Effects of E-2078, a stable dynorphin A(1-8) analog, on sedation and serum prolactin levels in rhesus monkeys.
BACKGROUND
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.
Butelman
E R
ER
Rockefeller University, New York, NY 10021, USA. butelme@rockvax.rockefeller.edu
Harris
T J
TJ
Kreek
M J
MJ
D000818:Animals; D001392:Azocines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005260:Female; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008253:Macaca mulatta; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011388:Prolactin / Q000097:blood*; D011759:Pyrrolidines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists; D013997:Time Factors
D001392:Azocines; D006993:Hypnotics and Sedatives; D009292:Narcotic Antagonists; D010446:Peptide Fragments; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C061285:E 2078; C060223:ICI 204448; D009271:Naltrexone; D004399:Dynorphins; D011388:Prolactin; C051272:spiradoline; C035969:quadazocine