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 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.

• DA00049/DA/NIDA NIH HHS/United States
• DA05130/DA/NIDA NIH HHS/United States
• DA11113/DA/NIDA NIH HHS/United States