Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain

Neuroscience. 2001;103(2):529-39. doi: 10.1016/s0306-4522(00)00574-1.

Abstract

The expression of interleukin-1beta and tumor necrosis factor has previously been shown to be up-regulated in the spinal cord of several rat mononeuropathy models. This present study was undertaken to determine whether blocking the action of central interleukin-1beta and tumor necrosis factor attenuates mechanical allodynia in a gender-specific manner in a rodent L5 spinal nerve transection model of neuropathic pain, and whether this inhibition occurs via down-regulation of the central cytokine cascade or blockade of glial activation. Interleukin-1 receptor antagonist or soluble tumor necrosis factor receptor was administered intrathecally via lumbar puncture to male Holtzman rats in a preventative pain strategy, in which therapy was initiated 1h prior to surgery. Administration of soluble tumor necrosis factor receptor attenuated mechanical allodynia, while interleukin-1 receptor antagonist alone was unable to decrease allodynia. Interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor, administered to both male and female rats in a preventative pain strategy, significantly reduced mechanical allodynia in a dose-dependent manner (P<0.01). The magnitude of attenuation in allodynia was similar in both males and females. Immunohistochemistry on L5 spinal cord revealed similar astrocytic and microglial activation regardless of treatment. At days 3 and 7 post-transection, animals receiving daily interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibited significantly less interleukin-6, but not interleukin-1beta, in the L5 spinal cord compared to vehicle-treated animals. In an existing pain paradigm, in which treatment was initiated on day 7 post-transection, interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor attenuated mechanical allodynia (P<0.05) in male rats. These findings further support a role for central interleukin-1beta and tumor necrosis factor in the development and maintenance of neuropathic pain through induction of a proinflammatory cytokine cascade.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Etanercept
  • Female
  • Immunoglobulin G / pharmacology*
  • Injections, Spinal
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1 / metabolism
  • Interleukin-6 / metabolism
  • Male
  • Neuralgia / drug therapy*
  • Neuralgia / immunology
  • Neuralgia / metabolism*
  • Neuroglia / immunology
  • Neuroglia / metabolism
  • Neurons / immunology
  • Neurons / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Tumor Necrosis Factor
  • Sex Factors
  • Sialoglycoproteins / pharmacology*
  • Spinal Cord / cytology
  • Spinal Cord / metabolism
  • Spinal Cord / physiology
  • Spinal Nerves / physiopathology
  • Spinal Nerves / surgery
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Immunoglobulin G
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Interleukin-6
  • Receptors, Tumor Necrosis Factor
  • Sialoglycoproteins
  • Tumor Necrosis Factor-alpha
  • Etanercept