Assessment of physical dependence after continuous perfusion into the rat 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 dependence. Catheters were implanted for chronic i.v. drug administration in rats and connected to an infusion pump. On the fifth day of perfusion, the severity of naloxone (5 mg/kg s.c.)-precipitated withdrawal was evaluated. Large behavioral changes and body weight losses were observed in rats chronically treated with morphine (0.17 mg/120 microliters/h). In contrast, only one withdrawal symptom (tremor) was significant in rats treated with the mixed inhibitor of enkephalin-degrading enzymes, RB 101 (1.20 mg/120 microliters/h). Morphine and RB 101 were perfused at doses which give same analgesic responses 6 h after the start of perfusion. This lack of physical dependence after drastic conditions of administration emphasizes the potential clinical interest of systemically active mixed inhibitors as new analgesics.