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The Journal of Neuroscience, April 1, 2003, 23(7):3028
Increased Sensitivity of Injured and Adjacent Uninjured Rat
Primary Sensory Neurons to Exogenous Tumor Necrosis Factor- after
Spinal Nerve Ligation
Maria
Schäfers1,
Doo H.
Lee3,
Dominik
Brors2,
Tony L.
Yaksh1, and
Linda S.
Sorkin1
1 Anesthesiology Research Laboratory and
2 Department of Otolaryngology and Neuroscience, University
of California San Diego, La Jolla, California 92093-0818, and
3 Johnson & Johnson Pharmaceutical Research and
Development, San Diego, California 92121
Tumor necrosis factor- (TNF) is upregulated after nerve injury,
causes pain on injection, and its blockade reduces pain behavior resulting from nerve injury; thus it is strongly implicated in neuropathic pain. We investigated responses of intact and nerve-injured dorsal root ganglia (DRG) neurons to locally applied TNF using parallel
in vivo and in vitro paradigms. In
vivo, TNF (0.1-10 pg/ml) or vehicle was injected into L5 DRG
in naive rats and in rats that had received L5 and L6 spinal nerve
ligation (SNL) immediately before injection. In naive rats, TNF, but
not vehicle, elicited long-lasting allodynia. In SNL rats, subthreshold
doses of TNF synergized with nerve injury to elicit faster onset of
allodynia and spontaneous pain behavior. Tactile allodynia was present
in both injured and adjacent uninjured (L4) dermatomes. Preemptive treatment with the TNF antagonist etanercept reduced SNL-induced allodynia by almost 50%. In vitro, the
electrophysiological responses of naive, SNL-injured, or adjacent
uninjured DRG to TNF (0.1-1000 pg/ml) were assessed by single-fiber
recordings of teased dorsal root microfilaments. In
vitro perfusion of TNF (100-1000 pg/ml) to naive DRG evoked
short-lasting neuronal discharges. In injured DRG, TNF, at much lower
concentrations, elicited earlier onset, markedly higher, and
longer-lasting discharges. TNF concentrations that were subthreshold in
naive DRG also elicited high-frequency discharges when applied to
uninjured, adjacent DRG. We conclude that injured and adjacent
uninjured DRG neurons are sensitized to TNF after SNL. Sensitization to
endogenous TNF may be essential for the development and maintenance of
neuropathic pain.
Key words:
cytokines; tumor necrosis factor-; dorsal root
ganglion; excitability; spinal nerve ligation; injured and uninjured
fibers
Copyright © 2003 Society for Neuroscience 0270-6474/03/2373028-11$05.00/0
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