Differences in physical dependence induced by selective mu or delta opioid agonists and by endogenous enkephalins protected by peptidase inhibitors.
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.
Maldonado
R
R
Laboratoire de Pharmacologie, U 266 I.N.S.E.R.M., UA 498 C.N.R.S., Faculté des Sciences, Paris, France.
Feger
J
J
Fournié-Zaluski
M C
MC
Roques
B P
BP
D000818:Animals; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D004361:Drug Tolerance; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007276:Injections, Intraventricular; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D012016:Reference Values; D013375:Substance Withdrawal Syndrome; D019966:Substance-Related Disorders
D004745:Enkephalins; D006877:Hydroxamic Acids; D009842:Oligopeptides; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C061042:3-(N-hydroxycarboxamido-2-benzylpropanoyl)phenylalanine; C054868:tyrosyl-seryl(O-tert-butyl)-glycyl-phenylalanyl-leucyl-threonine; D009270:Naloxone; D010649:Phenylalanine; D015260:Neprilysin