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.2013 Jan;344(1):8-14.
doi: 10.1124/jpet.112.199331. Epub 2012 Sep 27.

Diuretic effects of cannabinoids

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Diuretic effects of cannabinoids

Carol A Paronis et al. J Pharmacol Exp Ther.2013 Jan.

Abstract

In vivo effects of cannabinoid (CB) agonists are often assessed using four well-established measures: locomotor activity, hypothermia, cataleptic-like effects, and analgesia. The present studies demonstrate that doses of CB agonists that produce these effects also reliably increase diuresis. Diuretic effects of several CB agonists were measured in female rats over 2 hours immediately after drug injection, and results were compared with hypothermic effects. Direct-acting CB1 agonists, including Δ(9)-tetrahydrocannabinol, WIN 55,212 [R-(1)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate], AM2389 [9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol], and AM4054 [9β-(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol], produced dose-dependent increases in diuresis and decreases in colonic temperature, with slightly lower ED(50) values for diuresis than for hypothermia. The highest doses of cannabinoid drugs yielded, on average, 26-32 g/kg urine; comparable effects were obtained with 10 mg/kg furosemide and 3.0 mg/kg trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50-488). Methanandamide (10.0 mg/kg) had lesser effect than other CB agonists, and the CB2 agonist AM1241 [1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole], the anandamide transport inhibitor AM404, and the CB antagonist rimonabant did not have diuretic effects. In further studies, the diuretic effects of the CB1 agonist AM4054 were similar in male and female rats, displayed a relatively rapid onset to action, and were dose-dependently antagonized by 30 minutes pretreatment with rimonabant, but not by the vanilloid receptor type I antagonist capsazepine, nor were the effects of WIN 55,212 antagonized by the CB2 antagonist AM630 [(6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone)]. These data indicate that cannabinoids have robust diuretic effects in rats that are mediated via CB1 receptor mechanisms.

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Figures

Fig. 1.
Fig. 1.
(A) Diuretic effects produced by p.o. injection of water (n = 12). (B) Diuretic effects produced by furosemide or U50-488 (n = 6). Abscissae: Volumes of water (A) or doses of drug (B) in milligrams per kilogram bodyweight; points to the left, above 0 or sal represent effects obtained after s.c. saline injection. Ordinates: Urine volume expressed as grams per kilogram bodyweight. Symbols and associated vertical lines represent the mean and S.E.M.; asterisks indicate values significantly different from saline control; *P < 0.05, **P < 0.01.
Fig. 2.
Fig. 2.
Effects of AM4054; Δ9-THC; AM2389; WIN 55,212; and rimonabant on diuresis (top) and hypothermia (bottom) (n=6 per drug); points above V represent the effects of vehicle, averaged from all groups. Bottom ordinate represents peak hypothermic effects obtained within 6 hours after drug injections and are expressed as a change from baseline values (mean, 38.55°C; range, 37.60-39.01°C); other details as in Fig 2.
Fig. 3.
Fig. 3.
Time course of diuretic and hypothermic effects of saline, 0.1–0.3 mg/kg AM4054, and 10 mg/kg furosemide (n=6 per drug). Abscissae: Time since injection (in minutes); other details as in Fig 2.
Fig. 4.
Fig. 4.
Effects of AM4054 alone (open symbols) or after 30-minutes pretreatment with rimonabant; other details as in Fig 2.
Fig. 5.
Fig. 5.
(A) Diuretic effects after injection of vehicle, 0.1 mg/kg AM4054, or 0.1 mg/kg AM4054 after a 15-minute pretreatment with 10 mg/kg capsazepine. (B) Diuretic effects after injection of vehicle; 3.0 mg/kg WIN 55,212; or 3.0 mg/kg WIN 55,212 after a 30-minute pretreatment with 10 mg/kg AM630; other details as in Fig 2.
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