Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 379, Issue 3, pp 263–270 | Cite as

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

Original Article

Abstract

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.

Keywords

Nalfurafine U50,488H Salvinorin A 2-Methoxymethyl-salvinorin B GNTI Diuresis 

Introduction

Diuresis is a well-recognized effect of traditional kappa opioid receptor agonists, for example, in mice (Rathbun et al. 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). This diuresis is characterized by an increase in urine flow as well as a decrease in urine osmolality without an associated increase 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 peripherally restricted) asimadoline are examples of arylacetamide-type kappa agonists tested in humans (Bellissant et al. 1996; Kramer et al. 2000). Niravoline caused water diuresis and was effective in moderate doses to relieve water retention in cirrhotic individuals. However, high doses induced personality disorders and mild confusion in the patients (Gadano et al. 2000). Asimadoline also caused diuresis in healthy volunteers; headache and tiredness were reported as side effects only when it was given together with hypertonic saline infusion (Kramer et al. 2000).

The renin–angiotensin–aldosterone axis and vasopressin (AVP) are two of the important systems involved in regulating serum and urine electrolytes and osmolality. Angiotensin II stimulates aldosterone release from the adrenal cortex, and aldosterone stimulates sodium reabsorption through Na+–H+ and Na+–K+ pumps. AVP is a polypeptide hormone released from the posterior pituitary gland in response to changes in blood pressure and plasma osmolality. It regulates the permeability of the distal tubule and collecting ducts and affects urine osmolality. Kappa opioid agonist-induced suppression of AVP release was established in several previous animal studies (Yamada et al. 1989; Craft et al. 2000).

In the present work, we investigated, for the first time, urine output and renal excretory response in conscious and euvolemic rats after administration of two non-arylacetamide kappa opioid receptor agonists, nalfurafine (Endoh et al. 1999; Togashi et al. 2002; Inan and Cowan 2004) and salvinorin A (Roth et al. 2002; Sheffler and Roth 2003; Wang et al. 2005), as well as 2-methoxymethyl-salvinorin B (MOM-sal B), a C-2 modified longer-acting analog of salvinorin A (Wang et al. 2008; Béguin et al. 2008). U50,488H (VonVoigtlander et al. 1983; Ko et al. 2003) served as the reference, arylacetamide kappa agonist.

Methods and materials

Animals

The study was conducted on 262 male, Sprague–Dawley rats (175–200 g; n = 6–10; Ace Laboratories, Boyertown, PA, USA). The rats were housed three per cage with free access to food and water in the Animal Facility for at least 4 days. A standard light/dark cycle was maintained with a timer-regulated light period from 7:00 a.m. to 7:00 p.m. Experiments were carried out between 10:00 a.m and 5:00 p.m. Experimental procedures were approved by the Temple University Institutional Animal Care and Use Committee.

On the experimental day, animals were brought to the laboratory and acclimated for at least 1 h with free access to food and water before injections. At the end of the experiments, animals were euthanized using carbon dioxide gas.

Diuresis study

Rats were given (s.c.) saline, nalfurafine (0.005–0.06 mg/kg), U50,488H (0.1–10 mg/kg), salvinorin A (0.1–10 mg/kg), MOM-sal B (0.625–5 mg/kg), or vehicle. The animals were then placed into individual metabolism cages with no access to food and water for urine collection over 5 h. Urine was collected in graduated cylinders, and total urine volume was recorded. Urine osmolality and Na+ levels were measured. To follow the time course of nalfurafine-induced diuresis and compare with saline, U50,488H, and MOM-sal B, rats were given saline, nalfurafine (0.02 mg/kg), U50,488H (10 mg/kg), or MOM-sal B (2.5 mg/kg), placed in observation cages, and urine output noted every 30 min for 5 h.

Other groups of rats were injected with saline, nalfurafine (0.02 mg/kg), U50,488H (10 mg/kg, s.c.), or MOM-sal B (2.5 mg/kg) to measure AVP levels at 2 h. After the injections, rats were placed into metabolism cages, and 2 h later, heart blood was drawn with the animals anesthetized with isofluorane.

In order to establish if centrally administered salvinorin A induces diuresis, rats were anesthetized with ketamine (80 mg/kg, i.p.) in combination with xylazine (8 mg/kg, i.p.), and the right lateral cerebroventricle was cannulated. Cannulas, made from PE 10 tubing, were implanted (incision bar at 0 position, anterior-posterior 2 mm, lateral 2 mm, and vertical 2 mm from bregma) using stereotaxic equipment and fixed with dental cement. Either 3 or 4 days after surgery, vehicle or a fixed dose of salvinorin A (50 μg/5 μl) was infused over 30 s through the cannula into the lateral ventricle. The animals were then placed into individual metabolism cages for 5 h for cumulative urine collection. To select the dose of salvinorin A, we were guided by Ansonoff et al. (2006) who used 1–30 μg in mice. If we obtained diuresis with a high dose, we would develop a dose–response curve. At the end of the experiment, methylene blue (5 μl) was injected into the lateral cerebroventricle, the rat was euthanized, the brain removed, and the cannula placement confirmed.

