KAPPA-OPIOID AGONIST INHIBITION OF OSMOTICALLY INDUCED AVP RELEASE - PREFERENTIAL ACTION AT HYPOTHALAMIC SITES

Although several studies indicate that kappa-opioid agonists induce a water diuresis by inhibiting vasopressin (AVP) secretion, the locus of the kappa-receptors (neurohypophysial vs. hypothalamic) responsible f or this effect remains unclear. We have ascertained the effect of the selective kappa-agonist BRL-52656 (BRL) on AVP secretion by using comp artmentalized rat hypothalamoneurohypophysial explants in culture. Whe n applied to the hypothalamus, nanomolar concentrations of BRL inhibit ed osmotically stimulated AVP secretion. This response was blocked by the highly selective kappa-opioid antagonist nor-binaltorphimine (BNI) . However, osmotically stimulated AVP release was suppressed at the ne urohypophysial site only by 100 nM BRL and was not reversed by BNI but only by naloxone. This dose of BRL, administered to the posterior pit uitary compartment, did not appear to act by the agonist gaining acces s to hypothalamic kappa-opiate receptors, because BNI added to the hyp othalamus failed to prevent the inhibition of AVP secretion. The data demonstrate that BRL is a potent inhibitor of osmotically stimulated A VP secretion via activation of kappa-opiate receptors within the hypot halamus, but that higher concentrations of the drug may also stimulate non-kappa-neurohypophysial opiate receptors that suppress AVP release .