During illnesses caused by infectious disease or other sources of inflammation, a suite of brain-mediated responses called the sickness syndrome occurs, which includes fever, anorexia, sleepiness, hyperalgesia and elevated corticosteroid secretion. Much of the sickness syndrome is mediated by prostaglandins acting on the brain and can be prevented by nonsteroidal anti-inflammatory drugs, such as aspirin or ibuprofen, that block prostaglandin synthesis. By examining which prostaglandins are produced at which sites and how they interact with the nervous system, researchers have identified specific neural circuits that underlie the sickness syndrome.
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Kozak, W., Conn, C.A. & Kluger, M.J. Lipopolysaccharide induces fever and depresses locomotor activity in unrestrained mice. Am. J. Physiol. 266, R125–R135 (1994).
Elmquist, J.K., Scammell, T.E. & Saper, C.B. Mechanisms of CNS response to systemic immune challenge: the febrile response. Trends Neurosci. 20, 565–570 (1997).
Konsman, J.P., Parnet, P. & Dantzer, R. Cytokine-induced sickness behaviour: mechanisms and implications. Trends Neurosci. 25, 154–159 (2002).
Romanovsky, A.A. et al. First and second phases of biphasic fever: two sequential stages of the sickness syndrome? Am. J. Physiol. 271, R244–R253 (1996).
Kluger, M.J., Kozak, W., Conn, C.A., Leon, L.R. & Soszynski, D. Role of fever in disease. Ann. N. Y. Acad. Sci. 856, 224–233 (1998).
Yates, D.T. et al. Effects of bacterial lipopolysaccharide injection on white blood cell counts, hematological variables, and serum glucose, insulin, and cortisol concentrations in ewes fed low- or high-protein diets. J. Anim. Sci. 89, 4286–4293 (2011).
Bode, J.G., Ehlting, C. & Häussinger, D. The macrophage response towards LPS and its control through the p38MAPK-STAT3 axis. Cell Signal. 24, 1185–1194 (2012).
Kalinski, P. Regulation of immune responses by prostaglandin E2 . J. Immunol. 188, 21–28 (2012).
Schiltz, J.C. & Sawchenko, P.E. Distinct brain vascular cell types manifest inducible cyclooxygenase expression as a function of the strength and nature of immune insults. J. Neurosci. 22, 5606–5618 (2002).
Breder, C.D. & Saper, C.B. Expression of inducible cyclooxygenase mRNA in the mouse brain after systemic administration of bacterial lipopolysaccharide. Brain Res. 713, 64–69 (1996).
Serrats, J. et al. Dual roles for perivascular macrophages in immune-to-brain signaling. Neuron 65, 94–106 (2010).
Woodward, D.F., Jones, R.L. & Narumiya, S. International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of prostanoid receptors, updating 15 years of progress. Pharmacol. Rev. 63, 471–538 (2011).
Maness, L.M., Kastin, A.J. & Banks, W.A. Relative contributions of a CVO and the microvascular bed to delivery of blood-borne IL-1α to the brain. Am. J. Physiol. 275, E207–E212 (1998).
Banks, W.A. & Erickson, M.A. The blood-brain barrier and immune function and dysfunction. Neurobiol. Dis. 37, 26–32 (2010).
Romanovsky, A.A., Simons, C.T. & Kulchitsky, V.A. “Biphasic” fevers often consist of more than two phases. Am. J. Physiol. 275, R323–R331 (1998).
Engblom, D. et al. Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis. Nat. Neurosci. 6, 1137–1138 (2003).
Steiner, A.A. et al. Cellular and molecular bases of the initiation of fever. PLoS Biol. 4, e284 (2006).
Ivanov, A.I. & Romanovsky, A.A. Prostaglandin E2 as a mediator of fever: synthesis and catabolism. Front. Biosci. 9, 1977–1993 (2004).
Matsumura, K. et al. Brain endothelial cells express cyclooxygenase-2 during lipopolysaccharide-induced fever: light and electron microscopic immunocytochemical studies. J. Neurosci. 18, 6279–6289 (1998).
Yamagata, K. et al. Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever. J. Neurosci. 21, 2669–2677 (2001).