Subchronic administration of nalfurafine

We conducted a multiple dose study with nalfurafine (0.02 mg/kg, s.c.) in rats to examine, first, whether tolerance develops to the diuretic effect and, second, to learn how serum and urine Na+ levels may be affected. We injected nalfurafine, U50,488H (10 mg/kg, s.c.), or saline once a day for seven consecutive days. Total cumulative urine output in 5 h was recorded on both days 1 and 7. Urine samples from day 7 were also used to measure urine osmolality and Na+ and K+ levels. Also, at the end of urine collection on day 7, heart blood was drawn with animals under isofluorane anesthesia. Serum was obtained to measure Na+ levels.

Experiments with 5′-guanidinonaltrindole, a kappa receptor antagonist

To potentially antagonize diuresis elicited by kappa opioid agonists, rats were pretreated s.c. with either saline or a fixed dose of 5′-guanidinonaltrindole (GNTI; 0.1 mg/kg) 30 min before the injection of either saline or a maximally effective dose of kappa agonist. Also, a dose–response curve for increasing doses of GNTI (0.1–3 mg/kg) against a maximally effective dose of nalfurafine was developed in rats. In order to establish if nalfurafine-induced diuresis is antagonized by centrally administered GNTI, the right lateral cerebroventricle of each animal was cannulated as mentioned previously. Either 3 or 4 days after surgery, saline or GNTI (0.005–25 μg/5 μl) was infused over 30 s through the cannula into the lateral ventricle. Nalfurafine (0.02 mg/kg) or saline was injected s.c. 15 min later, and rats were placed in metabolism cages for 5 h. Total cumulative urine volume was then recorded. At the end of the experiment, the cannula placement was again confirmed.

Measurement of adenylyl cyclase activity in hypothalamus of rats after subchronic injection of nalfurafine

Activation of kappa opioid receptors by an agonist inhibits adenylyl cyclase activity (Yasuda et al. 1993; Gharagozlou et al. 2006). Microinjection of U50,488H to the paraventricular area of the hypothalamus induces diuresis in rats (Gottlieb et al. 2005). To determine whether the hypothalamus is involved in nalfurafine-induced diuresis in rats, we measured adenylyl cyclase activity in this species. Rats, administered saline or nalfurafine (s.c., once a day for 7 days), were exposed to carbon dioxide gas for 15 s and subsequently killed by decapitation. Their brains were rapidly removed, and the hypothalamus was dissected on ice to measure adenylyl cyclase activity in crude membranes. These membranes were prepared by homogenizing the tissue in 5 ml of 20 mM Tris–HCl (pH 7.4), 2 mM ethylene glycol bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), 1 mM MgCl2, and 250 mM sucrose followed by centrifugation at 30,000×g for 15 min at 4°C. The pellets were resuspended in 5 ml of buffer and centrifuged again for 15 min. The supernatants were discarded and the pellets homogenized in 40 volumes of ice-cold buffer containing 2 mM Tris–HCl (pH 7.4) and 2 mM EGTA and stored at −80°C. Adenylyl cyclase activity was measured as described previously (Unterwald et al. 1993). Aliquots of tissue homogenate (10 μl) were incubated in 80 mM Tris–HCl (pH 7.4), 10 mM theophylline, 1 mM MgSO4, 0.8 mM EGTA, 30 mM NaCl, 0.25 mM adenosine triphosphate (ATP), and 0.01 mM guanosine triphosphate (GTP) in triplicate for 5 min at 30°C. Adenylyl cyclase activity was terminated by placing the tubes into boiling water for 2 min. The amount of adenosine 3′,5′-cyclic phosphate (cAMP) formed was determined by a [3H]cAMP protein binding assay (Brown et al. 1971). [3H]cAMP (final concentration 4 nM) in citrate phosphate buffer (pH 4.0), followed by binding protein prepared from bovine adrenal glands, were added to each sample. Additional samples were prepared, without tissue, containing known amounts of cAMP and served as standards for quantification. The binding reaction was allowed to reach equilibrium by incubation for 90 min at 4°C. The assay was terminated by the addition of charcoal and centrifugation to separate free cAMP from that bound to the binding protein. Aliquots of the supernatants were assayed for radioactivity by liquid scintillation spectrometry using CytoScint Scintillation Fluid (ICN Biomedicals, CA, USA). Radioactivity was converted to picomole of cAMP by comparison with the curve derived from standards.

