Blockade of TNF-α rapidly inhibits pain responses in the central nervous system.
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.
Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Internal Medicine 3, and Division of Neuroradiology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
Andreas
A
Hess
Roland
R
Axmann
Juergen
J
Rech
Stefanie
S
Finzel
Cornelia
C
Heindl
Silke
S
Kreitz
Marina
M
Sergeeva
Marc
M
Saake
Meritxell
M
Garcia
George
G
Kollias
Rainer H
RH
Straub
Olaf
O
Sporns
Arnd
A
Doerfler
Kay
K
Brune
Georg
G
Schett
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000473:pathology; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002908:Chronic Disease; D005260:Female; D006801:Humans; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D009619:Nociceptors / Q000378:metabolism; D010100:Oxygen / Q000097:blood; D010146:Pain / Q000150:complications / Q000473:pathology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D014409:Tumor Necrosis Factor-alpha; D010100:Oxygen
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