Kappa opiate agonist RU 51599 inhibits vasopressin gene expression and osmotically-induced vasopressin secretion in vitro.

Kappa (kappa) opioid agonists induce a water diuresis and inhibit vasopressin (AVP) secretion. Hypothalamic and neurohypophysial sites have both been implicated in the response. The present study was designed to ascertain if kappa-agonist inhibition of osmotically-stimulated AVP secretion is associated with parallel changes in AVP gene expression. Experiments were performed using the selective kappa-agonist RU 51599 (RU) in compartmentalized hypothalamo-neurohypophysial explants. When added to either the hypothalamus or the neural lobe, RU dose dependently inhibited osmotically-induced AVP secretion that was reversed by the highly selective kappa-antagonist nor-binaltorphimine (nor-BNI) only at the hypothalamic, not the neurohypophysial level. AVP mRNA content paralleled the changes in AVP secretory rate induced by hypothalamic kappa-agonism. AVP mRNA levels were unaltered when RU was applied to the neural lobe. Neurohypophysial AVP content did not change. These data indicate that hypothalamic kappa-agonism inhibits osmotically induced AVP secretion and that a non-kappa1 opiate receptor mediates posterior pituitary opioid inhibition of AVP release. Neural or receptor inputs to the hypothalamus or magnocellular cell body may downwardly modulate AVP mRNA content by altering AVP gene transcription and/or message stability. Inhibition of AVP release directly at the neurohypophysis can be uncoupled from the cellular mechanisms that generate changes in AVP mRNA content.