Measurements

Osmolality was measured by osmometric depression of the freezing point method (Advanced Instruments Osmometer 3300, MA, USA). Serum and urine Na+, as well as urine K+ levels, were measured using the connectivity method (Beckman LX20, Fullerton, CA, USA) in the clinical laboratory of Temple University Hospital, and urinary sodium excretion (UNaV) and urinary potassium excretion (UKV) were calculated. Serum AVP and angiotensin II levels were measured in duplicated samples using enzyme-linked immunosorbent assay kits described by the manufacturer (Phoenix Pharmaceuticals, CA, USA).

Compounds

U50,488H [(trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzene-acetamide)methane sulfonate] (Sigma, St. Louis, MO, USA), nalfurafine (a generous gift from Adolor Company, Exton, PA, USA), and 5′-guanidinonaltrindole (Tocris, Ellisville, MI, USA) were dissolved in saline. Salvinorin A and MOM-sal B were provided by Dr. D.Y.-W. Lee and dissolved in ethanol/Tween 80/water vehicle (1:1:8 proportion by volume).

[3H]cAMP (adenosine 3′,5′-cyclic phosphate, ammonium salt; specific activity 31.0 Ci/mmol) was obtained from PerkinElmer Life Sciences (Waltham, CA, USA). ATP, GTP, cAMP, theophylline, and EGTA were purchased from Sigma.

Statistical analysis

Data are expressed as mean ± standard deviation (SD) from mean and considered statistically significant at a p value of 0.05 or less. A one-way analysis of variance (ANOVA), followed by the Newman–Keuls test, was used to compare groups. The unpaired Student’s t test was used to compare two groups.

Results

Kappa agonist-induced diuresis in rats

Nalfurafine (0.005–0.06 mg/kg), U50,488H (0.1–10 mg/kg), and MOM-sal B (0.625–5 mg/kg) increased urine output in rats. Salvinorin A given either systemically (0.1–10 mg/kg) or i.c.v. (50 μg/5 μl, data not shown) had no marked effect on urine output (Fig. 1). Urine output for rats injected with saline (s.c.) was 1.37 ± 0.17 ml/5 h and, for rats injected with the vehicle (s.c.) for both salvinorin A and MOM-sal B, was 2.57 ± 0.46 ml/5 h. Our results showed that nalfurafine is a more potent diuretic than U50,488H and MOM-sal B. A centrally administered high dose of salvinorin A failed to increase urine output (2.65 ± 0.65 and 2.30 ± 0.59 ml/5 h after injections of salvinorin A and vehicle, respectively). Lower urine osmolality and low UNaV levels were found in rats injected with nalfurafine (0.02 mg/kg), U50,488H (10 mg/kg), and MOM-sal B (2.5 mg/kg) compared with saline-injected animals, suggesting a water diuresis which is typical for kappa agonist-induced diuresis (Table 1). The time course of nalfurafine-, U50,488H-, and MOM-sal B-induced diuresis is shown in Fig. 2. All compounds elicited their maximum effect around 210 min. Serum angiotensin II levels were similar in rats injected with saline–saline, GNTI-saline, saline-nalfurafine, saline-U50,488H, GNTI-nalfurafine and GNTI-U50,488H (data not shown). While nalfurafine and MOM-sal B had no effect on serum AVP levels (at 2 h), an increase in serum AVP level was detected in rats injected with saline-U50,488H (10 mg/kg; Fig. 3).
Fig. 1

Urine output in 5 h in rats treated s.c. with nalfurafine, U50,488H, salvinorin A, MOM-sal B, and vehicle (n = 6–10). Nalfurafine, U50,488H, and MOM-sal B cause increases in urine output. Urine output for rats injected with saline (s.c.) was 1.37 ± 0.17 ml/5 h and for rats injected with the vehicle (s.c.) for both salvinorin A and MOM-sal B was 2.57 ± 0.46 ml/5 h

Fig. 2

Time-course of diuresis induced by nalfurafine, U50,488H, and MOM-sal B in rats (n = 8). Animals were injected s.c. with saline, nalfurafine (0.02 mg/kg), U50,488H (10 mg/kg), MOM-sal B (2.5 mg/kg), or vehicle and urine output was measured every 30 min for 5 h

Fig. 3

Serum AVP levels in rats. An increase in serum arginine vasopressin level is obtained in rats (n = 6) injected s.c. with U50,488H (10 mg/kg) but not with nalfurafine (0.02 mg/kg) or MOM-sal B (2.5 mg/kg; *p < 0.05 one-way ANOVA and Newman–Keuls tests). Blood was drawn 2 h after the injection of compounds

Table 1

Mean ± SD values of cumulative urine output, urine osmolality, free water clearance, and urinary excretion of sodium in rats (n = 6) treated (s.c.) with saline, U50,488H, nalfurafine, and MOM-sal B

 

Saline

U50,488H

Nalfurafine

MOM-sal B

(10 mg/kg)

(0.02 mg/kg)

(2.5 mg/kg)

Urine output (ml/5 h)

2.1 ± 0.9

6.2 ± 0.9**

9.8 ± 1.2**

14.2 ± 1.99**

Uosm (mOsm/kg)

