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.