title: The roles of prostaglandin E2 and D2 in lipopolysaccharide-mediated changes in sleep.
abstract: When living organisms become sick as a result of a bacterial infection, a suite of brain-mediated responses occur, including fever, anorexia and sleepiness. Systemic administration of lipopolysaccharide (LPS), a common constituent of bacterial cell walls, increases body temperature and non-rapid eye movement (NREM) sleep in animals and induces the production of pro-inflammatory prostaglandins (PGs). PGE2 is the principal mediator of fever, and both PGE2 and PGD2 regulate sleep-wake behavior. The extent to which PGE2 and PGD2 are involved in the effect of LPS on NREM sleep remains to be clarified. Therefore, we examined LPS-induced changes in body temperature and NREM sleep in mice with nervous system-specific knockouts (KO) for the PGE2 receptors type EP3 or EP4, in mice with total body KO of microsomal PGE synthase-1 or the PGD2 receptor type DP, and in mice treated with the cyclooxygenase (COX) inhibitor meloxicam. We observed that LPS-induced NREM sleep was slightly attenuated in mice lacking EP4 receptors in the nervous system, but was not affected in any of the other KO mice or in mice pretreated with the COX inhibitor. These results suggest that the effect of LPS on NREM sleep is partially dependent on PGs and is likely mediated mainly by other pro-inflammatory substances. In addition, our data show that the main effect of LPS on body temperature is hypothermia in the absence of nervous system EP3 receptors or in the presence of a COX inhibitor.
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Yo
authors.initials: Y
authors.lastname: Oishi
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Scammell
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan; Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan; Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka, Japan. Electronic address: lazarus.michael.ka@u.tsukuba.ac.jp.
authors.forename: Michael
authors.initials: M
authors.lastname: Lazarus
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States. Electronic address: csaper@bidmc.harvard.edu.
authors.forename: Clifford B
authors.initials: CB
authors.lastname: Saper
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D000077239:Meloxicam; D051379:Mice; D018345:Mice, Knockout; D015230:Prostaglandin D2 / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000235:genetics / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects* / Q000235:genetics; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013843:Thiazines; D013844:Thiazoles; D015232:Dinoprostone; D015230:Prostaglandin D2; D000077239:Meloxicam
keywords: Cytokine; Delta power; EEG; Fever; LoxP; Nestin-Cre; Nonsteroidal anti-inflammatory drugs; Prostacyclin; Sleepiness; Thromboxane A