Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic administration of ethanol to mice by inhalation for 10 days produced physical dependence demonstrated by a characteristic syndrome of withdrawal. Free amino acid concentrations in whole brain were measured at intervals during the induction of dependence and during withdrawal. During the induction of dependence there was an initial increase in brain glycine, a sustained increase in brain tyrosine and reductions in brain GABA and proline. Serine and isoleucine concentrations were consistently reduced during the induction of dependence, but this change was not significant (P less than 0-05) at any single time interval studied. After the withdrawal of ethanol only the reductions in GABA and proline persisted during the withdrawal syndrome. In addition to these changes an increase in brain glycine concentration was observed during the ethanol withdrawal syndrome. In an attempt to discriminate between the immediate, metabolic effects of ethanol on central amino acid concentrations and those changes associated with the induction of ethanol dependence, the results were compared with those obtained when mice were exposed to a high concentration of ethanol vapour for 3 h. Although this produced similar blood ethanol concentrations, no evidence of physical dependence was observed. The changes in central amino acid concentrations differed from those seen during the induction of dependence in that no change in isoleucine concentration occurred, and that the reduced concentrations of GABA and proline very rapidly reverted to control values when ethanol was removed. The possible role of central amino acids in ethanol dependence is discussed.
 ...
PMID:Concentrations of free amino acids in brains of mice during the induction of physical dependence on ethanol and during the ethanol withdrawal syndrome. 55 41

This study investigated the antinociceptive properties of two alkylating derivatives of morphinone, 14 beta-(thioglycolamido)-7,8- dihydromorphinone (TAMO) and 14 beta-(bromoacetamido)-7,8-dihydromorphinone (H2BAMO) in the mouse tail-flick assay. Intracerebroventricular administration of either TAMO or H2BAMO produced short-term antinociception. Both TAMO and H2BAMO were 11.6-fold more potent than an i.c.v. administration of morphine. These effects were antagonized by the mu-selective antagonist, beta-funaltrexamine, but not by the delta-selective antagonist, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH. TAMO pretreatment from 8 to 48 hr produced a time-related, dose-dependent antagonism of morphine-induced antinociception without showing any agonistic effect. Pretreatment with TAMO for 24 hr antagonized antinociception produced by both H2BAMO and morphine, as well as TAMO itself, but not that of the delta-selective agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) or U50,488, a kappa-selective agonist. In order to distinguish this antagonistic effect from cross-tolerance between TAMO and morphine, two mu agonists, [D-Ala2,N(Me)Phe4,Gly-ol]enkephalin (DAMGO) and H2BAMO, were chosen for comparison. A single i.c.v. pretreatment of DAMGO or H2BAMO, at a dose that had equivalent analgesic effects as TAMO, attenuated morphine-induced antinociception, reaching a maximal effect at the time of the disappearance of agonistic effects of DAMGO and H2BAMO and lasting up to 24 hr. Additionally, a 16-hr pretreatment with TAMO, but not DAMGO or H2BAMO, reduced the development of physical dependence to morphine at 24 hr after morphine pellet implantation. Therefore, this study demonstrated that both TAMO and H2BAMO act as mu opioid agonists to produce short-term antinociception.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Antinociceptive properties of two alkylating derivatives of morphinone: 14 beta-(thioglycolamido)-7,8-dihydromorphinone (TAMO) and 14 beta-(bromoacetamido)-7,8-dihydromorphinone (H2BAMO). 138 79

The novel enkephalin analog Tyr-D-Met (O)-Gly-EtPhe-NHNHCOCH3 . AcOH (EK-399) was examined for psychic dependence potential by a self-administration test in rats. Five groups of experimentally naive rats were given an intravenous dose of EK-399 (0.032, 0.064 or 0.125 mg/kg), morphine HCl (0.5 mg/kg) or cocaine HCl (0.5 mg/kg) via a cannula implanted in the jugular vein when they pressed a lever. No animals initiated self-administration of EK-399 in the first 3 or 4 weeks of the experimental period. In contrast, almost all of the animals receiving morphine or cocaine initiated a high rate of self-administration within 1 or 2 weeks. However, when the doses of EK-399 were subsequently decreased, 4 of the 10 animals increased their rate of self-administration slightly. Furthermore, an increase in the rate of EK-399 self-administration was observed in 1 of 4 rats made physically dependent on EK-399. These results suggest that EK-399 has a very weak reinforcing effect on drug-taking behavior, which is slightly enhanced by the development of physical dependence on the compound, and it may possess a low psychic dependence potential.
 ...
PMID:Intravenous self-administration of an enkephalin analog, EK-399, by rats. 188 74

