Increased Sensitivity of Injured and Adjacent Uninjured Rat Primary Sensory Neurons to Exogenous Tumor Necrosis Factor-alpha After Spinal Nerve Ligation

Overview

Journal J Neurosci

Specialty Neurology

Date 2003 Apr 10

PMID 12684490

Citations 117

Authors

Maria Schafers

Doo H Lee

Dominik Brors

Tony L Yaksh

Linda S Sorkin

Affiliations

Soon will be listed here.

Abstract

Tumor necrosis factor-alpha (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.

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References

Ali Z, Ringkamp M, Hartke T, Chien H, Flavahan N, Campbell J . Uninjured C-fiber nociceptors develop spontaneous activity and alpha-adrenergic sensitivity following L6 spinal nerve ligation in monkey. J Neurophysiol. 1999; 81(2):455-66. DOI: 10.1152/jn.1999.81.2.455. View

Lee D, Liu X, Kim H, Chung K, Chung J . Receptor subtype mediating the adrenergic sensitivity of pain behavior and ectopic discharges in neuropathic Lewis rats. J Neurophysiol. 1999; 81(5):2226-33. DOI: 10.1152/jn.1999.81.5.2226. View

Porreca F, Lai J, Bian D, Wegert S, Ossipov M, Eglen R . A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain. Proc Natl Acad Sci U S A. 1999; 96(14):7640-4. PMC: 33594. DOI: 10.1073/pnas.96.14.7640. View

Devor M . Unexplained peculiarities of the dorsal root ganglion. Pain. 1999; Suppl 6:S27-S35. DOI: 10.1016/S0304-3959(99)00135-9. View

Liu X, Chung K, Chung J . Ectopic discharges and adrenergic sensitivity of sensory neurons after spinal nerve injury. Brain Res. 1999; 849(1-2):244-7. DOI: 10.1016/s0006-8993(99)02165-4. View

Junger H, Sorkin L . Nociceptive and inflammatory effects of subcutaneous TNFalpha. Pain. 2000; 85(1-2):145-51. DOI: 10.1016/s0304-3959(99)00262-6. View

Li Y, Dorsi M, Meyer R, Belzberg A . Mechanical hyperalgesia after an L5 spinal nerve lesion in the rat is not dependent on input from injured nerve fibers. Pain. 2000; 85(3):493-502. DOI: 10.1016/S0304-3959(00)00250-5. View

Liu C, Wall P, Ben-Dor E, Michaelis M, Amir R, Devor M . Tactile allodynia in the absence of C-fiber activation: altered firing properties of DRG neurons following spinal nerve injury. Pain. 2000; 85(3):503-521. DOI: 10.1016/S0304-3959(00)00251-7. View

Na H, Ko K, Back S, Sung B, Yoo D, Hong S . Role of signals from the dorsal root ganglion in neuropathic pain in a rat model. Neurosci Lett. 2000; 288(2):147-50. DOI: 10.1016/s0304-3940(00)01231-3. View

10.

Sorkin L, Doom C . Epineurial application of TNF elicits an acute mechanical hyperalgesia in the awake rat. J Peripher Nerv Syst. 2000; 5(2):96-100. DOI: 10.1046/j.1529-8027.2000.00012.x. View

11.

Eschenfelder S, Janig W . Dorsal root section elicits signs of neuropathic pain rather than reversing them in rats with L5 spinal nerve injury. Pain. 2000; 87(2):213-219. DOI: 10.1016/S0304-3959(00)00285-2. View

12.

Shubayev V, Myers R . Axonal transport of TNF-alpha in painful neuropathy: distribution of ligand tracer and TNF receptors. J Neuroimmunol. 2001; 114(1-2):48-56. DOI: 10.1016/s0165-5728(00)00453-7. View

13.

Diem R, Meyer R, Weishaupt J, Bahr M . Reduction of potassium currents and phosphatidylinositol 3-kinase-dependent AKT phosphorylation by tumor necrosis factor-(alpha) rescues axotomized retinal ganglion cells from retrograde cell death in vivo. J Neurosci. 2001; 21(6):2058-66. PMC: 6762605. View

14.

Sweitzer S, Martin D, DeLeo J . Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain. Neuroscience. 2001; 103(2):529-39. DOI: 10.1016/s0306-4522(00)00574-1. View

15.

Tsuzuki K, Kondo E, Fukuoka T, Yi D, Tsujino H, Sakagami M . Differential regulation of P2X(3) mRNA expression by peripheral nerve injury in intact and injured neurons in the rat sensory ganglia. Pain. 2001; 91(3):351-360. DOI: 10.1016/S0304-3959(00)00456-5. View

16.

Wu G, Ringkamp M, Hartke T, Murinson B, Campbell J, Griffin J . Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers. J Neurosci. 2001; 21(8):RC140. PMC: 6762537. View

17.

Yaksh T, Ozaki G, McCumber D, Rathbun M, Svensson C, Malkmus S . An automated flinch detecting system for use in the formalin nociceptive bioassay. J Appl Physiol (1985). 2001; 90(6):2386-402. DOI: 10.1152/jappl.2001.90.6.2386. View

18.

Hudson L, Bevan S, Wotherspoon G, Gentry C, Fox A, Winter J . VR1 protein expression increases in undamaged DRG neurons after partial nerve injury. Eur J Neurosci. 2001; 13(11):2105-14. DOI: 10.1046/j.0953-816x.2001.01591.x. View

19.

Fukuoka T, Kondo E, Dai Y, Hashimoto N, Noguchi K . Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model. J Neurosci. 2001; 21(13):4891-900. PMC: 6762362. View

20.

Schafers M, Brinkhoff J, Neukirchen S, Marziniak M, Sommer C . Combined epineurial therapy with neutralizing antibodies to tumor necrosis factor-alpha and interleukin-1 receptor has an additive effect in reducing neuropathic pain in mice. Neurosci Lett. 2001; 310(2-3):113-6. DOI: 10.1016/s0304-3940(01)02077-8. View