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

The action of prostaglandin E-2 (PGE(2)) 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 c ontrast, evidence from mice with EP receptor gene deletions indicates that the EP3 receptor is required for the initial (<1 hour) fever after intraven ous (i.v.) lipopolysaccharide (LPS). To investigate which subtypes of EP re ceptors mediate systemic infection-induced fever, we assessed the coexpress ion 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 respo nses. Two hours after the administration of i.v. LPS (5 <mu>g/kg), Fos-IR w as observed in the ventromedial preoptic nucleus, the median preoptic nucle us, and the paraventricular hypothalamic nucleus. In these nuclei, EP4 rece ptor mRNA was strongly expressed and the Fos-IR intensely colocalized with EP3 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 PGE(2) sensitive part s of the preoptic area. Although approximately half of the Fos-immunoreacti ve neurons also expressed EP1 receptor mRNA, EP1 mRNA expression was weak a nd its distribution was so diffuse in the preoptic area that it did not rep resent a specific relationship. In the paraventricular nucleus, EP4 mRNA wa s found in most Fos-immunoreactive neurons and levels of EP4 receptor expre ssion increased after i.v. LPS. Our findings indicate that neurons expressi ng EP4 receptor are activated during LPS-induced fever and suggest the invo lvement of EP4 receptors in the production of fever. (C) 2000 Wiley-Liss, I nc.