Rationale: The discriminative effects Of kappa-agonists may be mediated centrally, whereas their effects in a neuroendocrine biomarker assay (prolactin release) may be mediated by K-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 mu-opioids fentanyl delta-agonist SNC80. Selected kappa-opioids opioids (R84760 and spiradoline) were compared 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 K-agonist (spiradoline) from those of a selective kappa-agonist (fentanyl). A positive correlation (r=0.99) was noted between the mean log ED50 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 pKB experiments with nalmefene differentiated the receptor mediation (i.e. kappa or mu) of these compounds in the neuroendocrine biomarker assay.
