Comparison of the discriminative and neuroendocrine effects of centrally penetrating κ-opioid agonists in rhesus monkeys

Abstract

Rationale. The discriminative effects of κ-agonists may be mediated centrally, whereas their effects in a neuroendocrine biomarker assay (prolactin release) may be mediated by κ-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 κ-opioid ligands in vivo. The potency of centrally penetrating κ-agonists could be similar in these two assays, due to their ability to occupy κ-receptor pools inside and outside the blood-brain barrier, following SC administration.

Objective. To compare the potency of centrally penetrating κ-agonists in producing U69,593-like discriminative stimulus effects (U69,593 is considered a selective κ-agonist), and in producing prolactin release in rhesus monkeys.

Methods. Cumulative dose-effect curves of κ-agonists (R84760, bremazocine, spiradoline and U50,488) were investigated in a food-reinforced U69,593 discrimination (n=3), and compared to those for the µ-opioids fentanyl and nalbuphine and the δ-agonist SNC80. Selected κ-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 κ-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 κ-agonist (spiradoline) from those of a selective µ-agonist (fentanyl). A positive correlation (r=0.99) was noted between the mean log ED₅₀ of κ-agonists in the discrimination and neuroendocrine assays, from these and previous determinations.

Conclusions. The potency of centrally penetrating κ-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. κ or µ) of these compounds in the neuroendocrine biomarker assay.