Spinal tumor necrosis factor alpha neutralization reduces peripheral inflammation and hyperalgesia and suppresses autonomic responses in experimental arthritis: a role for spinal tumor necrosis factor alpha during induction and maintenance of peripheral inflammation

Arthritis Rheum. 2010 May;62(5):1308-18. doi: 10.1002/art.27380.


Objective: In addition to the sensitization of pain fibers in inflamed tissues, the increased excitability of the spinal cord is an important mechanism of inflammatory pain. Furthermore, spinal neuronal excitability has been suggested to play a role in modulating peripheral inflammation. This study was undertaken to test the hypothesis that spinal actions of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) add significantly to both hyperalgesia and maintenance of peripheral inflammation.

Methods: Rats with antigen-induced arthritis (AIA) were treated intrathecally with the TNFalpha-neutralizing compound etanercept continuously during the complete time course of AIA, which was 3 days for the acute phase and 21 days for the chronic phase. During this time, inflammation and pain-related behavior were monitored. Since a role for autonomic control of inflammation was proposed, measures from heart rate time series were obtained in the acute phase. Findings were compared with those in vehicle-treated animals and in animals receiving etanercept intraperitoneally.

Results: Spinally administered etanercept acutely reduced pain-related behavior, attenuated both the development and the maintenance of inflammation, and was superior to systemic administration. Parameters indicating autonomic modulation showed a shift toward a sympathetically dominated state in vehicle-treated animals, which was prevented by intrathecal etanercept.

Conclusion: Our findings indicate that spinal TNFalpha plays an important role in both pain signaling and modulation of peripheral inflammation. Thus, neutralizing this cytokine at the spinal site not only represents a putative therapeutic option for different pain syndromes, but may be directly used to attenuate peripheral inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Antirheumatic Agents / pharmacology*
  • Arthritis, Experimental* / drug therapy
  • Arthritis, Experimental* / immunology
  • Arthritis, Experimental* / metabolism
  • Autonomic Nervous System / drug effects
  • Autonomic Nervous System / immunology
  • Behavior, Animal / drug effects
  • Etanercept
  • Female
  • Heart Rate / physiology
  • Hyperalgesia* / drug therapy
  • Hyperalgesia* / immunology
  • Hyperalgesia* / metabolism
  • Immunoglobulin G / pharmacology*
  • Infusion Pumps, Implantable
  • Injections, Spinal
  • Knee Joint / immunology
  • Knee Joint / metabolism
  • Locomotion / drug effects
  • Nonlinear Dynamics
  • Rats
  • Rats, Inbred Lew
  • Receptors, Tumor Necrosis Factor
  • Spinal Cord / immunology
  • Spinal Cord / metabolism
  • Tumor Necrosis Factor-alpha* / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha* / immunology
  • Tumor Necrosis Factor-alpha* / metabolism


  • Antirheumatic Agents
  • Immunoglobulin G
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Etanercept