Abstract: Proinflammatory cytokines released by cells of myeloid lineage have the ability to stimulate different populations of neurons through intermediate molecules released by cells of the blood-brain barrier. The aim of the present study was to verify the hypothesis that prostaglandins (PGs) play a site-specific role in activating selective groups of neurons via a privileged interaction between PG of the E2 type and its EP4 receptor. In a first set of experiments, animals were treated with the inhibitor of PG synthesis ketorolac to determine the endogenous contribution of PG in mediating the neuronal activation and EP4 expression in response to circulating interleukin-1β (IL-1β). The subsequent experiment consisted of evaluating the role of PGE2 in activating EP4-expressing neurons in the rat brain. Ketorolac completely abolished the endogenous release of PGE2 in the liver and prevented the induction of immediate-early genes and up-regulation of EP4 mRNA in specific groups of neurons, such as the parvocellular paraventricular nucleus and the A1 catecholaminergic population of cells. This effect was, however, not generalized throughout the brain as PGE2 inhibition failed to abolish IL-1β-induced c-fos transcription in the nucleus of the solitary tract, parabrachial nucleus, bed nucleus of the stria terminalis, and the circumventricular organs. Of interest are the data that central PGE2 injection activated EP4 gene transcription in neurons that no longer responded to the intravenous IL-1β bolus when the animals were pretreated with ketorolac. Site-specific interaction between the ligand and its receptor was further supported by the induction of c-fos-immunoreactive nuclei within EP4-expressing neurons in response to intracerebroventricular PGE2 infusion. Both intracerebroventricular PGE2 and intravenous IL-1β injection provoked a sharp and rapid increase in plasma corticosterone levels, an effect that was completely prevented in inhibiting PG production in IL-1β-challenged rats. These data provide the evidence that EP4 is expressed in numerous nuclei involved in autonomic and neuroendocrine control, although a privileged interaction seems to take place in specific nuclei and areas, including the endocrine hypothalamus and the A1 cell group of the ventrolateral medulla. It is quite possible that EP4 acts as the functional receptor for PGE2 to activate the neuronal circuit involved in the activation of the glucocorticoid axis, as an essential neuroendocrine response for the appropriate control of systemic inflammation.