473 ± 46.7

75.8 ± 23.7**

106 ± 32.1**

63.8 ± 18.2**

CH2O (ml/5 h)

−1.4 ± 0.9

4.4 ± 0.9**

6.2 ± 1.1**

11.1 ± 2.3**

UNaV (mEq/5 h)

46.3 ± 21.2

2.7 ± 0.8**

2.9 ± 0.9**

1.3 ± 0.8**

Uosm urine osmolality, CH20 free water clearance, UNaV urinary excretion of sodium

**p < 0.01 (compared with saline)

Tolerance studies

Tolerance did not develop to the diuretic effect of nalfurafine (0.02 mg/kg, s.c.; Fig. 4). There was no statistically significant difference among urine outputs over the 7 days for nalfurafine (as well as for U50,488H). Day 1 urine volumes were 8.43 ± 2.0 and 7.56 ± 1.94 ml, whereas those on day 7 were 10.80 ± 2.40 and 8.59 ± 1.77 ml for nalfurafine and U50,488H, respectively. Urine osmolality was similar on days 1 and 7 for all three groups of rats (injected with saline, U50,488H, or nalfurafine) but was significantly lower in rats injected with U50,488H or nalfurafine compared with saline-injected rats both on days 1 and 7 (p < 0.01). On day 7, significantly lower UNaV and UKV levels were measured in rats injected with either U50,488H or nalfurafine compared with saline-injected rats. There was no difference among the three groups of rats for serum Na+ levels (Table 2).
Fig. 4

Daily urine output in rats injected with nalfurafine. The daily urine output, over 5 h, is similar for 7 days. Tolerance to the diuretic effect of nalfurafine (0.02 mg/kg, s.c.) does not develop during once a day injection of nalfurafine to rats (n = 6) for 7 days

Table 2

Mean ± SD values of urine output, urine osmolality, free water clearance, urinary excretion of sodium, and serum Na+ levels on day 7 in rats treated (s.c.) once a day for 7 days with saline, U50,488H, and nalfurafine

 

Saline

U50,488H

Nalfurafine

(10 mg/kg)

(0.02 mg/kg)

Urine output (ml/5 h)

2.2 ± 0.34

8.0 ± 1.91**

10.8 ± 0.94**

Uosm (mosm/kg)

290 ± 42.8

122 ± 63.9**

75 ± 25.9**

CH2O (ml/5 h)

−0.06 ± 0.31

4.7 ± 2.48**

7.9 ± 1.56**

UNaV (mEq/5 h)

56.3 ± 21.7

7.7 ± 4.27**

4.2 ± 2.0**

UKV (mEq/5 h)

67.7 ± 22.4

13.7 ± 8.0**

6.1 ± 2.87**

Serum Na+ (mmol/L)

134 ± 3.21

134 ± 7.1

132 ± 7.41

Uosm urine osmolality, CH20 free water clearance, UNaV urinary excretion of sodium, UKV urinary excretion of potassium

**p < 0.01 (compared to saline)

Antagonizing kappa agonist-induced diuresis with GNTI

Pretreatment of rats with GNTI (0.1 mg/kg, s.c., at −30 min) significantly decreased U50,488H-induced (10 mg/kg, s.c.) and MOM-sal B-induced (2.5 mg/kg, s.c.) diuresis (Fig. 5). GNTI (0.1–3 mg/kg, s.c. at −30 min) inhibited nalfurafine-induced (0.02 mg/kg, s.c.) diuresis in a dose-dependent manner (Fig. 6). Similarly, i.c.v. administration of GNTI (0.005–25 μg) antagonized this effect of nalfurafine in a dose-dependent manner (Fig. 7). A 25-μg dose of GNTI reduced urine output to control levels. Rats appeared behaviorally normal during systemic and i.c.v. injections of high doses of GNTI.
Fig. 5

GNTI (0.1 mg/kg, s.c.) antagonizes U50,488H (10 mg/kg, s.c.) as well as MOM-sal B-induced (2.5 mg/kg) diuresis (*p < 0.05, **p < 0.01, n = 6)

Fig. 6

GNTI (0.1–3 mg/kg, s.c. at −30 min) inhibits nalfurafine-induced (0.02 mg/kg, s.c.) diuresis in a dose-dependent manner. **p < 0.01 compared with saline-nalfurafine; single pound sign p < 0.05 and double pound sign p < 0.01 compared with different doses of GNTI pretreatment, n = 6–8

Fig. 7

Intracerebroventricular injection of GNTI (0.005–25 μg/5 μl at −15 min) inhibits nalfurafine-induced (0.02 mg/kg, s.c.) diuresis in rats (**p < 0.01; n = 6)

Nalfurafine’s effect on basal cAMP level in hypothalamus

Nalfurafine caused a significant decrease, compared to saline, in basal cAMP level in the hypothalamus of rats (142.16 ± 21.40 and 259.10 ± 31.12 pmol/mg protein, respectively, p < 0.01).

