Comparison of the diuretic effects of chemically diverse kappa opioid agonists in rats: nalfurafine, U50,488H, and salvinorin A
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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.
KeywordsNalfurafine U50,488H Salvinorin A 2-Methoxymethyl-salvinorin B GNTI Diuresis
We thank Dr. Concetta Harakal for valuable comments and Drs. Ellen M. Unterwald and Shane A. Perrine for help in measuring cAMP levels. This study was supported by T32DA07237 from the National Institute on Drug Abuse.
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