta-propyl levo isomer exacerbated the withdrawal syndrome.

Topics: Analgesics; Animals; Benzomorphans; Haplorhini; Humans; Mice; Morphinans; Morphine Dependence; Optical Rotation; Stereoisomerism; Substance-Related Disorders

Abstinence signs were precipitated in rats by naloxone (1 mg - kg-1 s.c.) injected at various times (from 1.5 to 16 h) after a single dose of morphine hydrochloride (15 or 50 mg - kg-1 s.c.) administered in aqueous solution. Increasing the dose of morphine increased the latency of the phenomena and the duration of the underlying state; "shifts" of signs as described by Bläsig et al. (1974) in chronically morphinized rats also occurred when increasing the dose of morphine and the time interval between the injections of morphine and of naloxone. Naltrexone and diprenorphine were also effective. These three antagonists, given before morphine, were able to prevent precipitated abstinence: however, naloxone was almost ineffective when the higher dose of morphine was used and when the time interval was long. In these latter conditions, naltrexone was definitely more effective and longer acting and diprenorphine still more so. The same characteristics were found for the protective action of the three antagonists in acutely morphinized mice and the same order for their potencies in precipitating abstinence in acutely morphinized mice. Like naloxone, naltrexone and diprenorphine facilitated a nociceptive reaction in normal mice. The abstinence signs precipitated in acutely morphinized rats or mice are probably not unmasked excitatory effects of morphine as such effects should have been increased rather than inhibited by previous administration of specific antagonists; they might correspond to potentiated effects of the antagonists themselves. The prevention by specific antagonists of the abstinence syndrome is most simply interpreted by antagonism (direct or indirect) of dependence induction, but other interpretations are not excluded.

Topics: Animals; Diprenorphine; Humans; Male; Mice; Morphinans; Morphine; Morphine Dependence; Naloxone; Naltrexone; Rats; Substance Withdrawal Syndrome; Time Factors

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

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

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

2,9beta-Dimethyl-2'-hydroxy-6,7-benzomorphan (18) has been synthesized from m-methoxyphenylacetone (6a) or m-methoxyphenylacetonitrile (1) via bromo-alpha-tetralone (10). Isomeric bromo-alpha-tetralone 9, instead of undergoing cyclization to a 6,7-benzomorphan, gave aromatization product 12. The structures and stereochemical assignments of 9, 10 (and thus 7 and 8), and 18 follow from analogy and from NMR data of 9, 10, 17, and 18. Compound 18 and the deoxy analog 16 are as potent as morphine and codeine, respectively, as analgetics (mice) and are without physical dependence capacity (monkeys).

Topics: Analgesics; Animals; Benzomorphans; Haplorhini; Hot Temperature; Humans; Macaca mulatta; Magnetic Resonance Spectroscopy; Morphinans; Morphine Dependence; Reaction Time; Stereoisomerism; Substance-Related Disorders

Topics: Animals; Binding Sites; Binding, Competitive; Brain; Drug Tolerance; Female; Humans; Hydromorphone; In Vitro Techniques; Male; Morphinans; Morphine; Morphine Dependence; Naloxone; Physostigmine; Rats; Receptors, Drug; Tritium

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; Depression, Chemical; Dextromethorphan; Drug Interactions; Drug Tolerance; Glutamates; Humans; Iontophoresis; Male; Microinjections; Morphinans; Morphine; Morphine Dependence; Motor Cortex; Naloxone; Neurons; Rats; Somatosensory Cortex; Stimulation, Chemical

Topics: Animals; Behavior, Animal; Columbidae; Cyclopropanes; Dose-Response Relationship, Drug; Humans; Male; Morphinans; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Reinforcement Schedule; Time Factors

Topics: Animals; Behavior, Animal; Body Temperature; Body Weight; Dogs; Dose-Response Relationship, Drug; Haloperidol; Hot Temperature; Humans; Morphinans; Morphine; Morphine Dependence; Naloxone; Propranolol; Pulse; Pupil; Reflex; Respiration; Skin; Substance Withdrawal Syndrome; Time Factors

