Editing Fever (section)

===Neural circuit mechanism with PGE2 action===
PGE2 release comes from the [[arachidonic acid]] pathway. This pathway (as it relates to fever), is mediated by the [[enzyme]]s [[phospholipase|phospholipase A2]] (PLA2), [[cyclooxygenase|cyclooxygenase-2]] (COX-2), and [[prostaglandin E2 synthase]]. These enzymes ultimately mediate the synthesis and release of PGE2.<ref>{{Cite journal |last=Samuelsson |first=Bengt |last2=Morgenstern |first2=Ralf |last3=Jakobsson |first3=Per-Johan |date=September 2007 |title=Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target |url=https://linkinghub.elsevier.com/retrieve/pii/S0031699724117267 |journal=Pharmacological Reviews |language=en |volume=59 |issue=3 |pages=207–224 |doi=10.1124/pr.59.3.1}}</ref>

PGE2 is the ultimate mediator of the febrile response. The setpoint temperature of the body will remain elevated until PGE2 is no longer present. PGE2 acts on neurons in the [[preoptic area]] (POA) through the [[prostaglandin E receptor 3]] (EP3).<ref>{{Cite journal |last=Nakamura |first=Kazuhiro |last2=Kaneko |first2=Takeshi |last3=Yamashita |first3=Yoko |last4=Hasegawa |first4=Hiroshi |last5=Katoh |first5=Hironori |last6=Ichikawa |first6=Atsushi |last7=Negishi |first7=Manabu |date=1999-01-29 |title=Immunocytochemical localization of prostaglandin EP3 receptor in the rat hypothalamus |url=https://linkinghub.elsevier.com/retrieve/pii/S0304394098009628 |journal=Neuroscience Letters |language=en |volume=260 |issue=2 |pages=117–120 |doi=10.1016/S0304-3940(98)00962-8}}</ref><ref name=":1">{{Cite journal |last=Nakamura |first=Kazuhiro |last2=Matsumura |first2=Kiyoshi |last3=Kaneko |first3=Takeshi |last4=Kobayashi |first4=Shigeo |last5=Katoh |first5=Hironori |last6=Negishi |first6=Manabu |date=2002-06-01 |title=The Rostral Raphe Pallidus Nucleus Mediates Pyrogenic Transmission from the Preoptic Area |url=https://www.jneurosci.org/lookup/doi/10.1523/JNEUROSCI.22-11-04600.2002 |journal=The Journal of Neuroscience |language=en |volume=22 |issue=11 |pages=4600–4610 |doi=10.1523/JNEUROSCI.22-11-04600.2002 |issn=0270-6474 |pmc=6758794 |pmid=12040067}}</ref><ref>{{Cite journal |last=Lazarus |first=Michael |last2=Yoshida |first2=Kyoko |last3=Coppari |first3=Roberto |last4=Bass |first4=Caroline E |last5=Mochizuki |first5=Takatoshi |last6=Lowell |first6=Bradford B |last7=Saper |first7=Clifford B |date=September 2007 |title=EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses |url=https://www.nature.com/articles/nn1949 |journal=Nature Neuroscience |language=en |volume=10 |issue=9 |pages=1131–1133 |doi=10.1038/nn1949 |issn=1097-6256}}</ref><ref name=":2">{{Cite journal |last=Nakamura |first=Yoshiko |last2=Yahiro |first2=Takaki |last3=Fukushima |first3=Akihiro |last4=Kataoka |first4=Naoya |last5=Hioki |first5=Hiroyuki |last6=Nakamura |first6=Kazuhiro |date=2022-12-23 |title=Prostaglandin EP3 receptor–expressing preoptic neurons bidirectionally control body temperature via tonic GABAergic signaling |url=https://www.science.org/doi/10.1126/sciadv.add5463 |journal=Science Advances |language=en |volume=8 |issue=51 |doi=10.1126/sciadv.add5463 |issn=2375-2548 |pmc=9788766 |pmid=36563142}}</ref> EP3-expressing neurons in the POA innervate the [[dorsomedial hypothalamus]] (DMH),<ref>{{Cite journal |last=Nakamura |first=Yoshiko |last2=Nakamura |first2=Kazuhiro |last3=Matsumura |first3=Kiyoshi |last4=Kobayashi |first4=Shigeo |last5=Kaneko |first5=Takeshi |last6=Morrison |first6=Shaun F. |date=December 2005 |title=Direct pyrogenic input from prostaglandin EP3 receptor‐expressing preoptic neurons to the dorsomedial hypothalamus |url=https://onlinelibrary.wiley.com/doi/10.1111/j.1460-9568.2005.04515.x |journal=European Journal of Neuroscience |language=en |volume=22 |issue=12 |pages=3137–3146 |doi=10.1111/j.1460-9568.2005.04515.x |issn=0953-816X |pmc=2441892 |pmid=16367780}}</ref><ref name=":3">{{Cite journal |last=Nakamura |first=Y. |last2=Nakamura |first2=K. |last3=Morrison |first3=S.F. |date=2009-06-30 |title=Different populations of prostaglandin EP3 receptor-expressing preoptic neurons project to two fever-mediating sympathoexcitatory brain regions |url=https://linkinghub.elsevier.com/retrieve/pii/S0306452209003960 |journal=Neuroscience |language=en |volume=161 |issue=2 |pages=614–620 |doi=10.1016/j.neuroscience.2009.03.041 |pmc=2857774 |pmid=19327390}}</ref> the rostral [[raphe]] pallidus nucleus in the [[medulla oblongata]] (rRPa),<ref name=":1" /><ref name=":3" /> and the [[paraventricular nucleus]] (PVN) of the [[hypothalamus]].<ref>{{Cite journal |last=Zhang |first=Zhi-Hua |last2=Yu |first2=Yang |last3=Wei |first3=Shun-Guang |last4=Nakamura |first4=Yoshiko |last5=Nakamura |first5=Kazuhiro |last6=Felder |first6=Robert B. |date=October 2011 |title=EP3 receptors mediate PGE2-induced hypothalamic paraventricular nucleus excitation and sympathetic activation |url=https://www.physiology.org/doi/10.1152/ajpheart.00262.2011 |journal=American Journal of Physiology-Heart and Circulatory Physiology |language=en |volume=301 |issue=4 |pages=H1559–H1569 |doi=10.1152/ajpheart.00262.2011 |issn=0363-6135 |pmc=3197370 |pmid=21803943}}</ref> Under normal conditions, EP3-expressing neurons in the POA are important [[Thermoregulation|thermoregulatory]] neurons, which provide continuous inhibitory signals with the transmitter [[GABA]] to control [[Sympathetic nervous system|sympathetic]] output neurons in the DMH and rRPa, thereby performing bidirectional regulation of basal body temperature.<ref name=":2" /> During infection, PGE2 produced in the brain inhibits the activity of EP3-expressing neurons in the POA to attenuate the inhibition of sympathetic output, and thereby activates the sympathetic output system, which evokes non-shivering thermogenesis to produce body heat and skin vasoconstriction to decrease heat loss from the body surface, leading to fever.<ref name=":2" /> It is presumed that the innervation from the POA to the PVN mediates the neuroendocrine effects of fever through the pathway involving [[pituitary gland]] and various [[endocrine organs]].