title: Peripheral selectivity and apparent efficacy of dynorphins: comparison to non-peptidic kappa-opioid agonists in rhesus monkeys.
abstract: The potency and effectiveness of dynorphin A(1-17), E-2078 (a synthetic dynorphin A(1-8) analog) and non-peptidic kappa-opioid agonists were studied in rhesus monkeys in two assays: 1) a drug discrimination assay with the centrally-penetrating kappa-agonist U69,593 as the training stimulus (n=3) and 2) a prolactin release assay; a neuroendocrine effect thought to be mediated by kappa-receptors located in hypothalamic nuclei outside the blood-brain barrier. The non-peptidic kappa-agonists, U69,593 and bremazocine (0.00032-0.01 mg/kg, s.c.) were dose-dependently generalized by all the subjects trained to discriminate U69,593. U69,593 and bremazocine also caused dose-dependent prolactin release (n=4). By contrast, dynorphin A(1-17) and E-2078 (0.1-1 mg/kg, i.v.) were only generalized by one of the U69,593 discriminating subjects. However, both these dynorphins produced potent and robust prolactin release (0.0032-0.032 mg/kg, i.v.), when tested under an identical time course design as above. Naltrexone (0.1 or 0.32 mg/kg), caused a parallel rightward shift in the dose-effect curves for all the above ligands, consistent with kappa-receptor mediation of this neuroendocrine effect. The peripherally selective antagonist, quaternary naltrexone (0.32 mg/kg, s.c.) partially blocked the neuroendocrine effects of U69,593 and E-2078 (0.0032 mg/kg, s.c. and i.v., respectively). Overall, these findings are consistent with the hypothesis that the dynorphins act as high efficacy, peripherally selective kappa-agonists following systemic administration in primates.
authors.affiliation: Laboratory on the Biology of Addictive Diseases, Rockefeller University (Box 171), 1230 York Avenue, New York, NY 10021, USA. butelme@mail.rockefeller.edu
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Butelman
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Ball
authors.forename: Mary-Jeanne
authors.initials: MJ
authors.lastname: Kreek
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage*; D000701:Analgesics, Opioid / Q000008:administration & dosage; D000818:Animals; D044482:Benzeneacetamides / Q000008:administration & dosage; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000008:administration & dosage*; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage; D009490:Neurosecretory Systems / Q000187:drug effects; D010446:Peptide Fragments / Q000008:administration & dosage; D011388:Prolactin / Q000097:blood / Q000187:drug effects; D011759:Pyrrolidines / Q000008:administration & dosage; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000187:drug effects
chemical_list: D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D044482:Benzeneacetamides; D010446:Peptide Fragments; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C061285:E 2078; D009271:Naltrexone; D004399:Dynorphins; D011388:Prolactin; C045444:U 69593