Microglial TNFα Induces COX2 and PGI2 Synthase Expression in Spinal Endothelial Cells during Neuropathic Pain

eNeuro. 2017 Apr 21;4(2):ENEURO.0064-17.2017. doi: 10.1523/ENEURO.0064-17.2017. eCollection 2017 Mar-Apr.


Prostaglandins (PGs) are typical lipid mediators that play a role in homeostasis and disease. They are synthesized from arachidonic acid by cyclooxygenase 1 (COX1) and COX2. Although COX2 has been reported to be upregulated in the spinal cord after 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 after 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-α (TNFα) in the spinal cord of a rat SNI model. Levels of TNFα mRNA transiently increased in the spinal microglia 24 h after SNI. The TNF receptors Tnfr1 and Tnfr2 mRNA were colocalized with COX2. Intrathecal injection of TNFα induced Cox2 and Pgis mRNA expression in endothelial cells. These results revealed that microglia-derived TNFα 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 TNFα is involved in the generation of neuropathic pain.

Keywords: Endothelial cells; Microglia; Neuropathic pain; PGI2; Spinal cord; TNFα.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclooxygenase 2 / metabolism*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Endothelial Cells / enzymology*
  • Inflammation / enzymology
  • Intramolecular Oxidoreductases / metabolism*
  • Male
  • Microglia / metabolism*
  • Neuralgia / metabolism*
  • Peripheral Nerve Injuries / metabolism
  • RNA, Messenger
  • Rats, Sprague-Dawley
  • Spinal Cord / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism*


  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Cytochrome P-450 Enzyme System
  • Cyclooxygenase 2
  • Ptgs2 protein, rat
  • Intramolecular Oxidoreductases
  • prostacyclin synthetase