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

Topics: Analgesics; Animals; Antitussive Agents; Codeine; Cyclazocine; Dextromethorphan; Dogs; Electric Stimulation; Guinea Pigs; Heroin; Humans; Hydroxylation; In Vitro Techniques; Mice; Morphinans; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Rats; Trachea

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: Aspirin; Drug Combinations; Drug Synergism; Humans; Morphinans; Morphine Dependence; Substance-Related Disorders

Topics: Adult; Alkaloids; Chromatography, Gas; Chromatography, Thin Layer; Codeine; Heroin; Humans; Mass Spectrometry; Morphinans; Morphine; Morphine Dependence; Noscapine; Opium; Papaverine; Thebaine

Topics: Adolescent; Adult; Female; Follow-Up Studies; Humans; Male; Morphinans; Morphine; Morphine Dependence; Socioeconomic Factors; Sweden; Unemployment

Topics: Chromosome Aberrations; Chromosome Disorders; Female; Humans; Infant, Newborn; Lysergic Acid Diethylamide; Morphinans; Morphine Dependence; Substance-Related Disorders

Naloxone hydrochloride, an opioid antagonist, was applied to several discrete brain regions of morphine-dependent rats to precipitate abstinence. Severe withdrawal signs were elicited after administration in the thalamus but not in neocortical, hippocampal, hypothalamic, or tegmental areas of the brain.

Topics: Animals; Brain; Cerebral Cortex; Diencephalon; Hippocampus; Humans; Hypothalamus; Male; Mesencephalon; Morphinans; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Rats; Stereotaxic Techniques; Substance Withdrawal Syndrome; Thalamus

Topics: Chemical Phenomena; Chemistry; Hallucinogens; Humans; Lysergic Acid Diethylamide; Meperidine; Methadone; Morphinans; Morphine Dependence; Pentazocine; Substance-Related Disorders

Topics: Denmark; Humans; Morphinans; Morphine Dependence

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

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

Topics: American Medical Association; Female; Health Education; Heroin; Humans; Legislation, Drug; Methadone; Morphinans; Morphine; Morphine Dependence; Pain; Personality; Pregnancy; Pregnancy Complications; Socioeconomic Factors; Substance Withdrawal Syndrome; United States

Topics: Allyl Compounds; Carbamates; Cyclazocine; Ethers, Cyclic; Humans; Male; Methadone; Morphinans; Morphine Dependence; Narcotic Antagonists; Substance Withdrawal Syndrome; Time Factors; Tranquilizing Agents

Topics: Analgesics; Azocines; Cyclazocine; Evaluation Studies as Topic; Heroin; Hospitalization; Hospitals, General; Hospitals, Teaching; Humans; Methadone; Morphinans; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; New York City; Outpatient Clinics, Hospital; Psychotherapy; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Brain; Brain Chemistry; Chlorine; Drug Tolerance; Humans; Hydroxyindoleacetic Acid; Male; Mice; Morphinans; Morphine; Morphine Dependence; Narcotic Antagonists; Pargyline; Phenylalanine; Placebos; Serotonin; Sodium Chloride; Substance Withdrawal Syndrome

Topics: Animals; Behavior, Animal; Caffeine; Catheterization; Chlorpromazine; Cocaine; Codeine; Dextroamphetamine; Ethanol; Haplorhini; Humans; Mescaline; Morphinans; Morphine; Morphine Dependence; Pentobarbital; Substance-Related Disorders

Topics: Allyl Compounds; Animals; Body Weight; Brain; Carbon Isotopes; Chromatography, Thin Layer; Cycloheximide; Drug Tolerance; Ethers, Cyclic; Female; Humans; Injections, Intraperitoneal; Injections, Intravenous; Injections, Subcutaneous; Kidney; Liver; Male; Mice; Morphinans; Morphine; Morphine Dependence; Pargyline; Serotonin; Time Factors