Discussion

We have studied diuretic effects of the chemically diverse kappa opioid agonists nalfurafine (an epoxymorphinan), U50,488H (an arylacetamide), salvinorin A (a neoclerodane diterpene), and MOM-sal B (the C-2 derivative of salvinorin A) in rats. Our results show that nalfurafine, U50,488H, and MOM-sal B induce water diuresis, whereas salvinorin A is ineffective. Nalfurafine-induced diuresis was antagonized dose-dependently by both systemic and central administration of the kappa opioid receptor antagonist, GNTI, suggesting that the diuresis is mediated by kappa opioid receptors. Additionally, a fixed dose of GNTI inhibited fixed doses of both U50,488H- and MOM-sal B-induced diuresis in rats. A decrease in the basal cAMP level after subchronic injection of nalfurafine indicates that the hypothalamus is involved in nalfurafine-induced diuresis in rats.

Salvinorin A is an active (hallucinatory) ingredient of the psychoactive plant Salvia divinorum that has been used by the Mazatec people in Mexico for traditional spiritual practices. The leaves of the plant and various extracts are available over the internet. Salvinorin A is the first non-nitrogenous, naturally occurring, highly selective kappa opioid receptor agonist (Roth et al. 2002; Sheffler and Roth 2003; Wang et al. 2005; Prisinzano and Rothman 2008). It has hallucinogenic effects which last approximately 1 h in doses between 200 and 500 μg after smoking by humans (Prisinzano 2005). Carlezon et al. (2006) described a depressive-like effect in rats with 0.125–2 mg/kg, i.p. doses of salvinorin A using the forced swim test. Butelman et al. (2004) reported that salvinorin A elicits kappa opioid agonist-like discriminative effects in rhesus monkeys. Salvinorin A (s.c.) was inactive in mice as an antipruritic against compound 48/80-induced scratching behavior and showed only brief antinociception in this species (Wang et al. 2005; Ansonoff et al. 2006; McCurdy et al. 2006).

Salvinorin A was not a diuretic in rats. Furthermore, salvinorin A (1–4 mg/kg, both i.p. and s.c.) did not increase urine output in mice (unpublished data). Schmidt et al. (2005) determined salvinorin A and its inactive metabolite, salvinorin B, in body fluids (from monkeys and humans) using high-performance liquid chromatography-atmospheric pressure chemical ionization. From their work, the duration of action of salvinorin A seems to be short. This brief duration of action is probably responsible for the ineffectiveness of salvinorin A. It has been suggested that the site of interaction of salvinorin A to kappa opioid receptors differs from that of its analogs (Prisinzano and Rothman 2008). This might provide another reason for the lack of diuresis associated with salvinorin A. MOM-sal B, the longer acting derivative of salvinorin A, shows antinociceptive and hypothermic effects in rats (Wang et al. 2008). Furthermore, we report here that MOM-sal B increases urine output in this species.

Nalfurafine possesses antinociceptive (Endoh et al. 1999, 2000, 2001; Suzuki et al. 2004) and antipruritic (Togashi et al. 2002; Inan and Cowan 2004, 2006a, b) effects in animals. Critically, for drug development in the field of kappa opioid research, nalfurafine has been found effective in patients suffering from uremic pruritus (Wikström et al. 2005). Side effects traditionally associated with kappa agonists (e.g., paresthesia, abnormal thinking, dysphoria) were absent. Diuresis was not mentioned. Our results indicate that nalfurafine may be a candidate diuretic for treating water retention. First of all, this kappa agonist induces diuresis without electrolyte imbalance in rats and perhaps in other species. During acute injection of nalfurafine, antinatriuresis was noted. In our multiple-dose study, serum Na+ levels remained within normal physiological limits. In clinical practice, maintenance of electrolyte levels during diuretic treatment is desirable. Furosemide and other loop diuretics cause diuresis as well as natriuresis and kaliuresis. Acute tolerance develops to the diuresis (Hammarlund et al. 1985; Wakelkamp et al. 1996) and natriuresis (Wakelkamp et al. 1996) after multiple doses of furosemide in healthy volunteers. In our study, after once a day injection of nalfurafine to rats for 7 days, daily urine volumes were comparable, suggesting that tolerance does not develop. Similarly, tolerance to the diuretic effect of U50,488H does not develop during chronic injections in rats (VonVoigtlander et al. 1983) and in monkeys (Ko et al. 2003).

