Systemic effects of E-2078, a stabilized dynorphin A(1-8) analog, in rhesus monkeys

Eduardo R. Butelman, Jeffrey A. Vivian, Jim Yu, Mary Jeanne Kreek, James H. Woods

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Rationale: E-2078 ([N-methyl-Tyr1, N-methyl-Arg7, v-Leu8] dynorphin A(1-8) ethylamide) is a dynorphin A(1-8) analog with a reduced tendency to be biotransformed, when compared to the unmodified opioid peptide. E-2078 has been found to produce κ-opioid agonist effects in vivo in rodents. Objective: In the present studies, we investigated whether systemically administered E-2078 could produce κ-agonist effects in rhesus monkeys, in tests of antinociception, diuresis and ethylketocyclazocine (EKC) discrimination. Methods: E-2078 (0.32-18 mg/kg, SC, IM or IV) was tested in the warm water (50°, 55°C) tail withdrawal assay of thermal antinociception. The diuretic effects of E-2078 (0.0561.8 mg/kg, SC) were also compared to those of the κ-agonist, U69,593 (0.01-0.32 mg/kg, SC). Lastly, the effects of E-2078 (0.1-3.2 mg/kg, SC or IV) were studied in rhesus monkeys trained to discriminate EKC (0.0056 mg/kg SC) from vehicle, in a food-reinforced operant procedure. Results: E-2078 did not produce thermal antinociception in rhesus monkeys following SC or IM administration, up to the largest doses presently studied (i.e., 18 and 10 mg/kg, respectively). E- 2078 caused thermal antinociception by the IV route, but this effect was not apparently mediated by κ- or μ-opioid receptors, as shown by its insensitivity to quadazocine (1 mg/kg) pretreatment. However, SC E-2078 caused diuresis, and this effect was blocked by quadazocine pretreatment, consistent with mediation by κ-opioid receptors. E-2078 generalized in EKC- discriminating monkeys, but only after the largest dose (3.2 mg/kg), and only following IV administration. Conclusions: The present studies suggest that systemically administered E-2078 can produce some κ-receptor mediated effects in rhesus monkeys, but its profile of action is not identical to non- peptidic κ-agonists following all routes of administration, or across all experimental situations.

Original languageEnglish (US)
Pages (from-to)190-196
Number of pages7
JournalPsychopharmacology
Volume143
Issue number2
DOIs
StatePublished - 1999
Externally publishedYes

Keywords

  • Antinociception
  • Diuresis
  • Macaca mulatta
  • κ-Opioid receptors

ASJC Scopus subject areas

  • Pharmacology

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