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

Pro-Leu-Gly-NH2 (MIF) and several structural analogues, all injected in 50-microgram doses daily in mice receiving morphine chronically, were found to prevent development of physical dependence as measured by changes in body temperature associated with naloxone-induced withdrawal. Dose-response studies, using again a protocol of daily injections of peptide at 50, 5, 0.5, 0.05, 0.005 microgram per mouse revealed MIF and cyclo(Leu-Gly) to be the most potent peptides and to be effective in blocking physical dependence to morphine at a dose as low as 0.5 and 0.05 microgram per mouse, respectively. The benzyloxycarbonyl derivative of MIF, Pro-Leu, and Pro- -Leu exhibited significant activities down to a dose of 5 microgram of peptide per mouse.
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PMID:Prolyl-leucyl-glycinamide, cyclo(leucylglycine), and derivatives block development of physical dependence on morphine in mice. 28 70

We have previously reported that the administration of cyclo(Leu-Gly) to mice prior to morphinization blocked the development of tolerance to the analgesic effects of morphine as well as the development of some signs of physical dependence. In the present series of experiments, the effect of the same peptide treatment on changes in dopamine receptor sensitivity induced by chronic morphine treatment were determined. Changes in dopamine receptor sensitivity were determined by measuring (i) the effect of the dopamine agonist apomorphine on locomotor activity and (ii) the hypothermic response to another dopamine agonist, piribedil. Mice that had received the chronic morphine treatment were found to require significantly less apomorphine to produce an increase in locomotor activity, and they exhibited a significantly greater hypothermic response to piribedil than did morphine-naive mice. The injection of 0.2 mumol of cyclo(Leu-Gly) per mouse 2 hr prio to morphine treatment prevented this increased response to both dopamine agonists. Administration of the peptide after the tolerance and dependence had developed did not alter morphine tolerant and dependent states states or the enhanced response to apomorphine or piribedil. It is concluded that dopamine receptor supersensitivity may be involved in the development of narcotic tolerance and physical dependence.
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PMID:Blockage of narcotic-induced dopamine receptor supersensitivity by cyclo(Leu-Gly). 29 96

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)
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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

Rats were trained to lever-press on a multiple-trial, fixed-interval, 3-min schedule of food-reinforcement; each trial consisted of a 10-min time-out and a 9.5-min response period. Naltrexone, injected s.c. prior to each trial, reduced response rates in a dose-related fashion, with an ED50 of 21 mg/kg. Four-hour pretreatment with i.c.v. morphine (3.0-30 micrograms) produced leftward shifts of the naltrexone dose-effect curve of up to 3 orders of magnitude. The selective mu agonist, [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAGO; 0.1-0.3 microgram i.c.v.), sensitized animals to the rate-decreasing effects of naltrexone by more than 2 orders of magnitude. Pretreatment with the selective kappa agonist, dynorphin A-(1-17) (30 micrograms i.c.v.) or the selective delta agonist, [D-Pen2, D-Pen5]enkephalin (DPDPE; 30-100 micrograms i.c.v.) induced moderate sensitization with leftward shifts of 1.0-1.5 log units. Thus, the naltrexone-sensitizing effect of acute opioid pretreatment is centrally mediated, consistent with the hypothesis that the phenomenon is related to the initiation of opioid physical dependence. Further, the effect appears to be mediated predominantly by mu-opioid receptors, because mu agonists consistently produced the largest sensitization to naltrexone.
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PMID:Naltrexone-sensitizing effects of centrally administered morphine and opioid peptides. 167 8

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.
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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.
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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.
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PMID:Physical dependence potential of an enkephalin analog, EK-399, in rats. 221 69

The objective of this study was to describe, quantitate and compare naloxone-induced abstinence syndromes in rats infused centrally (Sylvian aqueduct) with agonists that are currently the most selective for mu [( D-Ala2, MePhe4, Gly-ol5]enkephalin), delta [( D-Pen2, D-Pen5]enkephalin) and kappa (3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide) (U-50,488H) opioid receptors, respectively. Morphine, ethylketazocine and dynorphin A served as reference compounds. After 70 hr of infusion from s.c. implanted osmotic minipumps, three levels of abstinence were associated with the injection of naloxone (3 mg/kg s.c.): 1) negligible syndromes (scores of less than 21) were obtained in rats on water or the kappa-directed ligands, U-50,488H and dynorphin A; 2) a low-to-moderate abstinence score (37-38) was recorded with rats receiving [D-Pen2, D-Pen5]enkephalin and ethylketazocine; and 3) a high abstinence score (64-73) was obtained with rats on morphine and DAGO. These results reinforce the concept of developing selective, nonbenzomorphan kappa agonists as clinically useful analgesics and emphasize that, when evaluating new analgesics, high selectivity for delta receptors does not, in itself, guarantee freedom from physical dependence.
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PMID:Direct dependence studies in rats with agents selective for different types of opioid receptor. 290 90

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.
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PMID:Antinociception and physical dependence produced by [D-Arg2] dermorphin tetrapeptide analogues and morphine in rats. 290 1

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.
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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


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