The mechanisms underlying the diuresis induced by kappa agonists are not clear. For example, kappa agonists have been shown to increase, decrease, or cause no change in serum AVP levels. Gottlieb et al. (2005) reported that microinjection of U50,488H to the magnocellular area of the hypothalamic paraventricular nucleus (PVN), but not the parvocellular area of the PVN, produces diuresis by inhibiting AVP secretion. Their data suggested that an increase in renal sympathetic outflow is responsible for the antinatriuretic effect of U50,488H. Decreased AVP levels in rats (Yamada et al. 1989; Craft et al. 2000) and the lack of diuresis in Brattleboro rats (which do not have endogenous AVP; Slizgi and Ludens 1986; Yamada et al. 1989) following systemically given kappa agonists have been reported. However, Ashton et al. (1989) demonstrated that U50,488H does not alter plasma AVP levels in rats. Kramer et al. (2000) investigated plasma AVP, cyclic adenosine monophosphate, and atrial natriuretic peptide levels as well as urine endothelin levels during administration of asimadoline, the peripherally directed kappa agonist. Under basal conditions, asimadoline did not change these parameters. Only plasma AVP levels were suppressed by high doses of asimadoline after stimulation with 2.5% saline infusion. Similarly, Rimoy et al. (1991) reported that spiradoline, an arylacetamide kappa agonist, causes water diuresis in human volunteers with no change in plasma AVP levels. After bremazocine (a benzomorphan kappa agonist) injection in rats, Huidobro-Toro and Parada (1985) reported an increase in plasma AVP, whereas Craft et al. (2000) found a decrease in plasma AVP. In the present study, we found an increase in serum AVP in rats injected with U50,488H but no change in rats injected with nalfurafine or MOM-sal B. We drew blood at the end of the 2-h experimental period. In previous studies, AVP levels were measured 20 min to 2 h after kappa agonist injection (Ashton et al. 1989; Craft et al. 2000). Also, most of the studies measured AVP after stimulated AVP secretion (induced by either hyperosmolar fluid infusion or 24 h water depletion). Craft et al. (2000) detected a decrease in AVP levels in 24 h water-deprived rats but not in normally hydrated rats. In our experiments, we used normally hydrated rats. Given these diverse results, it is not possible to conclude that kappa opioid agonists induce diuresis solely by inhibiting AVP secretion.

In summary, we investigated the effects of nalfurafine, salvinorin A, and MOM-sal B on urine output and renal excretory response in rats. Our results show that (1) nalfurafine induces water diuresis and may be a candidate diuretic for relieving water retention, and (2) salvinorin A, a recognized kappa opioid receptor agonist, does not cause diuresis, whereas its longer-acting C-2 derivative, MOM-sal B, increases urine output. The lack of diuresis associated with salvinorin A is probably due to its short duration of action.

Notes

Acknowledgements

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.