Inoue, W. et al. Brain-specific endothelial induction of prostaglandin E2 synthesis enzymes and its temporal relation to fever. Neurosci. Res. 44, 51–61 (2002).
Steiner, A.A. et al. Expanding the febrigenic role of cyclooxygenase-2 to the previously overlooked responses. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R1253–R1257 (2005).
Ushikubi, F. et al. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 395, 281–284 (1998).
Lazarus, M. et al. EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses. Nat. Neurosci. 10, 1131–1133 (2007).
Oka, T. et al. Characteristics of thermoregulatory and febrile responses in mice deficient in prostaglandin EP1 and EP3 receptors. J. Physiol. (Lond.) 551, 945–954 (2003).
Nakamura, K. et al. Immunohistochemical localization of prostaglandin EP3 receptor in the rat nervous system. J. Comp. Neurol. 421, 543–569 (2000).
Vasilache, A.M., Andersson, J. & Nilsberth, C. Expression of PGE2 EP3 receptor subtypes in the mouse preoptic region. Neurosci. Lett. 423, 179–183 (2007).
Scammell, T.E., Elmquist, J.K., Griffin, J.D. & Saper, C.B. Ventromedial preoptic prostaglandin E2 activates fever-producing autonomic pathways. J. Neurosci. 16, 6246–6254 (1996).
Scammell, T.E., Griffin, J.D., Elmquist, J.K. & Saper, C.B. Microinjection of a cyclooxygenase inhibitor into the anteroventral preoptic region attenuates LPS fever. Am. J. Physiol. 274, R783–R789 (1998).
Nakamura, K. et al. The rostral raphe pallidus nucleus mediates pyrogenic transmission from the preoptic area. J. Neurosci. 22, 4600–4610 (2002).
Nakamura, K. Central circuitries for body temperature regulation and fever. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R1207–R1228 (2011).
Székely, M. & Szelényi, Z. Endotoxin fever in the rat. Acta Physiol. Acad. Sci. Hung. 53, 265–277 (1979).
Szelényi, Z., Bartho, L., Székely, M. & Romanovsky, A.A. Cholecystokinin octapeptide (CCK-8) injected into a cerebral ventricle induces a fever-like thermoregulatory response mediated by type B CCK-receptors in the rat. Brain Res. 638, 69–77 (1994).
Tanaka, M., McKinley, M.J. & McAllen, R.M. Roles of two preoptic cell groups in tonic and febrile control of rat tail sympathetic fibers. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296, R1248–R1257 (2009).
Yoshida, K., Li, X., Cano, G., Lazarus, M. & Saper, C.B. Parallel preoptic pathways for thermoregulation. J. Neurosci. 29, 11954–11964 (2009).
Morrison, S.F. 2010 Carl Ludwig Distinguished Lectureship of the APS Neural Control and Autonomic Regulation Section: Central neural pathways for thermoregulatory cold defense. J. Appl. Physiol. 110, 1137–1149 (2011).
Huang, Q.H., Hruby, V.J. & Tatro, J.B. Role of central melanocortins in endotoxin-induced anorexia. Am. J. Physiol. 276, R864–R871 (1999).
Kishi, T. et al. Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J. Comp. Neurol. 457, 213–235 (2003).
Almeida, M.C., Steiner, A.A., Branco, L.G. & Romanovsky, A.A. Cold-seeking behavior as a thermoregulatory strategy in systemic inflammation. Eur. J. Neurosci. 23, 3359–3367 (2006).
Romanovsky, A.A. Thermoregulation: some concepts have changed. Functional architecture of the thermoregulatory system. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R37–R46 (2007).
Craig, A.D. How do you feel? Interoception: the sense of the physiological condition of the body. Nat. Rev. Neurosci. 3, 655–666 (2002).
Saper, C.B., Fuller, P.M., Pedersen, N.P., Lu, J. & Scammell, T.E. Sleep state switching. Neuron 68, 1023–1042 (2010).
Mullington, J. et al. Dose-dependent effects of endotoxin on human sleep. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278, R947–R955 (2000).
Morrow, J.D. & Opp, M.R. Diurnal variation of lipopolysaccharide-induced alterations in sleep and body temperature of interleukin-6-deficient mice. Brain Behav. Immun. 19, 40–51 (2005).
