Lack of physical dependence in mice after repeated systemic administration of the mixed inhibitor prodrug of enkephalin-degrading enzymes, RB101.
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.
Noble
F
F
Unité de Pharmacochimie Moléculaire et Structurale, U266 INSERM-URA D 1500 CNRS, Université René Descartes, UFR des Sciences Pharmaceutiques et Biologiques, Paris, France.
Coric
P
P
Fournié-Zaluski
M C
MC
Roques
B P
BP
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004220:Disulfides / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009020:Morphine; D009270:Naloxone / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D019966:Substance-Related Disorders / Q000523:psychology*
D004220:Disulfides; D011355:Prodrugs; C074024:RB 101; D009270:Naloxone; D010649:Phenylalanine; D009020:Morphine