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The Red Nucleus TNF-α Participates in the Initiation and Maintenance of Neuropathic Pain Through Different Signaling Pathways

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Abstract

Previous studies have demonstrated that tumor necrosis factor-alpha (TNF-α) in the red nucleus (RN) plays a facilitated role in the development of neuropathic pain. Here, we further investigated the expression changes and roles of the downstream signaling molecules of the red nucleus TNF-α, including nuclear factor-kappa B (NF-κB), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), in the initiation and maintenance of neuropathic pain induced by spared nerve injury (SNI). Immunohistochemistry demonstrated that increased expressions of NF-κB, phospho-ERK (p-ERK) and p-p38 MAPK were observed in the RN contralateral (but not ipsilateral) to the nerve injury side at 3 days after SNI compared with sham-operated and normal rats, the up-regulations of NF-κB and p-ERK but not p-p38 MAPK remained at high levels till 14 days later. An elevated expression of p-JNK occurred at 14 days (but not 3 and 7 days) after SNI, which was later than those of NF-κB, p-ERK and p-p38 MAPK. The up-regulations of NF-κB, p-ERK, p-p38 MAPK and p-JNK all could be abolished by microinjection of anti-TNF-α antibody into the RN of rats with SNI. Microinjection of NF-κB inhibitor PDTC, ERK inhibitor PD98059, p38 MAPK inhibitor SB203580 but not JNK inhibitor SP600125 into the RN contralateral to the nerve injury side at 3 days postinjury significantly alleviated SNI-induced mechanical allodynia. In addition, microinjection of PDTC, PD98059 and SP600125 but not SB203580 into the RN at 14 days postinjury significantly alleviated SNI-induced mechanical allodynia. These results suggest that the red nucleus TNF-α produces the algesic effect through activating NF-κB, ERK and p38 MAPK in the early initiation stage but relying on the activation of NF-κB, ERK and JNK in the later maintenance stage of SNI-induced neuropathic pain.

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References

  1. Basso DM, Beattie MS, Bresnahan JC (2002) Descending systems contributing to locomotor recovery after mild or moderate spinal cord injury in rats: experimental evidence and a review of literature. Restor Neurol Neurosci 20:189–218

    PubMed  Google Scholar 

  2. Küchler M, Fouad K, Weinmann O, Schwab ME, Raineteau O (2002) Red nucleus projections to distinct motor neuron pools in the rat spinal cord. J Comp Neurol 448:349–359

    Article  PubMed  Google Scholar 

  3. Lavoie S, Drew T (2002) Discharge characteristics of neurons in the red nucleus during voluntary gait modifications: a comparison with the motor cortex. J Neurophysiol 88:1791–1814

    PubMed  Google Scholar 

  4. Muir GD, Whishaw IQ (2000) Red nucleus lesions impair overground locomotion in rats: a kinetic analysis. Eur J Neurosci 12:1113–1122

    Article  CAS  PubMed  Google Scholar 

  5. Zelenin PV, Beloozerova IN, Sirota MG, Orlovsky GN, Deliagina TG (2010) Activity of red nucleus neurons in the cat during postural corrections. J Neurosci 30:14533–14542

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Satoh Y, Ishizuka K, Murakami T (2007) Changes in cortically induced rhythmic jaw movements after lesioning of the red nucleus in rats. Brain Res 1165:60–70

    Article  CAS  PubMed  Google Scholar 

  7. Satoh Y, Yajima E, Ishizuka K, Nagamine Y, Iwasaki S (2013) Modulation of two types of jaw-opening reflex by stimulation of the red nucleus. Brain Res Bull 97:24–31

    Article  PubMed  Google Scholar 

  8. Liu M, Liu X, Liu B (1991) The analgesia effect of red nucleus and strengthening effect thereof to the acupuncture analgesia. Zhen Ci Yan Jiu 16:48–53

    CAS  PubMed  Google Scholar 

  9. Huang M, Liu M, Li X (1992) The analgesic effect of red nucleus and preliminary research on its mechanism. Zhen Ci Yan Jiu 17:166–170

    CAS  PubMed  Google Scholar 

  10. Steffens H, Rathelot JA, Padel Y (2000) Effects of noxious skin heating on spontaneous cell activity in the magnocellular red nucleus of the cat. Exp Brain Res 131:215–224

