THE EFFECTS OF SPIRADOLINE (U-62066E), A KAPPA-OPIOID RECEPTOR AGONIST, ON NEUROENDOCRINE FUNCTION IN MAN

1 Opioid drugs act on specific receptors which are principally classif ied into mu, delta and kappa subtypes. Spiradoline (U-62066E) is a kap pa-selective agent which has been shown to possess potent anti-nocicep tive effects but does not show cross tolerance with morphine. 2 We hav e assessed the neuroendocrine effects of spiradoline in healthy volunt eers with two doses (1.6 and 4.0 mu g kg(-1), i.m.) of the compound. S ix male non-smokers aged 19-27 years were studied by use of a randomiz ed, double-blind three-limb placebo-controlled cross-over design. Bloo d was taken from an in-dwelling venous cannula basally and at 15 min i ntervals for 2 h for determination of serum cortisol, prolactin, growt h hormone (GH) and catecholamines. 3 Psychological function was assess ed by the Stanford Sleepiness Scale (SSS) and the Addiction Research C entre Inventory (ARCI) administered before the medication and at 35 mi n, 1 h 25 min and 2 h afterwards. Cardiovascular variables were record ed at 10 min intervals. Results were analysed by analysis of variance. 4 Spiradoline showed a significant (P<0.05) dose-dependent increase i n free water clearance, as predicted for a kappa-opioid agonist. It al so caused a dose-dependent stimulation of prolactin, (increment over b aseline for higher dose 214%), GH (433%) and cortisol(215%) release (P <0.05). There were no significant drug-related changes in plasma catec holamines, blood pressure, pulse or psychological variables. 5 We have therefore confirmed that kappa-opioids increase free-water clearance and may participate in the stimulation of prolactin and GH release. In contrast to mu and delta-opioid agonists, this novel kappa-agonist st imulates cortisol release in man.