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)

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 discriminative stimulus properties, reinforcing effects and physical dependence potential of acetorphan, a parenterally-active enkephalinase (E.C. 3.4.21.11) inhibitor, were assessed in the present studies. Rats trained to discriminate 2 mg/kg morphine from saline did not generalize to acetorphan at any dose tested (5-50 mg/kg). Acetorphan also had minimal reinforcing effects in rhesus monkeys. When acetorphan was substituted for cocaine, one dose (300 micrograms/kg per inj.) maintained responding somewhat above the range of vehicle values in only two of the four monkeys tested. In physical dependence studies, acetorphan also failed to produce opioid-like effects. In morphine-dependent monkeys and rats, acetorphan failed to suppress withdrawal. Additionally, there were no overt withdrawal signs observed following the termination of chronic acetorphan infusion in the rat. Together, these results indicate that acetorphan appears to have minimal abuse potential.
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PMID:Assessment of the abuse potential of acetorphan, an enkephalinase inhibitor. 270 24

The effect of the enkephalinase inhibitor phosphoramidon on the withdrawal syndrome following acute and chronic morphine-induced physical dependence in mice, was investigated. Phosphoramidon administered intracerebroventricularly (50-200 micrograms) suppressed significantly the naloxone-precipitated withdrawal jumping and wet dog shakes while forelimb shakes were potentiated in both acute and chronic morphine-dependent mice. It is suggested that increased saturation of the opioid receptors by endogenous opioid peptides following enkephalinase inhibition, might suppress the severity of the withdrawal syndrome.
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PMID:Enkephalinase inhibition suppresses naloxone-induced jumping in morphine-dependent mice. 353 55

Since enkephalins were discovered in 1975, it has become clear that they play an antisecretory role in the gastrointestinal tract. Hence a rational research programme was directed at the development of a drug that would preserve these neurotransmitter peptides in the gut by preventing their inactivation. This research programme has resulted in the development of the enkephalinase inhibitor, racecadotril. Preclinical studies have demonstrated the efficacy of racecadotril in two models of hypersecretory diarrhoea: infusion of cholera toxin and castor oil-induced diarrhoea. Moreover, unlike loperamide, racecadotril did not prolong transit time in the small intestine or colon. Further experiments have shown that racecadotril does not promote bacterial overgrowth in the small intestine. Racecadotril lacks any potential for neurotoxicity, and radiolabelled studies have demonstrated that the drug does not enter the brain after oral administration. No potential for abuse or physical dependence has been seen. It is concluded that racecadotril demonstrates specificity of antisecretory action on the gastrointestinal tract without any adverse effect on gastrointestinal motility, and that the results of the preclinical studies indicate the potential usefulness in the treatment of hypersecretory diarrhoea in man.
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PMID:Racecadotril: a new approach to the treatment of diarrhoea. 1071 5