Targeting anti-inflammatory treatment can ameliorate injury-induced neuropathic pain

PLoS One. 2013;8(2):e57721. doi: 10.1371/journal.pone.0057721. Epub 2013 Feb 28.


Tumor necrosis factor-α plays important roles in immune system development, immune response regulation, and T-cell-mediated tissue injury. The present study assessed the net value of anti-tumor necrosis factor-α treatment in terms of functional recovery and inhibition of hypersensitivity after peripheral nerve crush injury. We created a right sciatic nerve crush injury model using a Sugita aneurysm clip. Animals were separated into 3 groups: the first group received only a skin incision; the second group received nerve crush injury and intraperitoneal vehicle injection; and the third group received nerve crush injury and intraperitoneal etanercept (6 mg/kg). Etanercept treatment improved recovery of motor nerve conduction velocity, muscle weight loss, and sciatic functional index. Plantar thermal and von Frey mechanical withdrawal thresholds recovered faster in the etanercept group than in the control group. On day 7 after crush injury, the numbers of ED-1-positive cells in crushed nerves of the control and etanercept groups were increased compared to that in the sham-treated group. After 21 days, ED-1-positive cells had nearly disappeared from the etanercept group. Etanercept reduced expression of interleukin-6 and monocyte chemotactic and activating factor-1 at the crushed sciatic nerve. These findings demonstrate the utility of etanercept, in terms of both enhancing functional recovery and suppressing hypersensitivity after nerve crush. Etanercept does not impede the onset or progression of Wallerian degeneration, but optimizes the involvement of macrophages and the secretion of inflammatory mediators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Axons / drug effects
  • Axons / physiology
  • Behavior, Animal / drug effects
  • Electrophysiological Phenomena / drug effects
  • Etanercept
  • Hyperalgesia / complications
  • Hyperalgesia / drug therapy
  • Immunoglobulin G / pharmacology
  • Immunoglobulin G / therapeutic use
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / genetics
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / pathology
  • Neuralgia / complications*
  • Neuralgia / drug therapy*
  • Neuralgia / metabolism
  • Neuralgia / physiopathology
  • Organ Size / drug effects
  • Peripheral Nerve Injuries / complications*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Receptors, Tumor Necrosis Factor / therapeutic use
  • Regeneration / drug effects
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / genetics
  • Wallerian Degeneration / complications


  • Anti-Inflammatory Agents
  • Immunoglobulin G
  • Interleukin-6
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Etanercept

Grant support

This work was supported by the Health and Labour Sciences Research Grant on Intractable Diseases (Pathogenesis and Diagnostic Accuracy of Neuropathic Pain) from the Ministry of Health, Labour and Welfare of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.