Unlike morphine the endogenous enkephalins protected by RB101 are unable to establish a conditioned place preference in mice.

The mixed inhibitor prodrug, RB101, was used to study the motivational properties of the endogenous opioid peptides, the enkephalins. In the conditioned place preference test, which is commonly used to investigate the reinforcing properties of drugs, mice alternately treated with morphine (3 mg/kg i.p.) on the initially non-preferred compartment and with saline on the preferred one, for four place pairings, spent more time in the drug-associated compartment. This shift in place preference after the conditioning procedure was not found after treatment with RB101 (80 mg/kg i.p.). Administration of naloxone (1 mg/kg s.c.) after the conditioning phase increased the preference for the drug-associated compartment of mice treated with 6 mg/kg (i.p.) of morphine. This illustrates the negative motivational properties of morphine withdrawal or the establishment of psychic dependence on the drug. In contrast, no modification of preference was observed after injection of naloxone in animals treated with a high dose of RB101 (160 mg/kg i.p.). The failure to establish conditioned place preference by inhibiting endogenous enkephalin metabolism, and the lack of development of psychic dependence after RB101 administration demonstrate for the first time the interest of mixed inhibitors of enkephalin-degrading enzymes as potent new non-addictive analgesics.