BACKGROUND: The cytokine tumor necrosis factor α (TNFα) is an established pain modulator in both the peripheral and central nervous systems. Modulation of nociceptive synaptic transmission in the spinal cord dorsal horn (DH) is thought to be involved in the development and maintenance of several pathological pain states. Increased levels of TNFα and its receptors (TNFR) in dorsal root ganglion (DRG) cells and in the spinal cord DH have been shown to play an essential role in neuropathic pain processing. In the present experiments the effect of TNFα incubation on modulation of primary afferent synaptic activity was investigated in a model of peripheral neuropathy. METHODS: Spontaneous and miniature excitatory postsynaptic currents (sEPSC and mEPSCs) were recorded in superficial DH neurons in acute spinal cord slices prepared from animals 5 days after sciatic nerve transection and in controls. RESULTS: In slices after axotomy the sEPSC frequency was 2.8 ± 0.8 Hz, while neurons recorded from slices after TNFα incubation had significantly higher sEPSC frequency (7.9 ± 2.2 Hz). The effect of TNFα treatment was smaller in the slices from the control animals, where sEPSC frequency was 1.2 ± 0.2 Hz in slices without and 2.0 ± 0.5 Hz with TNFα incubation. Tetrodotoxin (TTX) application in slices from axotomized animals and after TNFα incubation decreased the mEPSC frequency to only 37.4 ± 6.9% of the sEPSC frequency. This decrease was significantly higher than in the slices without the TNFα treatment (64.4 ± 6.4%). TTX application in the control slices reduced the sEPSC frequency to about 80% in both TNFα untreated and treated slices. Application of low concentration TRPV1 receptors endogenous agonist N-oleoyldopamine (OLDA, 0.2 μM) in slices after axotomy induced a significant increase in mEPSC frequency (175.9 ± 17.3%), similar to the group with TNFα pretreatment (158.1 ± 19.5%). CONCLUSIONS: Our results indicate that TNFα may enhance spontaneous transmitter release from primary afferent fibres in the spinal cord DH by modulation of TTX-sensitive sodium channels following sciatic nerve transection. This nerve injury also leads to enhanced sensitivity of presynaptic TRPV1 receptors to endogenous agonist. Modulation of presynaptic receptor activity on primary sensory terminals by TNFα may play an important role in neuropathic pain development.

Department of Functional Morphology Institute of Physiology Academy of Sciences of the Czech Republic Prague Czech Republic

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McMahon SB, Cafferty WB, Marchand F. Immune and glial cell factors as pain mediators and modulators. Exp Neurol. 2005;192:444–462. doi: 10.1016/j.expneurol.2004.11.001. PubMed DOI

Marchand F, Perretti M, McMahon SB. Role of the immune system in chronic pain. Nat Rev Neurosci. 2005;6:521–532. PubMed

Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci. 2007;10:1361–1368. doi: 10.1038/nn1992. PubMed DOI

Sommer C. Painful neuropathies. Curr Opin Neurol. 2003;16:623–628. doi: 10.1097/00019052-200310000-00009. PubMed DOI

Leung L, Cahill CM. TNF-alpha and neuropathic pain--a review. J Neuroinflammation. 2010;7:27. doi: 10.1186/1742-2094-7-27. PubMed DOI PMC

Jancalek R, Dubovy P, Svizenska I, Klusakova I. Bilateral changes of TNF-alpha and IL-10 protein in the lumbar and cervical dorsal root ganglia following a unilateral chronic constriction injury of the sciatic nerve. J Neuroinflammation. 2010;7:11. doi: 10.1186/1742-2094-7-11. PubMed DOI PMC

Schafers M, Geis C, Brors D, Yaksh TL, Sommer C. Anterograde transport of tumor necrosis factor-alpha in the intact and injured rat sciatic nerve. J Neurosci. 2002;22:536–545. PubMed PMC

Schafers M, Geis C, Svensson CI, Luo ZD, Sommer C. Selective increase of tumour necrosis factor-alpha in injured and spared myelinated primary afferents after chronic constrictive injury of rat sciatic nerve. Eur J Neurosci. 2003;17:791–804. doi: 10.1046/j.1460-9568.2003.02504.x. PubMed DOI

DeLeo JA, Colburn RW, Rickman AJ. Cytokine and growth factor immunohistochemical spinal profiles in two animal models of mononeuropathy. Brain Res. 1997;759:50–57. doi: 10.1016/S0006-8993(97)00209-6. PubMed DOI

Winkelstein BA, Rutkowski MD, Sweitzer SM, Pahl JL, DeLeo JA. Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment. J Comp Neurol. 2001;439:127–139. doi: 10.1002/cne.2000. PubMed DOI

