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.2016 Aug;358(2):334-41.
doi: 10.1124/jpet.116.232132. Epub 2016 May 26.

Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a κ-Opioid Agonist in THC-Treated Mice

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Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a κ-Opioid Agonist in THC-Treated Mice

Girish R Chopda et al. J Pharmacol Exp Ther.2016 Aug.

Abstract

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 Δ(9)-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.

Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

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Figures

Fig. 1.
Fig. 1.
Cannabinoid diuresis over 6 hours. (A) Effects of THC before (closed symbols) and 24 hours or 14 days after 7 days of THC administration. (B) Effects of AM4054 before (closed symbols) and 24 hours, 7 days, or 14 days after 7-day THC administration. Each point represents the mean of 6–10 mice (exceptn = 3 after 10 mg/kg AM4054), and vertical bars indicate ±S.E.M. The shaded area in between dotted lines marks the 99% CI for urine volume after saline injection. Ordinates: urine output over 6 hours in ml/kg of body weight. Abscissae: drug dose in mg/kg.
Fig. 2.
Fig. 2.
Diuretic effects of U50,488 before (closed symbols) and 24 hours, 7 days, or 14 days after 7-day THC administration (n = 6–10); other details as in Fig. 1.
Fig. 3.
Fig. 3.
Time course of the antinociceptive effects of AM4054. Ordinate: antinociceptive response, expressed as a percentage of maximum possible effect (%MPE). Abscissae: time (in minutes) since injection of AM4054.
Fig. 4.
Fig. 4.
Antinociceptive effects of AM4054 and THC. (A) Effects of THC before and after 7-day THC administration (n = 8). (B) Effects of AM4054 before and after 7-day THC administration (n = 8). Ordinates: antinociceptive response, expressed as a percentage of maximum possible effect (%MPE). Abscissae: cumulative drug dose in mg/kg of body weight.
Fig. 5.
Fig. 5.
Linear Scatchard transformations of the binding of [125I]AM281 to cerebellum in mice sacrificed after 7-day vehicle administration (closed circles) or in mice sacrificed 24 hours after 7-day THC administration (open squares).
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