The aim of the present study was to investigate if a physical dependence could be induced by chronic activation of the endogenous enkephalinergic system. We have therefore evaluated naloxone-induced withdrawal syndrome in rats after central infusion during 7 days of comparable antinociceptive doses of RB 38 A ((R,S)HONH-CO-CH2-CH(CH2C6H5)-CONH-CH(CH2C6H5)-COOH), a mixed enkephalin catabolism blocker and of the selective mu, DAGO (Tyr-D-Ala-Gly-(Me)Phe-Gly-ol) and delta, DSTBULET (Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr), opioid agonists. The responses were compared to those induced by RB 38 B ((S,S)HONH-CO-CH2-CH(CH2C6H5)-CONH-CH(CH2C6H5)-COOH), a selective inhibitor of the 24.11 neutral endopeptidase (NEP) 'enkephalinase'. DAGO induced a severe withdrawal syndrome evidenced by a large weight loss, hypothermia, jumping, mastication, teeth chattering, diarrhoea, lacrimation and salivation. In contrast, DSTBULET and RB 38 A produced only a moderate physical dependence. Only two signs were statistically different in these two groups: wet dog shakes and temperature. Chronic i.c.v. administration of DAGO, DSTBULET and RB 38 A produced a time-dependent reduction in analgesia, but 120 h after continuous infusion only RB 38 A was able to still induce a significative antinociceptive effect. The present data suggest that even in the drastic conditions used here long-term complete inhibition of enkephalin catabolism induces a weak tolerance and a moderate physical dependence, similar to that produced by delta opioid agonists. This effect was not observed after chronic selective inhibition of NEP by RB 38 B.
 ...
PMID:Differences in physical dependence induced by selective mu or delta opioid agonists and by endogenous enkephalins protected by peptidase inhibitors. 216 53

The physical dependence potential of Tyr-D-Met(O)-Gly-EtPhe-NHNHCOCH3.AcOH (EK-399), a novel enkephalin analog with a potent analgesic effect, was assessed in rats. The animals were given EK-399 (0.008, 0.032, 0.125, or 0.5 mg/kg), morphine (0.125, 0.5, or 2 mg/kg), pethidine (2 or 8 mg/kg), or pentazocine (2 or 8 mg/kg) every hour through an implanted intravenous cannula. After 3 days of treatment, precipitated withdrawal tests were conducted: naloxone (5 mg/kg) was administered subcutaneously. Rats treated with morphine showed withdrawal signs such as hyperirritability, salivation, diarrhea, and weight loss. Rats treated with pethidine, pentazocine, or EK-399 showed similar signs, but they were less evident than those in morphine-treated rats. In abrupt withdrawal tests after 7 days of treatment, rats treated with morphine, pethidine, or pentazocine showed weight loss, whereas rats treated with EK-399 showed little or no weight loss. In substitution tests, EK-399 suppressed the withdrawal signs in morphine-dependent rats, and vice versa. These results show that EK-399 has a morphine-like physical dependence potential that is weaker than that of morphine, pethidine, or pentazocine in rats.
 ...
PMID:Physical dependence potential of an enkephalin analog, EK-399, in rats. 221 69

Development of morphine-like physical dependence of the [D-Arg2, beta-Ala4]-dermorphin tetrapeptide (H-Tyr-D-Arg-Phe-beta-Ala-OH) has been evaluated and compared with the physical dependence liability of morphine or pentazocine. Degree of the physical dependence was assessed by the naloxone-precipitated jumping behaviour in mice after treatment of a single dose of each compound. The number of jumps and the time of latency to first jump were recorded in this experiment. Number of jumps in a group pretreated with the peptide showed less than that in morphine-treated group. In addition, latency to the appearance of the first jump in the peptide-treated mice was later than that in the morphine-treated group. The present results indicate that the physical dependence induced by [D-Arg2, beta-Ala4]-dermorphin tetrapeptide may be less marked than that produced by morphine. It is also interesting to note that the antinociceptive effect of this opioid peptide is more powerful and of longer duration than that induced by morphine or pentazocine.
 ...
PMID:A new class opioid peptide, [D-Arg2, beta-Ala4]-dermorphin tetrapeptide; physical dependence liability in mice. 256 74

1. The antinociceptive effects of [D-Arg2] dermorphin tetrapeptide analogues, H-Tyr-D-Arg-Phe-Gly-NH2 and H-Tyr-D-Arg-Phe-beta-Ala-OH when administered subcutaneously (s.c.) in rats were measured by the tail-flick test. In addition, the appearance of typical withdrawal signs upon cessation of administration or on subsequent treatment with naloxone were measured after chronic administration of either peptide or morphine. 2. The dose of peptides and of morphine in the physical dependence test was determined from the AD50 to inhibit the tail-flick test in rats. Doses from 4 to 64 times the AD50 doses were employed in the s.c. administration schedules. 3. The intensity of the antinociception induced by either peptide was greater than that produced by morphine. Moreover, the antinociception induced by the peptides was of much longer duration than that produced by morphine. 4. Abrupt withdrawal after chronic administration of either peptide produced only slight loss of body weight. In contrast, morphine withdrawal produced sharp loss of body weight. 5. Naloxone precipitated withdrawal signs after chronic administration of either peptide were less intense than those after chronic morphine. 6. These results suggest that the antinociception produced by these peptides is more intense and of longer duration than that produced by morphine. It is also interesting to note that the physical dependence produced by these peptides is less marked than that produced by morphine.
 ...
PMID:Antinociception and physical dependence produced by [D-Arg2] dermorphin tetrapeptide analogues and morphine in rats. 290 1