Ohtori S, Takahashi K, Moriya H, Myers RR. TNF-alpha and TNF-alpha receptor type 1 upregulation in glia and neurons after peripheral nerve injury: studies in murine DRG and spinal cord. Spine (Phila Pa 1976) 2004;29:1082–1088. doi: 10.1097/00007632-200405150-00006. PubMed DOI

Hao S, Mata M, Glorioso JC, Fink DJ. Gene transfer to interfere with TNFalpha signaling in neuropathic pain. Gene Ther. 2007;14:1010–1016. doi: 10.1038/sj.gt.3302950. PubMed DOI

Kawasaki Y, Zhang L, Cheng JK, Ji RR. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci. 2008;28:5189–5194. doi: 10.1523/JNEUROSCI.3338-07.2008. PubMed DOI PMC

Gao YJ, Zhang L, Samad OA, Suter MR, Yasuhiko K, Xu ZZ, Park JY, Lind AL, Ma Q, Ji RR. JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci. 2009;29:4096–4108. doi: 10.1523/JNEUROSCI.3623-08.2009. PubMed DOI PMC

Zhang L, Berta T, Xu ZZ, Liu T, Park JY, Ji RR. TNF-alpha contributes to spinal cord synaptic plasticity and inflammatory pain: distinct role of TNF receptor subtypes 1 and 2. Pain. 2011;152:419–427. doi: 10.1016/j.pain.2010.11.014. PubMed DOI PMC

Spicarova D, Palecek J. Tumor necrosis factor alpha sensitizes spinal cord TRPV1 receptors to the endogenous agonist N-oleoyldopamine. J Neuroinflammation. 2010;7:49. doi: 10.1186/1742-2094-7-49. PubMed DOI PMC

Zhang H, Nei H, Dougherty PM. A p38 mitogen-activated protein kinase-dependent mechanism of disinhibition in spinal synaptic transmission induced by tumor necrosis factor-alpha. J Neurosci. 2010;30:12844–12855. doi: 10.1523/JNEUROSCI.2437-10.2010. PubMed DOI PMC

Zhang H, Dougherty PM. Acute inhibition of signalling phenotype of spinal GABAergic neurons by tumour necrosis factor. J Physiol. 2011;589:4511–4526. PubMed PMC

Schafers M, Svensson CI, Sommer C, Sorkin LS. Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci. 2003;23:2517–2521. PubMed PMC

Sommer C, Schafers M, Marziniak M, Toyka KV. Etanercept reduces hyperalgesia in experimental painful neuropathy. J Peripher Nerv Syst. 2001;6:67–72. doi: 10.1046/j.1529-8027.2001.01010.x. PubMed DOI

Pollock J, McFarlane SM, Connell MC, Zehavi U, Vandenabeele P, MacEwan DJ, Scott RH. TNF-alpha receptors simultaneously activate Ca2+ mobilisation and stress kinases in cultured sensory neurones. Neuropharmacology. 2002;42:93–106. doi: 10.1016/S0028-3908(01)00163-0. PubMed DOI

Yan P, Liu N, Kim GM, Xu J, Xu J, Li Q, Hsu CY, Xu XM. Expression of the type 1 and type 2 receptors for tumor necrosis factor after traumatic spinal cord injury in adult rats. Exp Neurol. 2003;183:286–297. doi: 10.1016/S0014-4886(03)00135-3. PubMed DOI

Dubovy P, Jancalek R, Klusakova I, Svizenska I, Pejchalova K. Intra- and extraneuronal changes of immunofluorescence staining for TNF-alpha and TNFR1 in the dorsal root ganglia of rat peripheral neuropathic pain models. Cell Mol Neurobiol. 2006;26:1205–1217. PubMed PMC

Shubayev VI, Myers RR. Axonal transport of TNF-alpha in painful neuropathy: distribution of ligand tracer and TNF receptors. J Neuroimmunol. 2001;114:48–56. doi: 10.1016/S0165-5728(00)00453-7. PubMed DOI

Schafers M, Sorkin LS, Geis C, Shubayev VI. Spinal nerve ligation induces transient upregulation of tumor necrosis factor receptors 1 and 2 in injured and adjacent uninjured dorsal root ganglia in the rat. Neurosci Lett. 2003;347:179–182. doi: 10.1016/S0304-3940(03)00695-5. PubMed DOI

Xu JT, Xin WJ, Zang Y, Wu CY, Liu XG. The role of tumor necrosis factor-alpha in the neuropathic pain induced by Lumbar 5 ventral root transection in rat. Pain. 2006;123:306–321. doi: 10.1016/j.pain.2006.03.011. PubMed DOI

Sommer C, Schmidt C, George A. Hyperalgesia in experimental neuropathy is dependent on the TNF receptor 1. Exp Neurol. 1998;151:138–142. doi: 10.1006/exnr.1998.6797. PubMed DOI

