The effect of selective opioid antagonists on vasopressin secretion in the rat

We have shown previously that the nonselective opioid antagonist diprenorphine inhibits the vasopressin response to an acute hypovolemic stimulus in rats. To elucidate the type of endogenous opioid receptor at which this inhibition occurs, we investigated whether more selective antagonists, administered alone or in combination with diprenorphine, also inhibited the vasopressin response to hypovolemia induced by ip injection of polyethylene glycol. We found that the rise in plasma vasopressin was inhibited by the kappa-antagonist Mr 2266 BS at doses 30- to 300-fold higher than those of diprenorphine. Over the same dose range (0.003-100 mumol/kg), the kappa 1-selective antagonist norbinaltorphimine and the mu-selective antagonist naloxone had no effect or enhanced the vasopressin response, whereas the delta-antagonist ICI 154,129 had no effect. By augmenting the vasopressin response to hypovolemia, higher doses of naloxone or nor-binaltorphimine offset the inhibitory effect of concurrently administered diprenorphine. Mr 2266 BS did not facilitate, inhibit, or offset the action of diprenorphine. The results support the hypothesis that the inhibition of vasopressin by diprenorphine is due to antagonism of an opioid receptor and suggest that it is one of the recently discovered kappa-subtypes. They also suggest that the vasopressin response to acute hypovolemia is normally restrained by simultaneous activation of a distinct inhibitory pathway that is blocked by kappa 1- or mu-antagonists.