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)

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

Development of physical dependence is observed after treatment with opioid agonists, but not after chronic i.c.v. administration of mixed inhibitors of enkephalin-degrading enzymes. The aim of this study was to investigate further this promising result of repeated administration of the systemically active mixed inhibitor prodrug RB101, N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyldithio]-1-oxopro pyl]- L-phenylalanine benzyl ester. In a comparative study, the naloxone-evoked withdrawal syndrome was quantified in mice chronically treated with i.p. administered morphine or RB101 (6 and 160 mg/kg, respectively) for 5 days, twice daily. After administration of naloxone (5 mg/kg s.c.) on the sixth day, large behavioral changes (jumps, paw shakes, wet-dog shakes, tremor, teeth chattering) and body weight losses occurred in the morphine-treated mice. In contrast, no significant behavioral signs of physical dependence, or body weight changes were observed in the RB101-treated mice. The difference between morphine and RB101 could be partially due to a very low tonic release of enkephalins in the locus coeruleus, a brain region critically involved in the development of physical dependence. These results confirm the potential of mixed inhibitors of enkephalin-degrading enzymes as new non-addictive analgesics.
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PMID:Lack of physical dependence in mice after repeated systemic administration of the mixed inhibitor prodrug of enkephalin-degrading enzymes, RB101. 147 61

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

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.
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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.
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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

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.
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PMID:Physical dependence of a dermorphin tetrapeptide analog, [D-Arg2, Sar4]-dermorphin (1-4) in the rat. 394 63

The effect of chronic morphine treatment on the in vitro biosynthesis of beta-endorphin by rat pars intermedia was investigated. Tolerance and physical dependence were induced in 200 g rats by the subcutaneous implantation of 75 mg morphine pellets for either 3 days or 15 days. Immediately following sacrifice of the animals the neurointermediate lobes were removed and incubated with [3H] phenylalanine. The protein extracts of the lobes were analyzed for the incorporation of the labelled amino acid into total protein, pro-opiomelanocortin, beta-lipotropin (beta-LPH) and beta-endorphin. the biosynthesized products were purified by immunoprecipitation with an antiserum to beta-endorphin. The identity and purity of beta-endorphin were verified by polyacrylamide disc gel electrophoresis with sodium dodecyl sulfate, and microsequencing. The identity of pro-opiomelanocortin (POMC) was verified by peptide mapping of its tryptic digestion products. The results showed that morphine treatment induced a decrease in the incorporation of the radioactive amino acid into total protein, pro-opiomelanocortin, beta-LPH and beta-endorphin. The decrease was more pronounced for the incorporation into beta-LPH and beta-endorphin than into pro-opiomelanocortin and total proteins, suggesting an effect of morphine treatment on the processing of the pro-opiomelanocortin to its final maturation products.
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PMID:Effect of chronic morphine treatment on beta-endorphin biosynthesis by the rat neurointermediate lobe. 626 19

Filippi et al. (1979) have claimed that substitution of cyclohexylalanine for phenylalanine in leucine-enkephalin and its L-Ser3 derivative resulted in synthetic analogs which were non-addicting. We have examined the hexahydro derivative of [D-Met2, Pro-NH2(5)]-enkephalin, a potent analgesic agent, to determine if dependence liability can be separated from short-term opiate actions after hydrogenation of the phenylalanine residue. In contrast to Filippi et al.'s observations, we found that the hexahydro derivative of [D-Met2, Pro-NH2(5)]-enkephalin gives rise to physical dependence and that its short-term potencies generally paralleled its long-term ability to produce physical dependence.
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PMID:Hexahydro derivative of (D-Met2, Pro-NH2(5)]-enkephalin gives rise to physical dependence. 719 91

The aim of this study was to investigate the possible interaction between neuronal cholecystokinin (CCK) and opiate dependence. Rats were made dependent to morphine and the ability of cholecystokinin-octapeptide (CCK-8) and Tyr(SO3H)-gNle-mGly-Trp-(NMe)Nle-Asp-Phe-NH2 (BC 264), a selective agonist of CCK-B receptors, to induce signs of morphine withdrawal after ICV injection was tested. Behavioral responses were compared to those occurring during the naloxone-precipitated morphine withdrawal syndrome. In contrast to naloxone, CCK-8 (0.1, 1, and 10 micrograms, ICV) did not precipitate any sign of withdrawal. BC 264 (0.1, 1, and 10 micrograms, ICV) induced a strong hyperlocomotion and wet dog shakes in morphine-dependent rats, the latter effect also observed in nondependent animals. In rats receiving acute morphine, BC 264 induced an opposite effect (i.e., blockade of morphine-induced hyperactivity). Taken together, these results suggest that CCK plays only a minor role in the expression of morphine physical dependence.
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PMID:Effects induced by BC 264, a selective agonist of CCK-B receptors, on morphine-dependent rats. 809 Aug 2


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