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

Rationale: The dynorphins are endogenous opioid Peptides with relative binding selectivity for kappa-receptors. It is unclear whether the dynorphins share the pharmacological profile observed with synthetic kappa-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 kappa-opioid ligands, spiradoline (a reference arylacetamide kappa-agonist) and ICI204,448 (a "peripherally selective" kappa-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 kappa-agonists.