Effects of the Selective Kappa-opioid Agonist U50,488 Upon the Electrical Activity of Supraoptic Neurones in Morphine-tolerant and Morphine-naive Rats

Spontaneous electrical activity of oxytocin-secreting neurones in the rat supraoptic nucleus is depressed by the mu-opiate receptor agonist morphine, leading to a reduction in plasma oxytocin concentration. In the present experiments, the electrical activity of single neurones was recorded from the supraoptic nucleus of urethane-anaesthetized rats. For 5 days prior to the experiments the rats had received a continuous infusion of either morphine or vehicle into a lateral cerebral ventricle; this regimen of morphine treatment results in tolerance to, and dependence upon, morphine in the central mechanisms controlling oxytocin secretion. Intravenous injection of the specific kappa-opioid agonist U50,488 at low doses resulted in small but significant increases in the electrical discharge activity of some putative oxytocin neurones in both morphine-treated and morphine-naive rats. At higher doses, the kappa-agonist consistently inhibited almost all cells tested. Morphine-treated rats, despite showing tolerance to morphine itself, showed no cross-tolerance to the inhibitory actions of U50,488 upon the oxytocin system. In separate experiments both morphine and U50,488 were effective in inhibiting supraoptic neuronal activation evoked by stimulation of the region anterior and ventral to the third ventricle, and activation following systemic injection of cholecystokinin, suggesting that both opioids act upon the final common pathway--the oxytocin neurone itself.