Abstract
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.
Highlights
Fever is a physiological response to pathological conditions such as infection, malignancy, or severe tissue damage
Before investigating the possible role of monoacyglycerol lipase (MAGL) in fever, we compared the profile of core body temperature (CBT) of Mgll-/- and Mgll+/+ mice
Both groups of animals showed similar and normal CBT profiles in the dark, in the light and during the transitions between phases. This indicates that MAGL is not required for the maintenance of the basal CBT and temperature homeostasis and identify Mgll-/- mice as a suitable model to investigate the role of MAGL in fever
Summary
Fever is a physiological response to pathological conditions such as infection, malignancy, or severe tissue damage. Fever typically occurs when cells of the immune system respond to exogenous or endogenous insults by producing and releasing specific cytokines that lead to the production of the pyrogenic prostaglandin E2 (PGE2) in either the brain vasculature or peripheral tissues [1,2]. PGE2 elicits febrile responses largely through stimulating prostaglandin E receptor 3 (EP3) on neurons of the medial and the median preoptic nuclei (MPO and MnO, respectively) of the preoptic area (POA), leading to disinhibition of thermogenic neurons in caudal brain regions and activation of thermoregulatory effectors to increase heat production and reduce heat loss [3,4,5,6,7,8,9,10,11,12,13,14,15,16]. PGE2-lowering cyclooxygenase (COX) inhibitors, such as aspirin and ibuprofen, have been used for over a century as fever-lowering agents.
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