Life Sciences, Vol. 33, Sup. I, 1983, pp. 361-364 Pergamon Press Printed in the U.S.A. SYSTEMIC AND INTRACEREBROVENTRICULAR EFFECTS OF OPIOID PEPTIDES IN WITHDRAWN MORPHINE-DEPENDENT RHESUS MONKEYS Debra E. Gmerek, Jonathan L. Katz, Charles P. France and James H. Woods Department of Pharmacology, University of Michigan Ann Arbor, Michigan 48109 (Received in final form June 26, 1983) Summary The effects of the degradation-resistant enkephalin analogs FK 33-824 and metkephamid were determined after systemic and intracerebroventricular (i.c.v.) administration in withdrawn morphine-dependent rhesus monkeys. Both peptides suppressed completely signs of 12-hr morphine deprivation, as does the prototype mu-receptor agonist morphine. The peptides were 100 and 2000 times more potent, respectively, after i.c.v. than s.c. injection. Thus, although peptidase- resistant, these compounds have restricted entrance into the central nervous system after systemic admin- istration. The i.c.v, administration of compounds in rhesus monkeys should prove to be a valuable tool in the study of peptide ligands for opiate receptors. Centrally acting compounds which are large molecular weight and poorly soluble in lipids have difficulty penetrating the blood-brain barrier (BBB). Some compounds (e.g., peptides) are in addition rapidly metabolized in peripheral tissues. Thus, these compounds may be more readily and economically studied by injecting them directly into the cerebroventricular system. This technique is particularly useful when investigating activ- ities of endogenous opioid peptides and their analogs. The single-dose suppression (SDS) test in morphine- dependent rhesus monkeys is a well-established method for determining various activities of opioids in non-human primates. In this procedure, dependent monkeys (3 mg/kg/6 hr) are deprived of two consecutive maintenance doses of morphine. Single doses of test agents are then administered to the withdrawn animals and their behavior is monitored. Compounds which act at mu- receptors suppress signs of abstinence in morphine-deprived dependent monkeys (i). Very few peptides have been studied, in part, perhaps, due to the presumed rapid systemic degradation and poor central nervous system penetration. We have now established a procedure for intracerebroventricular (i.c.v.) administration of opioids in rhesus monkeys. In preparation for 0024-3205/83 $3.00 + .00 Copyright (c) 1983 Pergamon Press Ltd.