Prostaglandin E2 that triggers fever is synthesized through an endocannabinoid- dependent pathway

It was recently shown that genetic or pharmacological inhibition of monoacylglycerol lipase (MAGL) blunted the fever response in mice. MAGL hydrolyzes the endocannabinoid 2-arachidonoylglycerol into arachidonic acid, providing a phospholipase-independent source of substrate for the synthesis of prostaglandin E2 (PGE2). These findings bring new light on the mechanisms of fever and identify MAGL as an antipyretic target. Perhaps it is surprising that a phenomenon so common, so extensively investigated and for the most part well controlled pharmacologically such as fever has something new and important to reveal. Or perhaps, as it is sometimes the case, the knowledge acquired on the subject is considered so solid that new findings appear unlikely or after all, marginally relevant. However, two recent studies show that the mechanisms of fever are not to be taken for granted. Fever is an old companion of humans who consider it a sign of sickness and learned to treat it before they understood it. Eventually, it was elegantly and exhaustively demonstrated that fever occurs when prostaglandin E2 act via the specific EP3 receptor to affect hypothalamic neurons that regulate thermoregulation. It was also discovered that the synthesis of PGE2 is triggered by endogenous pyrogens, i.e. interleukin 1 among other cytokines, as well as by exogenous pyrogens, i.e., bacterial lipopolysaccharides, which acted at least in part by stimulating the production of endogenous pyrogenic cytokines. This demonstrated that the pathways leading to fever can converge into a unique mechanism and identified the biochemical pathway for the synthesis of PGE as a suitable pharmacological target for the control of fever response. Indeed, fever can be controlled by inhibiting cyclooxygenases (COXs), the enzymes that convert arachidonic acid (AA) into prostaglandin G2, the precursor of PGE2 and of other prostanoids. AA can be derived from membrane phospholipids by the action of phospholipases A2 (PLA2) a calciumdependent enzyme that has generally been considered to be the main source of AA for prostaglandin production. However, less than a decade ago, Rosenberg and colleagues found that PLA2-deficient mice had unaltered brain levels of AA, suggesting the existence of an additional source of AA. Consistent with this premise, studies in the 1970s and 80s pointed to the existence of potentially alternative AA-prostaglandin pathways that involve neutral lipases converting diacylglycerols and monoacylglycerols to AA. The physiological significance of these alternative pathways, especially as pertains to the nervous system, however, remained unknown. More recently, Nomura and colleagues discovered that hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) by mono-acylglycerol lipase (MAGL) serves as a major source for AA in the brain. (Fig. 1). This novel and PLA-independent route for AA production is biologically significant as genetic or pharmacological inhibition of MAGL effectively reduced PGE2 and neuroinflammation in mice. The role of the 2-AG-MAGL pathway in fever was investigated independently by Kita and colleagues at the University of Tokyo and by Sanchez-Alavez and colleagues at The Scripps Research Institute. Both groups