Antinociceptive effects of tumor necrosis factor alpha neutralization in a rat model of antigen-induced arthritis: evidence of a neuronal target.
OBJECTIVE
The reduction of pain in the course of antiinflammatory therapy can result from an attenuation of the inflammatory process and/or from the neutralization of endogenous mediators of inflammation that act directly on nociceptive neurons. The purpose of this study was to investigate whether analgesic effects of the neutralization of tumor necrosis factor alpha (TNFalpha) are due to an attenuation of inflammation or whether direct neuronal effects significantly contribute to pain relief in the course of therapy.


METHODS
Locomotor and pain-related behavior and histology were assessed in rats with chronic antigen-induced arthritis (AIA) in the knee joint, and the rats were treated with systemic saline, etanercept, or infliximab. The expression of TNF receptors (TNFRs) in dorsal root ganglia was measured using immunohistochemical analysis and polymerase chain reaction. Action potentials were recorded from afferent Adelta fibers and C fibers of the medial knee joint nerve, and etanercept and infliximab were injected intraarticularly into normal or inflamed knee joints (AIA or kaolin/carrageenan-induced inflammation).


RESULTS
In rats with AIA, both etanercept and infliximab significantly decreased inflammation-induced locomotor and pain-related behavior, while joint swelling was only weakly attenuated and histomorphology still revealed pronounced inflammation. A large proportion of dorsal root ganglion neurons showed TNFRI- and TNFRII-like immunoreactivity. Intraarticular injection of etanercept reduced the responses of joint afferents to mechanical stimulation of the inflamed joint starting 30 minutes after injection, but had no effect on responses to mechanical stimulation of the uninflamed joint.


CONCLUSIONS
Overall, these data show the pronounced antinociceptive effects of TNFalpha neutralization, thus suggesting that reduction of the effects of TNFalpha on pain fibers themselves significantly contributes to pain relief.
Boettger
Michael K
MK
University Hospital of Jena, Jena, Germany.
Hensellek
Susanne
S
Richter
Frank
F
Gajda
Mieczyslaw
M
Stöckigt
Renate
R
von Banchet
Gisela Segond
GS
Bräuer
Rolf
R
Schaible
Hans-Georg
HG
D000276:Adjuvants, Immunologic; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018771:Arthralgia / Q000188:drug therapy / Q000503:physiopathology; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D000068800:Etanercept; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use*; D000069285:Infliximab; D007719:Knee Joint / Q000294:innervation; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D011917:Rats, Inbred Lew; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068800:Etanercept