Daily treatment with cannabinoids results in tolerance to many, but not all, of their behavioral and physiologic effects. The present studies investigated the effects of 7-day exposure to 10 mg/kg daily of 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. After determination of control dose-response functions, mice received 10 mg/kg daily of THC for 7 days, and dose-response functions were re-determined 24 hours, 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 of urine, respectively. In contrast, antinociceptive effects of both drugs increased monotonically with dose to >90% of maximal possible effect. Treatment with THC produced 9- and 7-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 after 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, whereas 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 receptors (CB1). 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.
- Received May 19, 2016.
- Accepted May 23, 2016.
This work was supported by Northeastern University Institutional funds and the National Institutes of Health (Grant DA035411).
Portions of this work were previously presented in G.R.C.’s doctoral dissertation defense: Cannabinoid-mediated diuresis in mice. Doctoral dissertation, Northeastern University, Boston, Massachusetts, and as Sonti S, Chopda GR, Paronis, CA, Gatley SJ. (2013). The effects of acute and chronic administration of delta-9-tetrahydrocannabinol (Δ9-THC) on receptor downregulation in mice at the 23rd Annual Symposium of the International Cannabinoid Research Society, Vancouver, BC, Canada.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics