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

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 D 9-tetrahydrocannabinol (THC) on the diuretic and antinociceptive effects of THC and the synthetic cannabinoid AM4054. Comparison studies determined diuretic responses to the k-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 doseresponse 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 B max 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 doseeffect curves and to antinociceptive effects while resulting in a flattening of the U50,488 diuresis dose-effect function.

Convulsant Effects of Abused Synthetic Cannabinoids JWH-018 and 5F-AB-PINACA Are Mediated by Agonist Actions at CB1 Receptors in Mice

“…Similarly, pharmacokinetic differences in drug disposition might have minimized kindling with the SCBs using this particular administration schedule, and a more aggressive dosing regimen (once per day, instead of every other day) might have resulted in different effects with the SCBs. That seems unlikely, however, given that daily administration of a convulsant dose (10 mg/kg) of JWH-018 or 5F-AB-PINACA resulted in a progressive attenuation of convulsant effects, consistent with the commonly observed phenomenon of tolerance to cannabinoid effects in rodents (e.g., McMillan et al, 1972;Breivogel and Vaghela, 2015;Tai et al, 2015, Chopda et al, 2016. The fact that mice tolerant to the convulsant effects of the SCBs exhibited no crosstolerance whatsoever to PTZ-elicited convulsions further underscores the dramatic dissociations between convulsant effects of these compounds.…”

Stimulation of diuresis and natriuresis by renomedullary infusion of a dual inhibitor of fatty acid amide hydrolase and monoacylglycerol lipase

“…Paronis and colleagues (4,5,31) recently reported that various cannabinoid type 1 (CB 1 ) receptor agonists share the capacity to stimulate diuresis (defined as an increased loss of urine due to increased formation and/or increased micturition) in mice and rats. These findings suggest that the diuretic actions of anandamide or its COX-2 metabolites formed on intramedullary infusion of anandamide or IDFP could be CB 1mediated (Fig.…”

Long-Lasting In Vivo Effects of the Cannabinoid CB1 Antagonist AM6538

“…Injection Procedures. Complete dose-effect functions for agonists were generated in each mouse in single sessions using cumulative dosing procedures similar to those described previously (Chopda et al, 2016). Briefly, 60 minutes after an injection, tail-withdrawal latencies were determined and, then, mice were injected with the next dose; each injection increased the total cumulative dose by 0.5 log units.…”