    Article  CAS  PubMed  Google Scholar 

  11. Li X, Wang J, Wang Z, Dong C, Dong X, Jing Y, Yuan Y, Fan G (2008) Tumor necrosis factor-alpha of red nucleus involved in the development of neuropathic allodynia. Brain Res Bull 77:233–236

    Article  CAS  PubMed  Google Scholar 

  12. Wang Z, Wang J, Li X, Yuan Y, Fan G (2008) Interleukin-1 beta of red nucleus involved in the development of allodynia in spared nerve injury rats. Exp Brain Res 188:379–384

    Article  CAS  PubMed  Google Scholar 

  13. Jing YY, Wang JY, Li XL, Wang ZH, Pei L, Pan MM, Dong XP, Fan GX, Yuan YK (2009) Nerve growth factor of red nucleus involvement in pain induced by spared nerve injury of the rat sciatic nerve. Neurochem Res 34:1612–1618

    Article  CAS  PubMed  Google Scholar 

  14. Zhang Q, Wang J, Duan MT, Han SP, Zeng XY, Wang JY (2013) NF-κB, ERK, p38 MAPK and JNK contribute to the initiation and/or maintenance of mechanical allodynia induced by tumor necrosis factor-alpha in the red nucleus. Brain Res Bull 99:132–139

    Article  CAS  PubMed  Google Scholar 

  15. Wang ZH, Zeng XY, Han SP, Fan GX, Wang JY (2012) Interleukin-10 of red nucleus plays anti-allodynia effect in neuropathic pain rats with spared nerve injury. Neurochem Res 37:1811–1819

    Article  CAS  PubMed  Google Scholar 

  16. Zeng XY, Zhang Q, Wang J, Yu J, Han SP, Wang JY (2014) Distinct role of tumor necrosis factor receptor subtypes 1 and 2 in the red nucleus in the development of neuropathic pain. Neurosci Lett 569:43–48

    Article  CAS  PubMed  Google Scholar 

  17. Austin PJ, Moalem-Taylor G (2010) The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol 229:26–50

    Article  CAS  PubMed  Google Scholar 

  18. Leung L, Cahill CM (2010) TNF-α and neuropathic pain—a review. J Neuroinflammation 7:27

    Article  PubMed Central  PubMed  Google Scholar 

  19. Andrade P, Visser-Vandewalle V, Hoffmann C, Steinbusch HWM, Daemen MA, Hoogland G (2011) Role of TNF-alpha during central sensitization in preclinical studies. Neurol Sci 32:757–771

    Article  PubMed Central  PubMed  Google Scholar 

  20. Ignatowski TA, Covey WC, Knight PR, Severin CM, Nickola TJ, Spengler RN (1999) Brain-derived TNFα mediates neuropathic pain. Brain Res 841:70–77

    Article  CAS  PubMed  Google Scholar 

  21. Covey WC, Ignatowski TA, Knight PR, Spengler RN (2000) Brain-derived TNFα: involvement in neuroplastic changes implicated in the conscious perception of persistent pain. Brain Res 859:113–122

    Article  CAS  PubMed  Google Scholar 

  22. Lee HL, Lee KM, Son SJ, Hwang SH, Cho HJ (2004) Temporal expression of cytokines and their receptors mRNAs in a neuropathic pain model. NeuroReport 15:2807–2811

    CAS  PubMed  Google Scholar 

  23. Dubový P, Jancálek R, Klusáková I, Svízenská I, Pejchalová K (2006) Intra- and extraneuronal changes of immunofluorescence staining for TNF-α and TNFR1 in the dorsal root ganglia of rat peripheral neuropathic pain models. Cell Mol Neurobiol 26:1205–1217

    PubMed  Google Scholar 

  24. Sacerdote P, Franchi S, Trovato AE, Valsecchi AE, Panerai AE, Colleoni M (2008) Transient early expression of TNF-α in sciatic nerve and dorsal root ganglia in a mouse model of painful peripheral neuropathy. Neurosci Lett 436:210–213

