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.