FURTHER STUDY OF KAPPA-OPIOIDS ON INCREASED URINATION

Abstract

The effects of various opioid agonists and antagonists on urination were studied in the normally hydrated rat. Two K agonists, U-50,488H [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide methanesulfonate] and proxorphan, markedly increased urination. The increased urination produced by U-50,488H was antagonized by opioid antagonists in a potency order which indicated that the effects were due to an action at K opioid receptors. Agonists decreased urination and were blocked by low doses (0.01 and 0.1 mg/kg) of naloxone, whereas K agonists increased urination and were only blocked by a high dose (10 mg/kg) of naloxone. The diuretic effects of U-50,488H and ketazocine, but not proxorphan and bremazocine, were reduced by morphine, consistent with the idea that proxorphan and bremazocine have morphine antagonist activity. Water deprivation produced a shift to the right for the dose-effect curve for bremazocine-induced diuresis. K agonists were ineffective in increasing urination in Brattleboro rats that were homozygous for diabetes insipidus, whereas .mu. agonists were still effective in decreasing urination. K agonists evidently inhibit release of vasopressin from the neurophyophysis and this decrease in vasopressin release leads to increased urination. The effects of opioids on urination in the normally hydrated rat can be extremely useful in classifying the activities of opioid on .mu. and K receptors in vivo.