    Article  CAS  PubMed  Google Scholar 

  25. Wei F, Guo W, Zou S, Ren K, Dubner R (2008) Supraspinal glial-neuronal interactions contribute to descending pain facilitation. J Neurosci 28:10482–10495

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Jancálek R, Dubový P, Svízenská I, Klusáková I (2010) 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 7:11

    Article  PubMed Central  PubMed  Google Scholar 

  27. Nadeau S, Filali M, Zhang J, Kerr BJ, Rivest S, Soulet D, Iwakura Y, de Rivero Vaccari JP, Keane RW, Lacroix S (2011) Functional recovery after peripheral nerve injury is dependent on the pro-inflammatory cytokines IL-1β and TNF: implications for neuropathic pain. J Neurosci 31:12533–12542

    Article  CAS  PubMed  Google Scholar 

  28. Sommer C, Lindenlaub T, Teuteberg P, Schäfers M, Hartung T, Toyka KV (2001) Anti-TNF-neutralizing antibodies reduce pain-related behavior in two different mouse models of painful mononeuropathy. Brain Res 913:86–89

    Article  CAS  PubMed  Google Scholar 

  29. Sommer C, Schäfers M, Marziniak M, Toyka KV (2001) Etanercept reduces hyperalgesia in experimental painful neuropathy. J Peripher Nerv Syst 6:67–72

    Article  CAS  PubMed  Google Scholar 

  30. Sweitzer S, Martin D, DeLeo JA (2001) 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 103:529–539

    Article  CAS  PubMed  Google Scholar 

  31. Hao S, Mata M, Glorioso JC, Fink DJ (2007) Gene transfer to interfere with TNFα signaling in neuropathic pain. Gene Ther 14:1010–1016

    Article  CAS  PubMed  Google Scholar 

  32. Zelenka M, Schäfers M, Sommer C (2005) Intraneural injection of interleukin-1β and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain. Pain 116:257–263

    Article  CAS  PubMed  Google Scholar 

  33. Youn DH, Wang H, Jeong SJ (2008) Exogenous tumor necrosis factor-α rapidly alters synaptic and sensory transmission in the adult rat spinal cord dorsal horn. J Neurosci Res 86:2867–2875

    Article  CAS  PubMed  Google Scholar 

  34. Eijkelkamp N, Heijnen CJ, Carbajal AG, Willemen HL, Wang H, Minett MS, Wood JN, Schedlowski M, Dantzer R, Kelley KW, Kavelaars A (2012) G protein-coupled receptor kinase 6 acts as a critical regulator of cytokine-induced hyperalgesia by promoting phosphatidylinositol 3-kinase and inhibiting p38 signaling. Mol Med 18:556–564

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Wei XH, Zang Y, Wu CY, Xu JT, Xin WJ, Liu XG (2007) Peri-sciatic administration of recombinant rat TNF-α induces mechanical allodynia via upregulation of TNF-α in dorsal root ganglia and in spinal dorsal horn: the role of NF-kappa B pathway. Exp Neurol 205:471–484

    Article  CAS  PubMed  Google Scholar 

  36. Yamaguchi S, Tanabe K, Takai S, Matsushima-Nishiwaki R, Adachi S, Iida H, Kozawa O, Dohi S (2009) Involvement of Rho-kinase in tumor necrosis factor-α-induced interleukin-6 release from C6 glioma cells. Neurochem Int 55:438–445

    Article  CAS  PubMed  Google Scholar 

  37. Gao YJ, Zhang L, Samad OA, Suter MR, Yasuhiko K, Xu ZZ, Park JY, Lind AL, Ma Q, Ji RR (2009) JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci 29:4096–4108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Jin X, Gereau IVRW (2006) Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-α. J Neurosci 26:246–255

    Article  CAS  PubMed  Google Scholar 

  39. Zang Y, He XH, Xin WJ, Pang RP, Wei XH, Zhou LJ, Li YY, Liu XG (2010) Inhibition of NF-kappaB prevents mechanical allodynia induced by spinal ventral root transection and suppresses the re-expression of Nav1.3 in DRG neurons in vivo and in vitro. Brain Res 1363:151–158

    Article  CAS  PubMed  Google Scholar 

  40. Zang Y, Xin WJ, Pang RP, Li YY, Liu XG (2011) Upregulation of Nav1.3 channel induced by rrTNF in cultured adult rat DRG neurons via p38 MAPK and JNK pathways. Chin J Physiol 54:241–246

