CENTRAL ADMINISTRATION OF THE OPIOID ANTAGONIST, LY255582, DECREASES SHORT-TERM AND LONG-TERM FOOD-INTAKE IN RATS

A variety of opioid antagonists have been reported to decrease short-term food intake, but few appear to reduce long-term intake. In the present study we evaluated the effect of a relatively new class of opioid antagonists, 3,4-dimethyl-4-phenylpiperidines, on short-term and long-term food intake after central administration. We also evaluated their affinities for the mu and kappa-opioid receptor sites in synaptosomal membranes derived from rat whole brain tissue (minus cerebellum) and guinea-pig cortex, respectively. The affinities for the mu-receptor sites were LY255582 > LY217273 > LY256897 > naloxone > LY227444. The affinities for the kappa-receptor sites were LY255582 > LY256897 = LY217273 > LY227444. LY255582 reduced food intake for up to 24 h after a single intraventricular injection. Doses as low as 1-mu-g of LY255582 decreased food intake for up to 4 h. All other drugs were much less powerful. Naloxone and LY256897 only decreased food intake after injection of the 100-mu-g dose. LY227444 and LY217273 failed to decrease intake at all doses tested. LY255582 (100-mu-g) decreased food intake over a 7 day period when injected intraventricularly once per day. The body weight of the rats also decreased during the 7 day period. Upon cessation of drug administration body weights and food intake approached control levels. Thus, LY255582 appears to be a very potent and long-acting anorectic agent which may be useful in the treatment of obesity. The mu and kappa-binding profile of the phenylpiperidines does not seem to clearly correlate with their anorectic activity.