Relationship of EP1-4 prostaglandin receptors with rat hypothalamic cell groups involved in lipopolysaccharide fever responses

Takakazu Oka, Kae Oka, Thomas E. Scammell, Charlotte Lee, Joseph F. Kelly, Francois Nantel, Joel K. Elmquist, Clifford B. Saper

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119 Citations (Scopus)


The action of E2 (PGE2) in the preoptic area is thought to play an important role in producing fever. Pharmacologic evidence suggests that, among the four subtypes of E-series prostaglandin (EP) receptors, i.e., EP1, EP2, EP3, and EP4, the EP1 receptor mediates fever responses. In contrast, evidence from mice with EP receptor gene deletions indicates that the EP3 receptor is required for the initial (<1 hour) fever after intravenous (i.v.) lipopolysaccharide (LPS). To investigate which subtypes of E P receptors mediate systemic infection-induced fever, we assessed the coexpression of Fos-like immunoreactivity (Fos-IR) and EP1-4 receptor mRNA in nuclei in the rat hypothalamus that have been shown to be involved in fever responses. Two hours after the administration of i.v. LPS (5 μg/kg), Fos-IR was observed in the ventromedial preoptic nucleus, the median preoptic nucleus, and the paraventricular hypothalamic nucleus. In these nuclei, EP4 receptor mRNA was strongly expressed and the Fos-IR intensely colocalized with EP4 receptor mRNA. Strong EP3 receptor mRNA expression was only seen within the median preoptic nucleus but Fos-IR showed little coexpression with EP3 receptor mRNA. EP2 receptor mRNA was not seen in the PGE2 sensitive parts of the preoptic area. Although approximately half of the Fos-immunoreactive neurons also expressed EP1 receptor mRNA, EP1 mRNA expression was weak and its distribution was so diffuse in the preoptic area that it did not represent a specific relationship. In the paraventricular nucleus, EP4 mRNA was found in most Fos-immunoreactive neurons and levels of EP4 receptor expression increased after i.v. LPS. Our findings indicate that neurons expressing EP4 receptor are activated during LPS-induced fever and suggest the involvement of EP4 receptors in the production of fever. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)20-32
Number of pages13
JournalJournal of Comparative Neurology
Issue number1
Publication statusPublished - Dec 4 2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Neuroscience


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