title: Endocannabinoid Catabolic Enzymes Play Differential Roles in Thermal Homeostasis in Response to Environmental or Immune Challenge.
abstract: Cannabinoid receptor agonists, such as Δ(9)-THC, the primary active constituent of Cannabis sativa, have anti-pyrogenic effects in a variety of assays. Recently, attention has turned to the endogenous cannabinoid system and how endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide, regulate multiple homeostatic processes, including thermoregulation. Inhibiting endocannabinoid catabolic enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH), elevates levels of 2-AG or anandamide in vivo, respectively. The purpose of this experiment was to test the hypothesis that endocannabinoid catabolic enzymes function to maintain thermal homeostasis in response to hypothermic challenge. In separate experiments, male C57BL/6J mice were administered a MAGL or FAAH inhibitor, and then challenged with the bacterial endotoxin lipopolysaccharide (LPS; 2 mg/kg ip) or a cold (4 °C) ambient environment. Systemic LPS administration caused a significant decrease in core body temperature after 6 h, and this hypothermia persisted for at least 12 h. Similarly, cold environment induced mild hypothermia that resolved within 30 min. JZL184 exacerbated hypothermia induced by either LPS or cold challenge, both of which effects were blocked by rimonabant, but not SR144528, indicating a CB1 cannabinoid receptor mechanism of action. In contrast, the FAAH inhibitor, PF-3845, had no effect on either LPS-induced or cold-induced hypothermia. These data indicate that unlike direct acting cannabinoid receptor agonists, which elicit profound hypothermic responses on their own, neither MAGL nor FAAH inhibitors affect normal body temperature. However, these endocannabinoid catabolic enzymes play distinct roles in thermoregulation following hypothermic challenges.
authors.affiliation: Department of Psychology, West Virginia University, Morgantown, WV, 26506, USA.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Nass
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Long
authors.forename: Joel E
authors.initials: JE
authors.lastname: Schlosburg
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kinsey
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects / Q000276:immunology*; D063388:Endocannabinoids / Q000276:immunology* / Q000378:metabolism; D004777:Environment; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology*; D007035:Hypothermia / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008660:Metabolism / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D008994:Monoacylglycerol Lipases; D000099252:Fatty Acid Amide Hydrolases