Krueger, J.M., Kubillus, S., Shoham, S. & Davenne, D. Enhancement of slow-wave sleep by endotoxin and lipid A. Am. J. Physiol. 251, R591–R597 (1986).
Krueger, J.M. et al. Involvement of cytokines in slow wave sleep. Prog. Brain Res. 193, 39–47 (2011).
Imeri, L. & Opp, M.R. How (and why) the immune system makes us sleep. Nat. Rev. Neurosci. 10, 199–210 (2009).
Yoshida, H., Kubota, T. & Krueger, J.M. A cyclooxygenase-2 inhibitor attenuates spontaneous and TNF-α-induced non-rapid eye movement sleep in rabbits. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R99–R109 (2003).
Terao, A., Matsumura, H., Yoneda, H. & Saito, M. Enhancement of slow-wave sleep by tumor necrosis factor-α is mediated by cyclooxygenase-2 in rats. Neuroreport 9, 3791–3796 (1998).
Ueno, R. et al. Role of prostaglandin D2 in the hypothermia of rats caused by bacterial lipopolysaccharide. Proc. Natl. Acad. Sci. USA 79, 6093–6097 (1982).
Matsumura, H. et al. Prostaglandin D-2-sensitive, sleep-promoting zone defined in the ventral surface of the rostral basal forebrain. Proc. Natl. Acad. Sci. USA 91, 11998–12002 (1994).
Urade, Y. et al. Dominant expression of mRNA for prostaglandin D synthase in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. Proc. Natl. Acad. Sci. USA 90, 9070–9074 (1993).
Mizoguchi, A. et al. Dominant localization of prostaglandin D receptors on arachnoid trabecular cells in mouse basal forebrain and their involvement in the regulation of non-rapid eye movement sleep. Proc. Natl. Acad. Sci. USA 98, 11674–11679 (2001).
Urade, Y. & Hayaishi, O. Prostaglandin D2 and sleep/wake regulation. Sleep Med. Rev. 15, 411–418 (2011).
Bjorness, T.E. & Greene, R.W. Adenosine and sleep. Curr. Neuropharmacol. 7, 238–245 (2009).
Chamberlin, N.L. et al. Effects of adenosine on gabaergic synaptic inputs to identified ventrolateral preoptic neurons. Neuroscience 119, 913–918 (2003).
Oishi, Y., Huang, Z.L., Fredholm, B.B., Urade, Y. & Hayaishi, O. Adenosine in the tuberomammillary nucleus inhibits the histaminergic system via A1 receptors and promotes non-rapid eye movement sleep. Proc. Natl. Acad. Sci. USA 105, 19992–19997 (2008).
Scammell, T.E. et al. An adenosine A2a agonist increases sleep and induces Fos in ventrolateral preoptic neurons. Neuroscience 107, 653–663 (2001).
Satoh, S., Matsumura, H., Suzuki, F. & Hayaishi, O. Promotion of sleep mediated by the A2a-adenosine receptor and possible involvement of this receptor in the sleep induced by prostaglandin D2 in rats. Proc. Natl. Acad. Sci. USA 93, 5980–5984 (1996).
Lazarus, M. et al. Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens. J. Neurosci. 31, 10067–10075 (2011).
Onoe, H., Watanabe, Y., Ono, K., Koyama, Y. & Hayaishi, O. Prostaglandin E2 exerts an awaking effect in the posterior hypothalamus at a site distinct from that mediating its febrile action in the anterior hypothalamus. J. Neurosci. 12, 2715–2725 (1992).
Huang, Z.L. et al. Prostaglandin E2 activates the histaminergic system via the EP4 receptor to induce wakefulness in rats. J. Neurosci. 23, 5975–5983 (2003).
Swiergiel, A.H. & Dunn, A.J. Distinct roles for cyclooxygenases 1 and 2 in interleukin-1-induced behavioral changes. J. Pharmacol. Exp. Ther. 302, 1031–1036 (2002).
Wieczorek, M., Swiergiel, A.H., Pournajafi-Nazarloo, H. & Dunn, A.J. Physiological and behavioral responses to interleukin-1β and LPS in vagotomized mice. Physiol. Behav. 85, 500–511 (2005).
