PAIN-SUPPRESSIVE EFFECTS ON VARIOUS NOCICEPTIVE STIMULI (THERMAL, CHEMICAL, ELECTRICAL AND INFLAMMATORY) OF THE FIRST ORALLY-ACTIVE ENKEPHALIN-METABOLIZING ENZYME-INHIBITOR RB-120

RB 101 thyIthio)butyldithio]-1-oxopropyl)-L-phenylalanine benzyl ester ) is a full inhibitor of the enkephalin-catabolizing enzymes, which in duces strong naloxone-reversible antinociceptive responses after i.v. or i.p. administration, but is only slightly active after oral adminis tration. Chemical modifications were introduced on this compound, resu lting in molecules such as RE 120 o-4-methylthio)butyldithio]-1-oxopro pyl)-L-alanine benzyl ester), which was selected for a complete study, after oral administration, in various assays commonly used to select analgesics: mouse hot plate test, rat tail-flick test, electrical stim ulation of the tail in rats, paw pressure test on inflamed paws in rat s, acetic acid-induced writhing test and the formalin test in mice. RE 120 induced potent dose-dependent antinociceptive responses in all th ese tests after oral administration. The differences in antinociceptiv e effects induced by RE 120 in the various assays is probably related to the amount of enkephalins released and to the efficiency of peptida se inactivation in particular brain regions implicated in the control of a given nociceptive input. The goal of discovering orally active an algesics endowed with a potency similar to that of morphine but devoid of its major side-effects, seems now to have been reached with mixed neutral endopeptidase/aminopeptidase N (NEP/APN) inhibitors, although these compounds have yet to be evaluated in clinical trials. (C) 1997 International Association for the Study of Pain. Published by Elsevier Science B.V.