Kappa opioid antagonist effects of the novel kappa antagonist 5′-guanidinonaltrindole (GNTI) in an assay of schedule-controlled behavior in rhesus monkeys

Stevens S. Negus, Nancy K. Mello, David C. Linsenmayer, R. Jones, Philip S Portoghese

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Rationale: Opioid 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. Objectives: To evaluate the potency, time course, and selectivity of GNTI's opioid antagonist effects in rhesus monkeys in an assay of schedule-controlled responding. Methods: Five 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). Results: U50,488, 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. Conclusions: These 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.

Original languageEnglish (US)
Pages (from-to)412-419
Number of pages8
JournalPsychopharmacology
Volume163
Issue number3-4
DOIs
StatePublished - Oct 16 2002

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Narcotic Antagonists
Macaca mulatta
Appointments and Schedules
Morphine
kappa Opioid Receptor
Opioid Receptors
17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5'-guanidinyl-3,14-dihydroxyindolo(2',3'-6,7)morphinan
Reinforcement Schedule
delta Opioid Receptor
mu Opioid Receptor
Haplorhini
Food

Keywords

  • 5′-Guanidinonaltrindole
  • Kappa opioid receptor
  • Nor-binaltorphimine
  • Rhesus monkey

Cite this

Kappa opioid antagonist effects of the novel kappa antagonist 5′-guanidinonaltrindole (GNTI) in an assay of schedule-controlled behavior in rhesus monkeys. / Negus, Stevens S.; Mello, Nancy K.; Linsenmayer, David C.; Jones, R.; Portoghese, Philip S.

In: Psychopharmacology, Vol. 163, No. 3-4, 16.10.2002, p. 412-419.

Research output: Contribution to journalArticle

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abstract = "Rationale: Opioid 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. Objectives: To evaluate the potency, time course, and selectivity of GNTI's opioid antagonist effects in rhesus monkeys in an assay of schedule-controlled responding. Methods: Five 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). Results: U50,488, 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. Conclusions: These 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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AU - Portoghese, Philip S

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