    Article  CAS  PubMed  Google Scholar 

  41. Liu YL, Zhou LJ, Hu NW, Xu JT, Wu CY, Zhang T, Li YY, Liu XG (2007) Tumor necrosis factor-alpha induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn in rats with nerve injury: the role of NF-kappa B, JNK and p38 MAPK. Neuropharmacology 52:708–715

    Article  CAS  PubMed  Google Scholar 

  42. Schäfers M, Svensson CI, Sommer C, Sorkin LS (2003) Tumor necrosis factor-α induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci 23:2517–2521

    PubMed  Google Scholar 

  43. Svensson CI, Schäfers M, Jones TL, Powell H, Sorkin LS (2005) Spinal blockade of TNF blocks spinal nerve ligation-induced increases in spinal P-p38. Neurosci Lett 379:209–213

    Article  CAS  PubMed  Google Scholar 

  44. Xu JT, Xin WJ, Wei XH, Wu CY, Ge YX, Liu YL, Zang Y, Zhang T, Li YY, Liu XG (2007) 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 204:355–365

    Article  CAS  PubMed  Google Scholar 

  45. Takahashi N, Kikuchi S, Shubayev VI, Campana WM, Myers RR (2006) TNF-alpha and phosphorylation of ERK in DRG and spinal cord: insights into mechanisms of sciatica. Spine 31:523–529

    Article  PubMed  Google Scholar 

  46. Meotti FC, Posser T, Missau FC, Pizzolatti MG, Leal RB, Santos AR (2007) Involvement of p38 MAPK on the antinociceptive action of myricitrin in mice. Biochem Pharmacol 74:924–931

    Article  CAS  PubMed  Google Scholar 

  47. Zimmermann M (1983) Ethical guideline for investigations of experimental pain in conscious animals. Pain 16:109–110

    Article  CAS  PubMed  Google Scholar 

  48. Bourquin AF, Süveges M, Pertin M, Gilliard N, Sardy S, Davison AC, Spahn DR, Decosterd I (2006) Assessment and analysis of mechanical allodynia-like behavior induced by spared nerve injury (SNI) in the mouse. Pain 122:14.e1–14.e14

    Article  Google Scholar 

  49. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, Sydney

    Google Scholar 

  50. Jin SX, Zhuang ZY, Woolf CJ, Ji RR (2003) p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci 23:4017–4022

    CAS  PubMed  Google Scholar 

  51. Ledeboer A, Gamanos M, Lai W, Martin D, Maier SF, Watkins LR, Quan N (2005) Involvement of spinal cord nuclear factor kappaB activation in rat models of proinflammatory cytokine-mediated pain facilitation. Eur J Neurosci 22:1977–1986

    Article  PubMed  Google Scholar 

  52. Zhuang ZY, Gerner P, Woolf CJ, Ji RR (2005) ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 114:149–159

    Article  PubMed  Google Scholar 

  53. Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, Decosterd I, Ji RR (2006) A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 26:551–560

    Article  Google Scholar 

  54. Chaplan SR, Bach FW, Pogrel JW, Chung JW, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55–63

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The project was sponsored by the National Natural Science Foundation of China (No. 31070979) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry.

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Authors and Affiliations

  1. Department of Immunology and Pathogenic Biology, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, Shaanxi, China

    Qian Zhang, Jing Yu, Jing Wang, Cui-Ping Ding & Jun-Yang Wang

  2. Department of Laboratory Medicine, The First Affiliated Hospital, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, Shaanxi, China

    Xiao-Yan Zeng

  3. Department of Pathology, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, Shaanxi, China

    Shui-Ping Han

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  1. Qian Zhang
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Correspondence to Jun-Yang Wang.

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Zhang, Q., Yu, J., Wang, J. et al. The Red Nucleus TNF-α Participates in the Initiation and Maintenance of Neuropathic Pain Through Different Signaling Pathways. Neurochem Res 40, 1360–1371 (2015). https://doi.org/10.1007/s11064-015-1599-9

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  • DOI: https://doi.org/10.1007/s11064-015-1599-9

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