• S Stevens Negus, Nancy K Mello, David C Linsenmayer, R M Jones, and Philip S Portoghese.
• Alcohol and Drug Abuse Research Center, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. negus@mclean.harvard.edu
• Psychopharmacology (Berl.). 2002 Oct 1; 163 (3-4): 412-9.

RationaleOpioid receptors are divided into three types: kappa, mu, and delta receptors. Receptor-selective antagonists are useful experimental tools for evaluation of opioid receptor-mediated processes. 5'-Guanidinonaltrindole (GNTI) was recently developed as a novel kappa-selective antagonist.ObjectivesTo evaluate the potency, time course, and selectivity of GNTI's opioid antagonist effects in rhesus monkeys in an assay of schedule-controlled responding.MethodsFive rhesus monkeys were trained to respond under a fixed ratio 30 schedule of food reinforcement. The rate-decreasing effects of the kappa agonists U50,488 and U69,593, the mu agonist morphine, and the delta agonist SNC80 were examined alone and after pretreatment with GNTI (0.1 and 1.0 mg/kg i.m.; 1 h to 14 days).ResultsU50,488, U69,593, morphine, and SNC80 dose-dependently decreased response rates in this procedure. GNTI produced a dose- and time-dependent antagonism of the rate-decreasing effects of U50,488. The kappa antagonist effects of GNTI had a slow onset and a long duration of action, and peak antagonist effects were observed after 24 h. A higher dose of 3.2 mg/kg GNTI eliminated responding in one monkey and was not studied further. The antagonist effects of GNTI were kappa selective, because 1.0 mg/kg GNTI also antagonized the effects of U69,593, but not those of morphine or SNC80.ConclusionsThese results suggest that GNTI is a potent and selective kappa antagonist with a slow onset and long duration of action in rhesus monkeys. Relative to the prototype kappa antagonist nor-binaltorphimine, GNTI may have some advantages as a tool for the study of kappa receptor-mediated processes.

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