title: Comparison of the discriminative and neuroendocrine effects of centrally penetrating kappa-opioid agonists in rhesus monkeys.
abstract: BACKGROUND
  The discriminative effects of kappa-agonists may be mediated centrally, whereas their effects in a neuroendocrine biomarker assay (prolactin release) may be mediated by kappa-receptors in hypothalamic areas outside the blood-brain barrier. Prolactin may thus be a useful biomarker, due to its potential to provide quantitative pharmacodynamic data for kappa-opioid ligands in vivo. The potency of centrally penetrating kappa-agonists could be similar in these two assays, due to their ability to occupy kappa-receptor pools inside and outside the blood-brain barrier, following SC administration.
  
  
  OBJECTIVE
  To compare the potency of centrally penetrating kappa-agonists in producing U69,593-like discriminative stimulus effects (U69,593 is considered a selective kappa-agonist), and in producing prolactin release in rhesus monkeys.
  
  
  METHODS
  Cumulative dose-effect curves of kappa-agonists (R84760, bremazocine, spiradoline and U50,488) were investigated in a food-reinforced U69,593 discrimination ( n=3), and compared to those for the micro -opioids fentanyl and nalbuphine and the delta-agonist SNC80. Selected kappa-opioids (R84760 and spiradoline) were compared to fentanyl, nalbuphine and SNC80 in the neuroendocrine biomarker assay, in intact female rhesus monkeys ( n=4).
  
  
  RESULTS
  All the selective kappa-agonists caused dose-dependent generalization (i.e. at least 90% drug-appropriate responding) in the U69,593 discriminating subjects, and caused robust, dose-dependent prolactin release in female rhesus monkeys. By contrast, fentanyl, nalbuphine and SNC80 did not cause generalization in these subjects. Fentanyl and nalbuphine also caused prolactin release; quantitative antagonism (apparent pK(B)) experiments following nalmefene (0.01, 0.1 mg/kg) differentiated the effects of a selective kappa-agonist (spiradoline) from those of a selective micro -agonist (fentanyl). A positive correlation ( r=0.99) was noted between the mean log ED(50) of kappa-agonists in the discrimination and neuroendocrine assays, from these and previous determinations.
  
  
  CONCLUSIONS
  The potency of centrally penetrating kappa-agonists in causing their neuroendocrine effects is similar to their potency in causing discriminative effects. Furthermore, apparent pK(B) experiments with nalmefene differentiated the receptor mediation (i.e. kappa or micro ) of these compounds in the neuroendocrine biomarker assay.
authors.affiliation: The 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: D000818:Animals; D044482:Benzeneacetamides; D004192:Discrimination, Psychological / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D008253:Macaca mulatta; D009490:Neurosecretory Systems / Q000187:drug effects* / Q000502:physiology; D011388:Prolactin / Q000097:blood; D011759:Pyrrolidines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000502:physiology
chemical_list: D044482:Benzeneacetamides; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D011388:Prolactin; C045444:U 69593