35. Differential effects of endocannabinoid catabolic enzyme inhibition on thermal homeostasis following environmental or immunological stressors

Abstract

Cannabinoid receptor agonists have been repeatedly shown to have anti-pyrogenic effects in a variety of assays. In rodents, high doses of CB1 cannabinoid receptor agonists induce hypothermia. Recently, attention has turned to how endocannabinoids (eCBs), including 2-arachidonoyglycerol (2-AG) and anandamide (AEA), regulate a host of homeostatic processes including thermoregulation. Exogenous administration of 2-AG or AEA has limited efficacy, because of their rapid degradation by monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively. Inhibiting either enzyme elevates levels of each respective target eCB. This experiment tested the hypothesis that endocannabinoid catabolic enzymes function to maintain thermal homeostasis in response to hypothermic challenge. Male C57BL/6 J mice were administered a MAGL or FAAH inhibitor and challenged with a cold ambient environment or the bacterial endotoxin lipopolysaccharide (LPS; 2 mg/kg ip). MAGL inhibition exacerbated cold-induced hypothermia. Pretreatment with the selective CB1 receptor antagonist rimonabant blocked this decrease, whereas the selective CB2 antagonist SR144528 had no effect. MAGL inhibition also exacerbated LPS-induced hypothermia via CB1 receptors. In contrast, FAAH inhibition had no effect on Tb following either stressor. These data indicate that unlike direct acting cannabinoid receptor agonists, which elicit profound hypothermic responses, neither MAGL nor FAAH inhibitors affect normal body temperature. However, MAGL inhibition leads to a dysregulation of Tb via a CB1 receptor mechanism of action in mice subjected to physical or physiological stress.