Prostaglandin E2 (PGE2) is a principal fever mediator that induces hyperthermia when injected into the organum vasculosum lamina terminalis (OVLT) and the adjacent preoptic area of the hypothalamus (POA). PGE (EP) receptors have four subtypes, i.e. EP1, EP2, EP3, and EP4. In the rat OVLT/POA region, at least three of these receptors, i.e. EP1, EP3, and EP4 receptors, have distinctively different distribution patterns. In rats, intracerebroventricular injection of EP1 receptor agonists and EP3 receptor agonists increased core temperature (Tc) and that of an EP4 receptor agonist decreased it. IntraPOA injection of an EP1 receptor agonist increased Tc. IntraPOA injection of an EP3 receptor agonist, however, induced hyperalgesia but not hyperthermia. Studies using mice with EP receptor gene deletions have indicated that EP3 receptors play a crucial role in febrile response. Therefore, the involvement of EP3 receptors at other levels of the nervous system should be considered. Such nuclei include the raphe pallidus nucleus, intermediolateral cell column in the spinal cord, or the nucleus of the solitary tract.