Vogel C, Stallforth S, Sommer C. Altered pain behavior and regeneration after nerve injury in TNF receptor deficient mice. J Peripher Nerv Syst. 2006;11:294–303. doi: 10.1111/j.1529-8027.2006.00101.x. PubMed DOI

Schafers M, Sommer C, Geis C, Hagenacker T, Vandenabeele P, Sorkin LS. Selective stimulation of either tumor necrosis factor receptor differentially induces pain behavior in vivo and ectopic activity in sensory neurons in vitro. Neuroscience. 2008;157:414–423. doi: 10.1016/j.neuroscience.2008.08.067. PubMed DOI

Cummins TR, Sheets PL, Waxman SG. The roles of sodium channels in nociception: Implications for mechanisms of pain. Pain. 2007;131:243–257. doi: 10.1016/j.pain.2007.07.026. PubMed DOI PMC

Waxman SG, Kocsis JD, Black JA. Type III sodium channel mRNA is expressed in embryonic but not adult spinal sensory neurons, and is reexpressed following axotomy. J Neurophysiol. 1994;72:466–470. PubMed PMC

Dib-Hajj S, Black JA, Felts P, Waxman SG. Down-regulation of transcripts for Na channel alpha-SNS in spinal sensory neurons following axotomy. Proc Natl Acad Sci USA. 1996;93:14950–14954. doi: 10.1073/pnas.93.25.14950. PubMed DOI PMC

Cummins TR, Waxman SG. Downregulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons after nerve injury. J Neurosci. 1997;17:3503–3514. PubMed PMC

Lai J, Gold MS, Kim CS, Bian D, Ossipov MH, Hunter JC, Porreca F. Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain. 2002;95:143–152. doi: 10.1016/S0304-3959(01)00391-8. PubMed DOI

Joshi SK, Mikusa JP, Hernandez G, Baker S, Shieh CC, Neelands T, Zhang XF, Niforatos W, Kage K, Han P, Krafte D, Faltynek C, Sullivan JP, Jarvis MF, Honore P. Involvement of the TTX-resistant sodium channel Nav 1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain. 2006;123:75–82. doi: 10.1016/j.pain.2006.02.011. PubMed DOI

Decosterd I, Ji RR, Abdi S, Tate S, Woolf CJ. The pattern of expression of the voltage-gated sodium channels Na(v)1.8 and Na(v)1.9 does not change in uninjured primary sensory neurons in experimental neuropathic pain models. Pain. 2002;96:269–277. doi: 10.1016/S0304-3959(01)00456-0. PubMed DOI

Gold MS, Weinreich D, Kim CS, Wang R, Treanor J, Porreca F, Lai J. Redistribution of Na(V)1.8 in uninjured axons enables neuropathic pain. J Neurosci. 2003;23:158–166. PubMed PMC

He XH, Zang Y, Chen X, Pang RP, Xu JT, Zhou X, Wei XH, Li YY, Xin WJ, Qin ZH, Liu XG. TNF-alpha contributes to up-regulation of Nav1.3 and Nav1.8 in DRG neurons following motor fiber injury. Pain. 2010;151:266–279. doi: 10.1016/j.pain.2010.06.005. PubMed DOI

Spicarova D, Palecek J. The role of the TRPV1 endogenous agonist N-Oleoyldopamine in modulation of nociceptive signaling at the spinal cord level. J Neurophysiol. 2009;102:234–243. doi: 10.1152/jn.00024.2009. PubMed DOI

Premkumar LS. Targeting TRPV1 as an alternative approach to narcotic analgesics to treat chronic pain conditions. AAPS J. 2010;12:361–370. doi: 10.1208/s12248-010-9196-y. PubMed DOI PMC

Spicarova D, Palecek J. The role of spinal cord vanilloid (TRPV1) receptors in pain modulation. Physiol Res. 2008;57(Suppl 3):S69–77. PubMed

Li Y, Ji A, Weihe E, Schafer MK. Cell-specific expression and lipopolysaccharide-induced regulation of tumor necrosis factor alpha (TNFalpha) and TNF receptors in rat dorsal root ganglion. J Neurosci. 2004;24:9623–9631. doi: 10.1523/JNEUROSCI.2392-04.2004. PubMed DOI PMC

Hensellek S, Brell P, Schaible HG, Brauer R, Segond von Banchet G. The cytokine TNFalpha increases the proportion of DRG neurones expressing the TRPV1 receptor via the TNFR1 receptor and ERK activation. Mol Cell Neurosci. 2007;36:381–391. doi: 10.1016/j.mcn.2007.07.010. PubMed DOI

Nicol GD, Lopshire JC, Pafford CM. Tumor necrosis factor enhances the capsaicin sensitivity of rat sensory neurons. J Neurosci. 1997;17:975–982. PubMed PMC

