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ORIGINAL ARTICLEComparison of the diuretic effects of chemically diversekappa opioid agonists in rats: nalfurafine, U50,488H,and salvinorin AS. Inan & D. Y.-W. Lee & L. Y. Liu-Chen & A. CowanReceived: 9 July 2008 /Accepted: 15 September 2008 / Published online: 17 October 2008# Springer-Verlag 2008Abstract Kappa opioid receptor agonists induce waterdiuresis in animals and humans. We investigated the effectsof s.c. nalfurafine, U50,488H, salvinorin A, and its longer-acting analog, 2-methoxymethyl-salvinorin B (MOM-salB), on urinary output and sodium excretion over 5 h ineuvolemic rats. Nalfurafine (0.005–0.02 mg/kg), U50,488H(0.1–10 mg/kg), and MOM-sal B (0.625–5 mg/kg) induceddiuresis dose-dependently. Systemically (0.1–10 mg/kg) orcentrally (50 μg, i.c.v.) administered salvinorin A wasineffective. 5′-Guanidinonaltrindole, a kappa receptor an-tagonist, inhibited nalfurafine- and MOM-sal B-induceddiuresis. Nalfurafine and MOM-sal B had no effect onarginine vasopressin levels, measured at 2 h. Tolerance didnot develop to the diuresis accompanying subchronicadministration of nalfurafine (0.02 mg/kg). On the basisof our work, we (a) promote nalfurafine as a candidatediuretic to relieve water retention and (b) highlightsalvinorin A as a kappa agonist that does not cause diuresis,probably because of its short duration of action.Keywords Nalfurafine . U50,488H . SalvinorinA .2-Methoxymethyl-salvinorinB . GNTI . DiuresisIntroductionDiuresis is a well-recognized effect of traditional kappaopioid receptor agonists, for example, in mice (Rathbun etal. 1983), rats (VonVoigtlander et al. 1983; Craft et al.2000; Gottlieb et al. 2005), dogs (Brooks et al. 1997),monkeys (Ko et al. 2003), and humans (Bellissant et al.1996; Gadano et al. 2000; Kramer et al. 2000). Thisdiuresis is characterized by an increase in urine flow as wellas a decrease in urine osmolality without an associatedincrease in Na + excretion (VonVoigtlander et al. 1983;Ashton et al. 1989; Yamada et al. 1989; Gadano et al. 2000;Gottlieb et al. 2005). Niravoline and (the peripherallyrestricted) asimadoline are examples of arylacetamide-typekappa agonists tested in humans (Bellissant et al. 1996;Kramer et al. 2000). Niravoline caused water diuresis andwas effective in moderate doses to relieve water retention incirrhotic individuals. However, high doses induced person-ality disorders and mild confusion in the patients (Gadanoet al. 2000). Asimadoline also caused diuresis in healthyvolunteers; headache and tiredness were reported as sideeffects only when it was given together with hypertonicsaline infusion (Kramer et al. 2000).The renin–angiotensin–aldosterone axis and vasopressin(AVP) are two of the important systems involved inregulating serum and urine electrolytes and osmolality.Angiotensin II stimulates aldosterone release from theadrenal cortex, and aldosterone stimulates sodium reab-sorption through Na + –H + and Na + –K + pumps. AVP is apolypeptide hormone released from the posterior pituitarygland in response to changes in blood pressure and plasmaosmolality. It regulates the permeability of the distal tubuleand collecting ducts and affects urine osmolality. Kappaopioid agonist-induced suppression of AVP release wasNaunyn-Schmiedeberg’s Arch Pharmacol (2009) 379:263–270DOI 10.1007/s00210-008-0358-8S. Inan (*) : L. Y. Liu-Chen : A. CowanDepartment of Pharmacology and Center for Substance AbuseResearch, Temple University School of Medicine,3420 N. Broad Street,Philadelphia, PA 19140, USAe-mail: sinan@temple.eduD. Y.-W. LeeBio-Organic and Natural Products Laboratory, McLean Hospital,Harvard Medical School,Belmont, MA 02478, USA