The prostaglandin E2 receptor EP3 controls CC-chemokine ligand 2-mediated neuropathic pain induced by mechanical nerve damage

J Biol Chem. 2018 Jun 22;293(25):9685-9695. doi: 10.1074/jbc.RA118.002492. Epub 2018 May 11.


Prostaglandin (PG) E2 is an important lipid mediator that is involved in several pathophysiological processes contributing to fever, inflammation, and pain. Previous studies have shown that early and continuous application of nonsteroidal anti-inflammatory drugs significantly reduces pain behavior in the spared nerve injury (SNI) model for trauma-induced neuropathic pain. However, the role of PGE2 and its receptors in the development and maintenance of neuropathic pain is incompletely understood but may help inform strategies for pain management. Here, we sought to define the nociceptive roles of the individual PGE2 receptors (EP1-4) in the SNI model using EP knockout mice. We found that PGE2 levels at the site of injury were increased and that the expression of the terminal synthase for PGE2, cytosolic PGE synthase was up-regulated in resident positive macrophages located within the damaged nerve. Only genetic deletion of the EP3 receptor affected nociceptive behavior and reduced the development of late-stage mechanical allodynia as well as recruitment of immune cells to the injured nerve. Importantly, EP3 activation induced the release of CC-chemokine ligand 2 (CCL2), and antagonists against the CCL2 receptor reduced mechanical allodynia in WT but not in EP3 knockout mice. We conclude that selective inhibition of EP3 might present a potential approach for reducing chronic neuropathic pain.

Keywords: CCL2; G protein-coupled receptor (GPCR); Prostaglandin E2; chemokine; mast cells; neuroinflammation; neuropathic pain; pain; peripheral neuron; prostaglandin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chemokine CCL2 / toxicity*
  • Hyperalgesia / etiology
  • Hyperalgesia / metabolism
  • Hyperalgesia / pathology
  • Hyperalgesia / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuralgia / etiology
  • Neuralgia / metabolism
  • Neuralgia / pathology
  • Neuralgia / prevention & control*
  • Pain Measurement
  • Pyrrolidines / pharmacology
  • Receptors, CCR2 / antagonists & inhibitors
  • Receptors, CCR2 / metabolism
  • Receptors, Prostaglandin E, EP3 Subtype / physiology*
  • Sciatic Nerve / injuries
  • Sciatic Nerve / physiopathology*


  • Ccr2 protein, mouse
  • Chemokine CCL2
  • INCB3344
  • Ptger3 protein, mouse
  • Pyrrolidines
  • Receptors, CCR2
  • Receptors, Prostaglandin E, EP3 Subtype