Kozak, W. et al. Thermal and behavioral effects of lipopolysaccharide and influenza in interleukin-1 beta-deficient mice. Am. J. Physiol. 269, R969–R977 (1995).
Pecchi, E. et al. Involvement of central microsomal prostaglandin E synthase-1 in IL-1β-induced anorexia. Physiol. Genomics 25, 485–492 (2006).
Ohinata, K., Suetsugu, K., Fujiwara, Y. & Yoshikawa, M. Activation of prostaglandin E receptor EP4 subtype suppresses food intake in mice. Prostaglandins Other Lipid Mediat. 81, 31–36 (2006).
Oka, T. et al. Relationship of EP1–4 prostaglandin receptors with rat hypothalamic cell groups involved in lipopolysaccharide fever responses. J. Comp. Neurol. 428, 20–32 (2000).
Ohinata, K. et al. Central prostaglandin D2 stimulates food intake via the neuropeptide Y system in mice. FEBS Lett. 582, 679–684 (2008).
Elmquist, J.K., Scammell, T.E., Jacobson, C.D. & Saper, C.B. Distribution of Fos-like immunoreactivity in the rat brain following intravenous lipopolysaccharide administration. J. Comp. Neurol. 371, 85–103 (1996).
Rorato, R. et al. Prostaglandin mediates endotoxaemia-induced hypophagia by activation of pro-opiomelanocortin and corticotrophin-releasing factor neurons in rats. Exp. Physiol. 94, 371–379 (2009).
Elias, C.F. et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23, 775–786 (1999).
Elias, C.F. et al. Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J. Comp. Neurol. 402, 442–459 (1998).
Williams, G. et al. The hypothalamus and the control of energy homeostasis: different circuits, different purposes. Physiol. Behav. 74, 683–701 (2001).
Wang, L., Saint-Pierre, D.H. & Tache, Y. Peripheral ghrelin selectively increases Fos expression in neuropeptide Y–synthesizing neurons in mouse hypothalamic arcuate nucleus. Neurosci. Lett. 325, 47–51 (2002).
Wu, Q. & Palmiter, R.D. GABAergic signaling by AgRP neurons prevents anorexia via a melanocortin-independent mechanism. Eur. J. Pharmacol. 660, 21–27 (2011).
Wang, L. et al. LPS inhibits fasted plasma ghrelin levels in rats: role of IL-1 and PGs and functional implications. Am. J. Physiol. Gastrointest. Liver Physiol. 291, G611–G620 (2006).
Watkins, L.R. et al. Characterization of cytokine-induced hyperalgesia. Brain Res. 654, 15–26 (1994).
Schmelzer, K.R. et al. Enhancement of antinociception by coadministration of nonsteroidal anti-inflammatory drugs and soluble epoxide hydrolase inhibitors. Proc. Natl. Acad. Sci. USA 103, 13646–13651 (2006).
Romanovsky, A.A. et al. Lipopolysaccharide transport from the peritoneal cavity to the blood: is it controlled by the vagus nerve? Auton. Neurosci. 85, 133–140 (2000).
Hori, T., Oka, T., Hosoi, M., Abe, M. & Oka, K. Hypothalamic mechanisms of pain modulatory actions of cytokines and prostaglandin E2. Ann. N. Y. Acad. Sci. 917, 106–120 (2000).
Abe, M., Oka, T., Hori, T. & Takahashi, S. Prostanoids in the preoptic hypothalamus mediate systemic lipopolysaccharide-induced hyperalgesia in rats. Brain Res. 916, 41–49 (2001).
Uschakov, A., Gong, H., McGinty, D. & Szymusiak, R. Efferent projections from the median preoptic nucleus to sleep- and arousal-regulatory nuclei in the rat brain. Neuroscience 150, 104–120 (2007).
Rizvi, T.A., Murphy, A.Z., Ennis, M., Behbehani, M.M. & Shipley, M.T. Medial preoptic area afferents to periaqueductal gray medullo-output neurons: a combined Fos and tract tracing study. J. Neurosci. 16, 333–344 (1996).
Ueno, A. et al. Major roles of prostanoid receptors IP and EP(3) in endotoxin-induced enhancement of pain perception. Biochem. Pharmacol. 62, 157–160 (2001).
