Tolerance to the diuretic effects of cannabinoids and cross-tolerance to a kappa-opioid agonist in THC-treated mice.

Daily treatment with cannabinoids results in tolerance to many, but not all, of their behavioral and physiological effects. The present studies investigated the effects of 7-day exposure to 10 mg/kg/day Δ9-tetrahydrocannabinol (THC) on the diuretic and antinociceptive effects of THC and the synthetic cannabinoid AM4054. Comparison studies determined diuretic responses to the κ-opioid agonist U50,488 and furosemide. Following determination of control dose-response functions, mice received 10 mg/kg/day THC for 7 days, and dose-response functions were redetermined 24h, 7 days, or 14 days later. THC and AM4054 had biphasic diuretic effects under control conditions with maximum effects of 30 and 35 ml/kg urine, respectively. In contrast, antinociceptive effects of both drugs increased monotonically with dose to >90% MPE. Treatment with THC produced 9- and 3-fold rightward shifts of the diuresis and antinociception dose-response curves for THC and, respectively, 7- and 3-fold rightward shifts in the AM4054 dose-response functions. U50,488 and furosemide increased urine output to >35 ml/kg under control conditions. The effects of U50,488 were attenuated following 7-day treatment with THC, whereas the effects of furosemide were unaltered. Diuretic effects of THC and AM4054 recovered to near-baseline levels within 14 days after stopping daily THC injections, while tolerance to the antinociceptive effects persisted longer than 14 days. The tolerance induced by 7-day treatment with THC was accompanied by a 55% decrease in the Bmax value for cannabinoid CB1 receptors. These data indicate that repeated exposure to THC produces similar rightward shifts in the ascending and descending limbs of cannabinoid diuresis dose-effect curves, and to antinociceptive effects, while resulting in a flattening of the U50,488 diuresis dose-effect function.
The American Society for Pharmacology and Experimental Therapeutics.