title: Fever response to intravenous prostaglandin E2 is mediated by the brain but does not require afferent vagal signaling.
abstract: PGE2 produced in the periphery triggers the early phase of the febrile response to infection and may contribute to later phases. It can be hypothesized that peripherally synthesized PGE2 transmits febrigenic signals to the brain via vagal afferent nerves. Before testing this hypothesis, we investigated whether the febrigenic effect of intravenously administered PGE2 is mediated by the brain and is not the result of a direct action of PGE2 on thermoeffectors. In anesthetized rats, intravenously injected PGE2 (100 microg/kg) caused an increase in sympathetic discharge to interscapular brown adipose tissue (iBAT), as well as increases in iBAT thermogenesis, end-expired CO2, and colonic temperature (Tc). All these effects were prevented by inhibition of neuronal function in the raphe region of the medulla oblongata using an intra-raphe microinjection of muscimol. We then asked whether the brain-mediated PGE2 fever requires vagal signaling and answered this question by conducting two independent studies in rats. In a study in anesthetized rats, acute bilateral cervical vagotomy did not affect the effects of intravenously injected PGE2 (100 microg/kg) on iBAT sympathetic discharge and Tc. In a study in conscious rats, administration of PGE2 (280 microg/kg) via an indwelling jugular catheter caused tail skin vasoconstriction, tended to increase oxygen consumption, and increased Tc; none of these responses was affected by total truncal subdiaphragmatic vagotomy performed 2 wk before the experiment. We conclude that the febrile response to circulating PGE2 is mediated by the brain, but that it does not require vagal afferent signaling.
authors.affiliation: Department of Human Physiology, Centre for Neuroscience, Flinders University, Adelaide, Australia. youichirou.ootsuka@flinders.edu.au
authors.forename: Youichirou
authors.initials: Y
authors.lastname: Ootsuka
authors.forename: William W
authors.initials: WW
authors.lastname: Blessing
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Steiner
authors.forename: Andrej A
authors.initials: AA
authors.lastname: Romanovsky
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001831:Body Temperature; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002245:Carbon Dioxide / Q000378:metabolism; D015232:Dinoprostone / Q000008:administration & dosage / Q000378:metabolism*; D004195:Disease Models, Animal; D005334:Fever / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D007262:Infusions, Intravenous; D008297:Male; D009118:Muscimol / Q000008:administration & dosage; D009475:Neurons, Afferent / Q000378:metabolism; D010101:Oxygen Consumption; D011903:Raphe Nuclei / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000098:blood supply; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000503:physiopathology; D022722:Thermogenesis / Q000187:drug effects; D013997:Time Factors; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery; D014661:Vasoconstriction
chemical_list: D002245:Carbon Dioxide; D009118:Muscimol; D015232:Dinoprostone