%0 Journal Article %A Hirosato Kanda %A Kimiko Kobayashi %A Hiroki Yamanaka %A Masamichi Okubo %A Koichi Noguchi %T Microglial TNF Alpha Induces COX2 and PGI2 Synthase Expression in Spinal Endothelial Cells during Neuropathic Pain %D 2017 %R 10.1523/ENEURO.0064-17.2017 %J eneuro %P ENEURO.0064-17.2017 %X Prostaglandins (PG) are typical lipid mediators that play a role in homeostasis and disease. They are synthesized from arachidonic acid by cyclooxygenase-1 (COX1) and cyclooxygenase-2 (COX2). While COX2 has been reported to be upregulated in the spinal cord following nerve injury, its expression and functional roles in neuropathic pain remain unclear. In this study, we investigated the expression of Cox2, PGI2 synthase (Pgis), and prostaglandin I2 receptor (IP receptor) mRNA in the rat spinal cord following spared nerve injury (SNI). Levels of Cox2 and Pgis mRNA increased in endothelial cells from 24 to 48 h after nerve injury. IP receptor mRNA was constitutively expressed in dorsal horn neurons. A COX2 inhibitor and IP receptor antagonists attenuated pain behavior in the early phase of neuropathic pain. Furthermore, we examined the relationship between COX2 and tumor necrosis factor (TNF) alpha in the spinal cord of a rat SNI model. Levels of TNF alpha mRNA transiently increased in the spinal microglia 24 h after SNI. The TNF receptors Tnfr1 and Tnfr2 mRNA were co-localized with COX2. Intrathecal injection of TNF alpha induced Cox2 and Pgis mRNA expression in endothelial cells. These results revealed that microglia-derived TNF alpha induced COX2 and PGIS expression in spinal endothelial cells and that endothelial PGI2 played a critical role in neuropathic pain via neuronal IP receptor. These findings further suggest that the glia-endothelial cell interaction of the neurovascular unit via transient TNF alpha is involved in the generation of neuropathic pain.Significance Statement This study reports the expression of Cox2, PGIS, and IP receptor mRNA and proteins in the rat spinal cord following spared nerve injury. We found that Cox2 and Pgis increased in endothelial cells from 24-48 h after nerve injury, and a COX2 inhibitor and IP receptor antagonists attenuated pain behavior in the early phase of neuropathic pain. Moreover, our findings indicate that microglia-derived TNF alpha induced COX2 and PGIS expression in spinal endothelial cells and had a critical role in endothelial PGI2 via neuronal IP receptor in neuropathic pain. These findings suggest that the activation of glia-endothelial cell interaction by transient TNF alpha and endothelial cell-derived COX2-PGI2 have a modulatory effect in the generation of neuropathic pain. %U https://www.eneuro.org/content/eneuro/early/2017/04/13/ENEURO.0064-17.2017.full.pdf