Comparison of the diuretic effects of chemically diverse kappa opioid agonists in rats: nalfurafine, U50,488H, and salvinorin A

Kappa opioid receptor agonists induce water diuresis in animals and humans. We investigated the effects of s.c. nalfurafine, U50,488H, salvinorin A, and its longer-acting analog, 2-methoxymethyl-salvinorin B (MOM-sal B), on urinary output and sodium excretion over 5 h in euvolemic rats. Nalfurafine (0.005–0.02 mg/kg), U50,488H (0.1–10 mg/kg), and MOM-sal B (0.625–5 mg/kg) induced diuresis dose-dependently. Systemically (0.1–10 mg/kg) or centrally (50 μg, i.c.v.) administered salvinorin A was ineffective. 5′-Guanidinonaltrindole, a kappa receptor antagonist, inhibited nalfurafine- and MOM-sal B-induced diuresis. Nalfurafine and MOM-sal B had no effect on arginine vasopressin levels, measured at 2 h. Tolerance did not develop to the diuresis accompanying subchronic administration of nalfurafine (0.02 mg/kg). On the basis of our work, we (a) promote nalfurafine as a candidate diuretic to relieve water retention and (b) highlight salvinorin A as a kappa agonist that does not cause diuresis, probably because of its short duration of action.