ASSESSMENT OF PHYSICAL-DEPENDENCE AFTER CONTINUOUS PERFUSION INTO THERAT JUGULAR-VEIN OF THE MIXED INHIBITOR OF ENKEPHALIN-DEGRADING ENZYMES, RB-101

We investigated if continuous activation of opioid receptors by their endogenous ligands could lead to the development of physical dependenc e. Catheters were implanted for chronic i.v. drug administration in ra ts and connected to an infusion pump. On the fifth day of perfusion, t he severity of naloxone (5 mg/kg s.c.)-precipitated withdrawal was eva luated. Large behavioral changes and body weight losses were observed in rats chronically treated with morphine (0.17 mg/120 mu l/h). In con trast, only one withdrawal symptom (tremor) was significant in rats tr eated with the mixed inhibitor of enkephalin-degrading enzymes, RB 101 (1.20 mg/120 mu l/h). Morphine and RB 101 were perfused at doses whic h give same analgesic responses 6 h after the start of perfusion. This lack of physical dependence after drastic conditions of administratio n emphasizes the potential clinical interest of systemically active mi xed inhibitors as new analgesics.