Abstract
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.
Highlights
Prostaglandin (PG) E2 is an important lipid mediator that is involved in several pathophysiological processes contributing to fever, inflammation, and pain
We found that Prostaglandin E2 (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
First we investigated whether PGE2 levels in sciatic nerve, DRGs (L3–L5) and spinal cord (L3–L5) are altered 14 days after inducing the nerve injury according to the spared nerve injury (SNI) model when a stable mechanical allodynia was established [16]
Summary
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. Animal studies showed that early and continuous application of NSAIDs significantly reduces mechanical allodynia in the spared nerve injury (SNI) [3], the chronic constriction injury [4], and the partial sciatic nerve ligation [5] models for trauma-induced neuropathic pain. Prostaglandin E2 (PGE2) is known as an important lipid mediator that is involved in several pathophysiological processes contributing to fever, inflammation, and pain [10] It can activate four G protein– coupled receptors named EP1, EP2, EP3, and EP4, which are Gq (EP1), Gs (EP2 and EP4), or Gi (EP3) coupled.
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