References

  1. Ansonoff MA, Zhang J, Czyzyk T, Rothman RB, Stewart J, Xu H, Zjwiony J, Siebert DJ, Yang F, Roth BL, Pintar JE (2006) Antinociceptive and hypothermic effects of salvinorin A are abolished in a novel strain of κ-opioid receptor-1 knockout mice. J Pharmacol Exp Ther 318:641–648PubMedCrossRefGoogle Scholar
  2. Ashton N, Balment RJ, Blackburn TP (1989) Kappa-opioid-receptor agonists modulate the renal excretion of water and electrolytes in anaesthetized rats. Br J Pharmacol 99:181–185Google Scholar
  3. Béguin C, Potter DN, DiNieri JA, Munro TA, Richards MR, Paine TA, Berry L, Zhao Z, Roth BL, Xu W, Liu-Chen LY, Carlezon WA Jr, Cohen BM (2008) N-methylacetamide analog of salvinorin A: a highly potent and selective kappa-opioid agonist with oral efficacy. J Pharmacol Exp Ther 324:188–195PubMedCrossRefGoogle Scholar
  4. Bellissant E, Denolle T, Sinnassamy P, Bichet DG, Giudicelli JF, Lecoz F, Gandon JM, Allain H (1996) Systemic and regional hemodynamic and biological effects of a new kappa-opioid agonist, niravoline, in healthy volunteers. J Pharmacol Exp Ther 278:232–242PubMedGoogle Scholar
  5. Brooks DP, Valente M, Petrone G, Depalma PD, Sbacchi M, Clarke GD (1997) Comparison of the water diuretic activity of kappa receptor agonists and a vasopressin receptor antagonist in dogs. J Pharmacol Exp Ther 280:1176–1183PubMedGoogle Scholar
  6. Brown BL, Albano JDM, Ekins RP, Sgherzi AM, Tampion W (1971) A simple and sensitive saturation assay method for measurement of adenosine 3′,5′-cyclic monophosphate. Biochem J 121:561–562PubMedGoogle Scholar
  7. Butelman ER, Harris TJ, Kreek MJ (2004) The plant-derived hallucinogen, salvinorin A, produces κ-opioid agonist-like discriminative effects in rhesus monkeys. Psychopharmacology 172:220–224PubMedCrossRefGoogle Scholar
  8. Carlezon WA, Béguin C, Dinieri JA, Baumann MH, Richards MR, Todtenkopf MS, Rothman RB, Ma Z, Lee DY, Cohen BM (2006) Depressive-like effects of the κ-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats. J Pharmacol Exp Ther 316:440–447PubMedCrossRefGoogle Scholar
  9. Craft RM, Ulibarri CM, Raub DJ (2000) Kappa opioid-induced diuresis in female vs. male rats. Pharmacol Biochem Behav 65:53–59PubMedCrossRefGoogle Scholar
  10. Endoh T, Matsuura H, Tajima A, Izumimoto N, Tajima C, Suzuki T, Narita M, Tseng L, Nagase H (1999) Potent antinociceptive effects of TRK-820, a novel kappa-opioid receptor agonist. Life Sci 65:1685–1694PubMedCrossRefGoogle Scholar
  11. Endoh T, Tajima A, Suzuki T, Kamei J, Narita M, Tseng L, Nagase H (2000) Characterization of the antinociceptive effects of TRK-820 in the rat. Eur J Pharmacol 387:133–140PubMedCrossRefGoogle Scholar
  12. Endoh T, Tajima A, Izumimoto N, Suzuki T, Saitoh A, Suzuki T (2001) TRK-820, a selective kappa-opioid agonist, produces potent antinociception in cynomolgus monkeys. Jpn J Pharmacol 85:282–290PubMedCrossRefGoogle Scholar
  13. Gadano A, Moreau R, Pessione F, Trombino C, Giuily N, Sinnassamy P (2000) Aquaretic effects of niravoline, a kappa-opioid agonist, in patients with cirrhosis. J Hepatol 32:38–42PubMedCrossRefGoogle Scholar
  14. Gharagozlou P, Hashemi E, DeLorey TM, Clark JD, Lameh J (2006) Pharmacological profiles of opioid ligands at kappa opioid receptors. BMC Pharmacology 6:3PubMedCrossRefGoogle Scholar
  15. Gottlieb HB, Varner KJ, Kenigs VA, Cabral AM, Kapusta DR (2005) Differential cardiovascular and renal responses produced by microinjection of the κ-opioid U-50488H [(trans-3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzene-acetamide)methane sulfonate] into subregions of the paraventricular nucleus. J Pharmacol Exp Ther 312:678–685PubMedCrossRefGoogle Scholar
  16. Hammarlund MM, Odlind B, Paalzow LK (1985) Acute tolerance to furosemide diuresis in humans. Pharmacokinetic-pharmacodynamic modeling. J Pharmacol Exp Ther 233:447–453PubMedGoogle Scholar
  17. Huidobro-Toro JP, Parada S (1985) Kappa-opiates and urination: pharmacological evidence for an endogenous role of the kappa-opiate receptor in fluid and electrolyte balance. Eur J Pharmacol 107:1–10Google Scholar
  18. Inan S, Cowan A (2004) Kappa opioid agonists suppress choloroquine-induced scratching in mice. Eur J Pharmacol 502:233–237PubMedCrossRefGoogle Scholar
  19. Inan S, Cowan A (2006a) Agmatine-induced stereotyped scratching in mice is antagonized by nalfurafine, a kappa opioid agonist. Pharmacologist 48:38Google Scholar
  20. Inan S, Cowan A (2006b) Nalfurafine, a kappa opioid receptor agonist, inhibits scratching behavior secondary to cholestasis induced by chronic ethynylestradiol injections in rats. Pharmacol Biochem Behav 85:39–43PubMedCrossRefGoogle Scholar
  21. Ko MC, Willmont KJ, Lee H, Flory GS, Woods JH (2003) Ultra-long antagonism of kappa opioid agonist-induced diuresis by intracisternal nor-binaltorphimine in monkeys. Brain Res 982:38–44PubMedCrossRefGoogle Scholar