Parsadaniantz, S.M. et al. Effects of the inhibition of cyclo-oxygenase 1 or 2 or 5-lipoxygenase on the activation of the hypothalamic-pituitary-adrenal axis induced by interleukin-1β in the male rat. J. Neuroendocrinol. 12, 766–773 (2000).
Gadek-Michalska, A., Spyrka, J. & Bugajski, J. Psychosocial stress affects the involvement of prostaglandins and nitric oxide in the lipopolysaccharide-induced hypothalamic-pituitary-adrenal response. J. Physiol. Pharmacol. 56, 287–298 (2005).
Dunn, A.J. & Chuluyan, H.E. The role of cyclo-oxygenase and lipoxygenase in the interleukin-1-induced activation of the HPA axis: dependence on the route of injection. Life Sci. 51, 219–225 (1992).
Roth, J., Hubschle, T., Pehl, U., Ross, G. & Gerstberger, R. Influence of systemic treatment with cyclooxygenase inhibitors on lipopolysaccharide-induced fever and circulating levels of cytokines and cortisol in guinea-pigs. Pflugers Arch. 443, 411–417 (2002).
Nadjar, A., Sauvant, J., Combe, C., Parnet, P. & Konsman, J.P. Brain cyclooxygenase-2 mediates interleukin-1-induced cellular activation in preoptic and arcuate hypothalamus, but not sickness symptoms. Neurobiol. Dis. 39, 393–401 (2010).
Matsuoka, Y. et al. Impaired adrenocorticotropic hormone response to bacterial endotoxin in mice deficient in prostaglandin E receptor EP1 and EP3 subtypes. Proc. Natl. Acad. Sci. USA 100, 4132–4137 (2003).
García-Bueno, B., Serrats, J. & Sawchenko, P.E. Cerebrovascular cyclooxygenase-1 expression, regulation, and role in hypothalamic-pituitary-adrenal axis activation by inflammatory stimuli. J. Neurosci. 29, 12970–12981 (2009).
Schiltz, J.C. & Sawchenko, P.E. Specificity and generality of the involvement of catecholaminergic afferents in hypothalamic responses to immune insults. J. Comp. Neurol. 502, 455–467 (2007).
Ericsson, A., Kovacs, K.J. & Sawchenko, P.E. A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons. J. Neurosci. 14, 897–913 (1994).
Zhang, Y.H., Lu, J., Elmquist, J.K. & Saper, C.B. Specific roles of cyclooxygenase-1 and cyclooxygenase-2 in lipopolysaccharide-induced fever and Fos expression in rat brain. J. Comp. Neurol. 463, 3–12 (2003).
Romanovsky, A.A. Signaling the brain in the early sickness syndrome: are sensory nerves involved? Front. Biosci. 9, 494–504 (2004).
Romanovsky, A.A., Kulchitsky, V.A., Simons, C.T., Sugimoto, N. & Szekely, M. Febrile responsiveness of vagotomized rats is suppressed even in the absence of malnutrition. Am. J. Physiol. 273, R777–R783 (1997).
Romanovsky, A.A., Simons, C.T., Szekely, M. & Kulchitsky, V.A. The vagus nerve in the thermoregulatory response to systemic inflammation. Am. J. Physiol. 273, R407–R413 (1997).
Luheshi, G.N. et al. Vagotomy attenuates the behavioural but not the pyrogenic effects of interleukin-1 in rats. Auton. Neurosci. 85, 127–132 (2000).
Hansen, M.K. et al. Subdiaphragmatic vagotomy does not block intraperitoneal lipopolysaccharide-induced fever. Auton. Neurosci. 85, 83–87 (2000).
The authors acknowledge support from US Public Health Service grants NS055367 (T.E.S.), HL095491 (C.B.S., T.E.S.), NS072337 (C.B.S.) and NS41233 (A.A.R.).
The authors declare no competing financial interests.
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Saper, C., Romanovsky, A. & Scammell, T. Neural circuitry engaged by prostaglandins during the sickness syndrome. Nat Neurosci 15, 1088–1095 (2012). https://doi.org/10.1038/nn.3159
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