Inflammation is often accompanied with hyperalgesia. This hyperalgesia is mediated partly by prostaglandin(s) produced in the CNS through the cyclooxygenase-2 (COX-2) dependent pathway. However, it remains unclear where COX-2 is induced in the CNS during inflammation, and how it is involved in hyperalgesia. We studied the precise site of COX-2 induction in the CNS, the relation between the time course of COX-2 induction and that of hyperalgesia, and the effect of COX-2-selective inhibitor by using a carrageenan model. Carrageenan injection induced expression of COX-2-like immunoreactivity in vascular endothelial cells throughout the CNS. This response became evident by 3 h, and was most prominent at 6 h after carrageenan injection. This COX-2 induction was associated with an elevation of prostaglandin E2 in the cerebrospinal fluid, being evident at 3 h, larger at 6 h, and alleviated by a COX-2-selective inhibitor. Thermal hyperalgesia became evident at 1 h, further increased thereafter, and remained elevated until 6 h. Intrathecal administration of COX-2-selective inhibitor 2 h after the carrageenan injection exerted a prominent therapeutic effect on hyperalgesia. These results demonstrate that, during carrageenan-induced inflammation, endothelial cells are the major source of prostaglandin(s) in the CNS, and this endothelial expression of COX-2 is involved in the inflammation-induced hyperalgesia.