Brain Research, 566 (1991) 193-197 193 Elsevier BRES 17222 Central administration of the opioid antagonist, LY255582, decreases short- and long-term food intake in rats A.S. Levine 1-5, M. Grace 1, C.J. Billington ~'3 and D.M. Zimmerman 6 zVA Medical Center Research Service -- 151, University of Minnesota, Minneapolis, MN (U.S.A.), Departments of ZFood Science and Nutrition, 3Medicine, 4Psychiatry and SSurgery, Minneapolis, MN (U.S.A.) and 6Lilly Research Laboratories, Eli Lilly and Company, Minneapolis, MN (U.S.A.) (Accepted 16 July 1991) Key words: Opioid antagonist; Food intake; Anoretic; Phenylpiperidine A variety of opioid antagonists ha,,e been reported to decrease short-tern, food intake, but few appear to reduce long-term intake. In the present study we ev~uated 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/~ and ~¢ opioid receptor sites in synaptosomal membranes derived trom rat whole brain tissue (minus cerebellum) and guinea-pig cortex, respectively. The affinities for the # receptor sites were LY255582 > LY217273 > LY256897 > naloxone > LY227444. The affinities for the g 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 #g of LY255582 decreased food intake for up to 4 h, All other drugs were much less powerful. Naloxone and LY256897 only decreased food i-take after injection of the 100/48 dose. LY227444 and LY217273 failed to decrease intake at all doses tested. LY255582 (100 #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/~ and ~cbinding profile of the phenylpiperidines does not seem to clearly correlate with their anorectic activity. INTRODUCTION Naloxone was the first opioid antagonist found to de- crease feeding in rats 5. Since that time a variety of opi- old antagonists selective for the/~, 6 and ~¢receptor have been synthesized, p.Funaltrexamine ~-FNA) t'ts and naloxonazine tt, selective/~ opioid antagonists, decrease feeding when given to rats which were free feeding, de- prived or stimulated to eat with opioid ligands t°. Like- wise, nor.binaltorphimine (nor-BNI), selective for the ~c opioid site, decreases feeding in rats deprived of food or stimulated to eat with opioid lig~,ttds. Data with agonists also indicate that the/~, 6 and ~ opioid receptors are involved in consummatory behaviors 3's. Thus, food in- take does not seem to involve a given receptor opioid site, but may be dependent upon all known opioid re- ceptors. Zimmerman etal. 2° described a new class of opioid antagonists, trans.3,4-dimethyl-4-phenylpiperidine com- pounds, which have no measurable agonist activity. These compounds have a relatively long duration and have been shown to decrease food and water consump- tion after peripheral administration to lean and obese Zucker rats re. Chronic administration of two of these compounds, LY88329 and LYl17413, to obese Zucker rats reduced food consumption and body weight for as long as 42 days. Recently, Shaw et al. t5 have demon- strated that LY255582, a 3,4.dimethyl-4-phenyipiperi- dine, decreased feeding in Zucker rats more effectively than ephedrine, amphetamine, fenfluramine, naltrexone and nalmefene. In the present study, we compared the effect of centrally administered LY255582 and 3 other phenylpiperidines on food intake to naloxone Sprague- Dawley rats. We also evaluated the effect of the most potent of these phenylpiperidines on food intake and body weight for 7 days. MATERIALS AND METHODS Animals Male Sprague-Dawley rats (n = 66), approximately 250-300 g each, were anesthetized with Nembutal and stereotactically im- planted with right lateral ventricular cannulas (coordinates: 1.5 mm right lateral and -1.0 mm posterior to bregma). A 5-7 day period was allowed for recovery and the rats were housed singly in hang- ing stainless-steel cages. The vivarium was maintained at 21-22 *C with a 12 h light/12 h dark photoperiod (lights on at 07.00 h). Food (Purina certified Lab Chow) and water were a"ailable ad libitum, except when noted. All studies were conducted in the rats' home Correspondence: A.S. Levine, VA Medical Center, Research Service (151), One Veterans Drive, Minneapolis, MN 55417, U.S.A.