Effects of E-2078, a stable dynorphin A(1–8) analog, on sedation and serum prolactin levels in rhesus monkeys (original) (raw)

Abstract

Rationale: The dynorphins are endogenous opioid peptides with relative binding selectivity for κ- receptors. It is unclear whether the dynorphins share the pharmacological profile observed with synthetic κ-agonists in primates. Objective: The main objective of this study was to compare the effects of s.c. E-2078, a stable dynorphin A(1–8) analog, with two synthetic κ-opioid ligands, spiradoline (a reference arylacetamide κ-agonist) and ICI204,448 (a ”peripherally selective”κ-agonist) in behavioral and neuroendocrine endpoints in rhesus monkeys. Methods: Dose–effect curves were determined for s.c. E-2078, spiradoline and ICI204,448 in causing overt sedation and muscle relaxation (as detected in observational rating scales), in increasing latency to retrieve and consume a food pellet and in increasing serum levels of the anterior pituitary hormone, prolactin, in intact female rhesus monkeys. Results: E-2078 and ICI204,448 (0.1–3.2 mg/kg) caused increases in sedation and muscle relaxation scores, but were less potent and apparently less effective than spiradoline (0.001–0.1 mg/kg) up to the highest doses presently studied. All three agonists were equieffective and approximately equipotent in increasing the latency to retrieve and consume a pellet. Furthermore, E-2078 (0.001–0.032 mg/kg) was equipotent and equieffective with spiradoline in increasing serum prolactin levels, whereas ICI204,448 was less potent, but slightly more effective than the former two agonists. The effects of E-2078 on serum prolactin levels were surmountably antagonized by quadazocine (1 mg/kg) and naltrexone (0.1 mg/kg). Conclusions: The present studies show that serum prolactin levels are a highly sensitive, quantitative endpoint to study the potency and effectiveness of systemically administered E-2078, and show that the dynorphins may be potent and effective in causing some, but not all, the effects that are observed after the administration of synthetic κ-agonists.

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  1. Rockefeller University (Box 171), 1230 York Avenue, New York, NY 10021, USA e-mail: butelme@rockvax.rockefeller.edu, , , , , , US
    E. R. Butelman, Todd J. Harris & Mary-Jeanne Kreek

Authors

  1. E. R. Butelman
  2. Todd J. Harris
  3. Mary-Jeanne Kreek

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Received: 20 March 1999 / Final version: 27 May 1999

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Butelman, E., Harris, T. & Kreek, MJ. Effects of E-2078, a stable dynorphin A(1–8) analog, on sedation and serum prolactin levels in rhesus monkeys.Psychopharmacology 147, 73–80 (1999). https://doi.org/10.1007/s002130051144

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