Khan AA, Diogenes A, Jeske NA, Henry MA, Akopian A, Hargreaves KM. Tumor necrosis factor alpha enhances the sensitivity of rat trigeminal neurons to capsaicin. Neuroscience. 2008;155:503–509. doi: 10.1016/j.neuroscience.2008.05.036. PubMed DOI

Constantin CE, Mair N, Sailer CA, Andratsch M, Xu ZZ, Blumer MJ, Scherbakov N, Davis JB, Bluethmann H, Ji RR, Kress M. Endogenous tumor necrosis factor alpha (TNFalpha) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model. J Neurosci. 2008;28:5072–5081. doi: 10.1523/JNEUROSCI.4476-07.2008. PubMed DOI PMC

Huang J, Zhang X, McNaughton PA. Modulation of temperature-sensitive TRP channels. Semin Cell Dev Biol. 2006;17:638–645. doi: 10.1016/j.semcdb.2006.11.002. PubMed DOI

Jin X, Gereau RWt. Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha. J Neurosci. 2006;26:246–255. doi: 10.1523/JNEUROSCI.3858-05.2006. PubMed DOI PMC

Xu JT, Xin WJ, Wei XH, Wu CY, Ge YX, Liu YL, Zang Y, Zhang T, Li YY, Liu XG. p38 activation in uninjured primary afferent neurons and in spinal microglia contributes to the development of neuropathic pain induced by selective motor fiber injury. Exp Neurol. 2007;204:355–365. doi: 10.1016/j.expneurol.2006.11.016. PubMed DOI

Chen X, Pang RP, Shen KF, Zimmermann M, Xin WJ, Li YY, Liu XG. TNF-alpha enhances the currents of voltage gated sodium channels in uninjured dorsal root ganglion neurons following motor nerve injury. Exp Neurol. 2011;227:279–286. doi: 10.1016/j.expneurol.2010.11.017. PubMed DOI

Scheuer T. Regulation of sodium channel activity by phosphorylation. Semin Cell Dev Biol. 2011;22:160–165. doi: 10.1016/j.semcdb.2010.10.002. PubMed DOI PMC

Shao D, Okuse K, Djamgoz MB. Protein-protein interactions involving voltage-gated sodium channels: Post-translational regulation, intracellular trafficking and functional expression. Int J Biochem Cell Biol. 2009;41:1471–1481. doi: 10.1016/j.biocel.2009.01.016. PubMed DOI

Stamboulian S, Choi JS, Ahn HS, Chang YW, Tyrrell L, Black JA, Waxman SG, Dib-Hajj SD. ERK1/2 mitogen-activated protein kinase phosphorylates sodium channel Na(v)1.7 and alters its gating properties. J Neurosci. 2010;30:1637–1647. doi: 10.1523/JNEUROSCI.4872-09.2010. PubMed DOI PMC

Engel D, Jonas P. Presynaptic action potential amplification by voltage-gated Na+ channels in hippocampal mossy fiber boutons. Neuron. 2005;45:405–417. doi: 10.1016/j.neuron.2004.12.048. PubMed DOI

Hsia AY, Malenka RC, Nicoll RA. Development of excitatory circuitry in the hippocampus. J Neurophysiol. 1998;79:2013–2024. PubMed

Youn DH, Wang H, Jeong SJ. Exogenous tumor necrosis factor-alpha rapidly alters synaptic and sensory transmission in the adult rat spinal cord dorsal horn. J Neurosci Res. 2008;86:2867–2875. doi: 10.1002/jnr.21726. PubMed DOI

Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC. Control of synaptic strength by glial TNFalpha. Science. 2002;295:2282–2285. doi: 10.1126/science.1067859. PubMed DOI

Choi JI, Svensson CI, Koehrn FJ, Bhuskute A, Sorkin LS. Peripheral inflammation induces tumor necrosis factor dependent AMPA receptor trafficking and Akt phosphorylation in spinal cord in addition to pain behavior. Pain. 2010;149:243–253. doi: 10.1016/j.pain.2010.02.008. PubMed DOI PMC

Ferguson AR, Christensen RN, Gensel JC, Miller BA, Sun F, Beattie EC, Bresnahan JC, Beattie MS. Cell death after spinal cord injury is exacerbated by rapid TNF alpha-induced trafficking of GluR2-lacking AMPARs to the plasma membrane. J Neurosci. 2008;28:11391–11400. doi: 10.1523/JNEUROSCI.3708-08.2008. PubMed DOI PMC

Zhang X, Huang J, McNaughton PA. NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO J. 2005;24:4211–4223. doi: 10.1038/sj.emboj.7600893. PubMed DOI PMC

Staaf S, Oerther S, Lucas G, Mattsson JP, Ernfors P. Differential regulation of TRP channels in a rat model of neuropathic pain. Pain. 2009;144:187–199. doi: 10.1016/j.pain.2009.04.013. PubMed DOI

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