Brain prostaglandin E₂ (PGE₂) causes sympathetic activation such as pressor and tachycardiac effects. Brain PGE₂ is also known to elevate plasma level of noradrenaline, but not adrenaline. It is well elucidated that corticotropin-releasing factor (CRF) increases plasma catecholamine levels. We have reported that prostanoids other than thromboxane A₂ mediate the CRF-induced elevation of plasma noradrenaline level. In this study, we examined whether PGE₂ in the brain mediates the CRF-induced elevation of plasma noradrenaline level. Intracerebroventricular (ICV) administration of CRF increased PGE₂ level in PVN dialysates. ICV pretreatment with the antagonist of PGE₂ receptor EP₃ subtype suppressed the CRF-induced elevation of plasma noradrenaline level, while antagonists for other subtypes did not affect the elevation. Furthermore, we performed microinjection of EP₃ receptor antagonist into the paraventricular hypothalamic nucleus (PVN), the major integrative center for sympathetic regulation. Bilateral blockade of EP₃ receptors in the PVN suppressed the CRF-induced elevation. Our results suggest that PGE₂ mediates the CRF-induced elevation of plasma noradrenaline level via activation of EP₃ receptor in the PVN.