Blockade of TNF-α rapidly inhibits pain responses in the central nervous system

Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3731-6. doi: 10.1073/pnas.1011774108. Epub 2011 Jan 18.


There has been a consistent gap in understanding how TNF-α neutralization affects the disease state of arthritis patients so rapidly, considering that joint inflammation in rheumatoid arthritis is a chronic condition with structural changes. We thus hypothesized that neutralization of TNF-α acts through the CNS before directly affecting joint inflammation. Through use of functional MRI (fMRI), we demonstrate that within 24 h after neutralization of TNF-α, nociceptive CNS activity in the thalamus and somatosensoric cortex, but also the activation of the limbic system, is blocked. Brain areas showing blood-oxygen level-dependent signals, a validated method to assess neuronal activity elicited by pain, were significantly reduced as early as 24 h after an infusion of a monoclonal antibody to TNF-α. In contrast, clinical and laboratory markers of inflammation, such as joint swelling and acute phase reactants, were not affected by anti-TNF-α at these early time points. Moreover, arthritic mice overexpressing human TNF-α showed an altered pain behavior and a more intensive, widespread, and prolonged brain activity upon nociceptive stimuli compared with wild-type mice. Similar to humans, these changes, as well as the rewiring of CNS activity resulting in tight clustering in the thalamus, were rapidly reversed after neutralization of TNF-α. These results suggest that neutralization of TNF-α affects nociceptive brain activity in the context of arthritis, long before it achieves anti-inflammatory effects in the joints.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / complications
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / pathology
  • Central Nervous System / drug effects
  • Central Nervous System / metabolism
  • Central Nervous System / pathology*
  • Chronic Disease
  • Female
  • Humans
  • Limbic System / drug effects
  • Limbic System / metabolism
  • Limbic System / pathology
  • Mice
  • Middle Aged
  • Nociceptors / metabolism
  • Oxygen / blood
  • Pain / complications
  • Pain / pathology*
  • Time Factors
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism


  • Anti-Inflammatory Agents
  • Tumor Necrosis Factor-alpha
  • Oxygen