Racemates and enantiomers of 1-substituted 4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine derivatives (3-18) were synthesized, and their analgesic and other pharmacological activities and structure-activity relationships were investigated. The S-(+) enantiomers of 2a, 5, 7, 9, 10, and 15-18 had a stronger analgesic activity than their R-(-) enantiomers; analgesic activity of the strongest one [(S)-(+)-10] was 105 times as potent as that of morphine. The S-(+) enantiomers of these compounds had the opposite configuration to that of morphine with respect to its (C-9) asymmetric center but the same configuration to that of the tyrosine residue of Met5-enkephalin. The R-(-) enantiomers of 16 and 18 showed narcotic antagonist activity, but the S-(+) enantiomers did not. (R)-(-)-18 had analgesic and narcotic antagonist activities comparable to pentazocine but showed no significant physical dependence liability. From these results, it is suggested that these compounds show an uncommon enantioselectivity in comparison with morphine and its surrogates, and belong to a new series of compounds having a potent analgesic activity.
 ...
PMID:Synthesis and structure-activity relationships of 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives having narcotic agonist and antagonist activity. 365 54

The effect of D-Phenylalanine (D-Phe), putative carboxypeptidase A inhibitor and its four derivatives (T1-T4) on analgesia, development of tolerance and physical dependence to morphine, and on degradation of both exogenous and endogenous enkephalins was investigated. Systemic administration of either D-Phe or its derivatives produced naloxone-reversible analgesia in the hot-plate test in mice. Naloxone-precipitated morphine withdrawal syndrome was attenuated in mice after systemic subacute administration (7 days, 1.2 mmol/kg, sc) of D-phe derivatives, the development of tolerance to morphine being unchanged. In the presence of either D-Phe or its derivatives in incubation mixture (up to 10(-3) mol/l) the hydrolysis of exogenous 3H-Met5-and 3H-Leu5-enkephalin in striatal homogenates was slightly inhibited. Moreover, the addition of D-Phe or its derivatives seemed to increase the per cent of recovered endogenous Met5-enkephalin released from veratridine-depolarized striatal particles. In contrast, bestatin, an amino-peptidase inhibitor, and a mixture of dipeptides (Tyr-Tyr, Leu-Leu, Leu-Gly) markedly inhibited degradation of both endogenous and exogenous enkephalins in vitro. The results obtained in this study suggest that that pharmacological activity of D-Phe is not directly related to the endogenous opiate system.
 ...
PMID:The effects of D-phenylalanine and its derivatives on enkephalin degradation in vitro: relation to analgesia and attenuation of the morphine withdrawal syndrome. 376 85

The characteristics of an analog of tetrapeptide dermorphin (H-Tyr-D-Arg-Phe-Sar-OH), [D-Arg2, Sar4]-dermorphin (1-4) were examined in comparison with morphine by the appearance of typical withdrawal signs upon cessation of administration or treatment with naloxone, an opioid antagonist. The dose of [D-Arg2, Sar4]-dermorphin (1-4) or morphine in the physical dependence test can be quantified by determining the ED50 to inhibit the tail-flick response to thermal stimuli. Doses from 8 to 64 times the ED50 doses were employed in the subcutaneous injection schedules. The cessation of [D-Arg2, Sar4]-dermorphin (1-4) or naloxone treatment was largely without effect on body weight, in contrast to a marked loss of weight in morphine-dependent rats. The tetrapeptide failed to substitute for morphine in morphine-dependent rats. The physical dependence of [D-Arg2, Sar4]-dermorphin (1-4) was revealed by the behavioral signs of withdrawal precipitated by naloxone. However, the scores of lacrimation, diarrhea and urination were much lower in chronically tetrapeptide-treated rats than in morphine-treated rats, though the score of teeth chatter was higher. These findings indicate that [D-Arg2, Sar4]-dermorphin (1-4) may differ from morphine in physical dependence.
 ...
PMID:Physical dependence of a dermorphin tetrapeptide analog, [D-Arg2, Sar4]-dermorphin (1-4) in the rat. 394 63


1 2 3 Next >>