Peptides, Vol. 4, pp. 797-800, 1983. ~ ' ~ AnkhoInternational Inc. Printed in the U.S.A. Involvement of Dynorphin and the Kappa Opioid Receptor in Feeding JOHN E. MORLEY AND ALLEN S. LEVINE Neuroendocrine Research Laboratoo,, Minneapolis VA Medical Center, Minneapolis, MN 55417 and the Departments of Medicine and Food Science and Nutrition University of Minnesota, Minneapolis and St. Paul, MN Received 5 July 1983 MORLEY, J. E. AND A. S. LEVINE. Involvement of dym~rphin and the kappa opioid receptor in fi'eding. PEPTIDES 4(6) 797-800, 1983.--Dynorphin-( 1-17) produces a highly specific increase in food ingestion. Similar enhancement of food ingestion is found with dynorphin fragments (1-10), (I-I 1), (1-13) and (3-13) but not with (1-8) and (I-9). Dynorphin B (rimorphin) also enhances food intake. The highly specific kappa agonist U-50,488 also enhances food intake as do a number of other kappa-opiate receptor agonists. These studies provided further support for the role of a highly specific dynorphin-kappa opioid receptor in the modulation of feeding. Dynorphin Opioids Kappa receptor Feeding Appetite Rimorphin A number of lines of evidence have suggested that the en- dogenous opioid peptides play a role in the regulation of ingestive behaviors [9, 13, 22]. It is now recognized that a number of opioid receptors are present in the brain, each one of which has a specific high affinity for a different endoge- nous opioid peptide [1, 12, 27]. A number of studies have suggested that exogenous kappa receptor ligands produce marked increases in food ingestion [8, 19, 23, 25]. In addi- tion, dynorphin-(l-13) has been demonstrated to increase food intake without altering water ingestion [7, 11, 14] and ir-dynorphin concentrations are altered in the central nerv- ous system under a number of situations known to alter in- gestive behaviors [15, 21]. Dynorphin is the putative endog- enous ligand for the kappa opiate receptor [2, 5, 26]. For these reasons it has been suggested that dynorphin and the kappa opiate receptor may play a specific role in the mod- ulation of food intake [17,18]. In the series of studies re- ported here we have examined the effects of dynorphin-(1- 17), the complete endogenous dynorphin [4], as well as a variety of dynorphin fragments on food intake. Also, we have examined the effect of the highly selective kappa opioid agonist, U-50,488 (trans-3,4-dichloro-N-methyI-N(2-(l-pyr- rolidenyl)cyclo-hexyl)-benzeneacetamide) [20,24] on food intake and compared its effects to the classical opiate, mor- phine, and a number of other kappa-type agonists. METHOD For the first series of experiments we used 30 male Sprague-Dawley (150-200 g) rats with cannulae inserted into the lateral cerebroventricle [10]. Animals were housed indi- vidually in wire mesh cages and maintained on ad lib food and water with lights on from 0700-1900 hours. All experi- ments were carried out between 0830 and 1030 in animals allowed free access to food and water until the experiments were performed. This time was chosen as we have previ- ously found that opiates exert a maximum effect on food ingestion when injected at this period of the day [16]. All of the dynorphin-like peptides were obtained from Peninsula, San Francisco, CA and naloxone-hydrochloride from DuPont Pharmaceuticals, Wilmington, DE. They were administered intracerebroventricularly. Vehicle injections were equal parts per volume of methanol:0.1 N HCI. Im- mediately after injection, pre-weighed food pellets were placed into the cages. Food eaten, with careful collection of spillage, was quantitated at 60 and 120 minutes. Fluid inges- tion was measured to the nearest 0.1 ml using pre-weighed rubber stoppered bottles and collecting spillage in plastic cups placed under the cage. Behaviors were recorded every minute for 120 minutes by trained observers who were blind to the treatments the animals received. In the second set of experiments we administered the highly selective and novel kappa opioid agonist, U-50,488 [21,22]. Morphine sulfate (Winthrop Laboratories, New York, NY), butorphanol tartrate (Bristol Laboratories, Syracuse, NY), ketocyclazocine (A. E. Sofia, Sterling- Winthrop Research Institute, Rensselaer, NY), tifluadom (H. Zeugner, Kali-Chemie Pharma Ltd., Hannover, Ger- many) and U-50,488 (M. F. Piercey, Upjohn Company, Kalamazoo, MI) were all administered sub-cutaneously. A total of 117 male Sprague-Dawley rats (100-150 g) were used for these experiments. Animals were allowed food and water ad lib. Injections were given between 0830 and 0900 hours and food ingestion quantitated at 1, 2, 4 and 6 hours after injection. Food intake was corrected for spillage at each measurement. Except where noted, data in each experiment were analyzed in a one-way analysis of variance (ANOVA) at each time point followed by the least significance difference (LSD) procedure when the overall F value was significant. 797