  22. Kramer HJ, Uhl W, Lanstetter B, Bäcker A (2000) Influence of asimadoline, a new κ-opioid receptor agonist, on tubular water absorbtion and vasopressin secretion in man. Br J Clin Pharmacol 50:227–235PubMedCrossRefGoogle Scholar
  23. McCurdy CR, Sufka KJ, Smith GH, Warnick JE, Nieto MJ (2006) Antinociceptive profile of salvinorin A, structurally unique kappa opioid receptor agonist. Pharmacol Biochem Behav 83:109–113PubMedCrossRefGoogle Scholar
  24. Prisinzano TE (2005) Psychopharmacology of the hallucinogenic sage Salvia divinorum. Life Sci 78:527–531PubMedCrossRefGoogle Scholar
  25. Prisinzano TE, Rothman RB (2008) Salvinorin A analogs as probes in opioid pharmacology. Chem Rev 108:1732–1743PubMedCrossRefGoogle Scholar
  26. Rathbun RC, Kattau RW, Leander JD (1983) Effects of mu- and kappa-opioid receptor agonists on urinary output in mice. Pharmacol Biochem Behav 19:863–866PubMedCrossRefGoogle Scholar
  27. Rimoy GH, Bhaskar NK, Wright DM, Rubin PC (1991) Mechanism of diuretic action of spiradoline (U-62066E)-a kappa opioid receptor agonist in human. Br J Clin Pharmacol 32:611–615PubMedGoogle Scholar
  28. Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Emsberger P, Rothman RB (2002) Salvinorin A: a potent naturally occurring nonnitrogenous κ opioid selective agonist. Proc Natl Acad Sci USA 99:11934–11939PubMedCrossRefGoogle Scholar
  29. Schmidt MS, Prisinzano TE, Tidgewell K, Harding W, Butelman ER, Kreek MJ, Murry DJ (2005) Determination of salvinorin A in body fluids by high performance liquid chromatography-atmospheric pressure chemical ionization. J Chromatogr B 818:221–225CrossRefGoogle Scholar
  30. Sheffler DJ, Roth BL (2003) Salvinorin A: the “magic mint” hallucinogen finds a molecular target in the kappa opioid receptor. Trends Pharmacol Sci 24:107–109PubMedCrossRefGoogle Scholar
  31. Slizgi GR, Ludens JH (1986) Role of ADH in ethylketocyclazocine-induced diuresis studies in the Brattleboro rat. Life Sci 38:2437–2440PubMedCrossRefGoogle Scholar
  32. Suzuki T, Izumimoto N, Takezawa Y, Fujimura M, Togashi Y, Nagase H, Tanaka T, Endoh H (2004) Effect of repeated administration of TRK-820, a kappa opioid receptor agonist, on tolerance to its antinociceptive and sedative actions. Brain Res 995:167–175PubMedCrossRefGoogle Scholar
  33. Togashi Y, Umeuchi H, Okano K, Ando N, Yoshizawa Y, Honda T, Kawamura K, Endoh T, Utsumi J, Kamei J, Tanaka T, Nagase H (2002) Antipruritic activity of the κ-opioid receptor agonist, TRK-820. Eur J Pharmacol 435:259–264PubMedCrossRefGoogle Scholar
  34. Unterwald EM, Cox BM, Kreek MJ, Cote TE, Izenwasser S (1993) Chronic repeated cocaine administration alters basal and opioid-regulated adenylyl cyclase activity. Synapse 15:33–38PubMedCrossRefGoogle Scholar
  35. VonVoigtlander PF, Lahti RA, Ludens JH (1983) U-50,488: a selective and structurally novel non-mu (kappa) opioid agonist. J Pharmacol Exp Ther 224:7–12PubMedGoogle Scholar
  36. Wakelkamp M, Alvan G, Gabrielsson J, Paintaud G (1996) Pharmacodynamic modeling of furosemide tolerance after multiple intravenous administration. Clin Pharmacol Ther 60:75–88PubMedCrossRefGoogle Scholar
  37. Wang Y, Tang K, Inan S, Siebert D, Holzbrabe U, Lee DY, Huang P, Li JG, Cowan A, Liu-Chen LY (2005) Comparison of pharmacological activities of three distinct κ ligands (salvinorin A, TRK-820 and 3FLB) on κ opioid receptors in vitro and their antipruritic and antinociceptive activities in vivo. J Pharmacol Exp Ther 312:220–230PubMedCrossRefGoogle Scholar
  38. Wang Y, Chen Y, Xu W, Lee DYW, Ma Z, Rawls SM, Cowan A, Liu-Chen LY (2008) 2-Methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist with longer lasting action in vivo than salvinorin A. J Pharmacol Exp Ther 324:1073–1083PubMedCrossRefGoogle Scholar
  39. Wikström B, Gellert R, Ladefoged SD, Danda Y, Akai M, Ide K, Ogasawara M, Kawashima Y, Ueno K, Mori A, Ueno Y (2005) κ-Opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies. J Am Soc Nephrol 16:3742–3747PubMedCrossRefGoogle Scholar
  40. Yamada K, Imal M, Yoshida S (1989) Mechanism of diuretic action of U-62,066E, a kappa opioid receptor agonist. Eur J Pharmacol 160:229–237PubMedCrossRefGoogle Scholar
  41. Yasuda K, Raynor K, Kong H, Breder CD, Takeda J, Reisine T, Bell GI (1993) Cloning and functional comparison of κ and δ opioid receptors from mouse brain. Proc Natl Acad Sci USA 90:6736–6740PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • S. Inan
    • 1
  • D. Y.-W. Lee
    • 2
  • L. Y. Liu-Chen
    • 1
  • A. Cowan
    • 1
  1. 1.Department of Pharmacology and Center for Substance Abuse ResearchTemple University School of MedicinePhiladelphiaUSA
  2. 2.Bio-Organic and Natural Products Laboratory, McLean HospitalHarvard Medical SchoolBelmontUSA

Personalised recommendations