Monoacylglycerol Lipase Regulates Fever Response.
Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2). Historically, phospholipases have been considered to be the primary generator of the arachidonic acid (AA) precursor pool for generating PGE2 and other eicosanoids. However, recent studies have demonstrated that monoacyglycerol lipase (MAGL), through hydrolysis of the endocannabinoid 2-arachidonoylglycerol, provides a major source of AA for PGE2 synthesis in the mammalian brain under basal and neuroinflammatory states. We show here that either genetic or pharmacological ablation of MAGL leads to significantly reduced fever responses in both centrally or peripherally-administered lipopolysaccharide or interleukin-1β-induced fever models in mice. We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors. Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.
Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA, 92037, United States of America.
Manuel
M
Sanchez-Alavez
Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA, 92037, United States of America.
William
W
Nguyen
Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA, 92037, United States of America.
Simone
S
Mori
Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy.
Gianluca
G
Moroncini
Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA, 92037, United States of America.
Andreu
A
Viader
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, 94720, United States of America.
Daniel K
DK
Nomura
Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA, 92037, United States of America.
Benjamin F
BF
Cravatt
Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA, 92037, United States of America.
Bruno
B
Conti
D000818:Animals; D001831:Body Temperature; D063385:Cannabinoid Receptor Modulators / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005334:Fever / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors
D063385:Cannabinoid Receptor Modulators; D004791:Enzyme Inhibitors; D043884:Receptor, Cannabinoid, CB1; D008994:Monoacylglycerol Lipases