KAPPA-OPIATE AGONIST RU-51599 INHIBITS VASOPRESSIN GENE-EXPRESSION AND OSMOTICALLY-INDUCED VASOPRESSIN SECRETION IN-VITRO

Kappa (kappa) opioid agonists induce a water diuresis acid inhibit vas opressin (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 dependen tly inhibited osmotically-induced AVP secretion that was reversed by t he highly selective kappa-antagonist nor-binaltorphimine (nor-BNI) onl y at the hypothalamic, not the neurohypophysial level. AVP mRNA conten t 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 da ta indicate that hypothalamic kappa-agonism inhibits osmotically induc ed AVP secretion and that a non-kappa(1) opiate receptor mediates post erior pituitary opioid inhibition of AVP release. Neural or receptor i nputs to the hypothalamus or magnocellular cell body may downwardly mo dulate AVP mRNA content by altering AVP gene transcription and/or mess age stability. Inhibition of AVP release directly at the neurohypophys is can be uncoupled from the cellular mechanisms that generate changes in AVP mRNA content.