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Effects of interleukin-1 beta, interleukin-6, and tumor necrosis factor on sensitivity of dorsal root ganglion and peripheral receptive fields in rats

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Abstract

This study was designed to characterize the effects of low doses (0.5–5 ng) of pro-inflammatory cytokines, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF), on the neural activity of dorsal root ganglion (DRG) in rats. The purpose of this study was to examine the effects of cytokines (IL-1β, IL-6, and TNF) on the somatosensory neural response of DRG. The release of inflammatory cytokines by an injured disc may play a critical role in pain production at nerve endings, axons, and nerve cell bodies. Herniated disc tissue has been shown to release IL-1β, IL-6, TNF, and other algesic chemicals. Their effects on nerve endings in disc and adjacent tissue may lead to low back pain and their effects on dorsal root axons and ganglia may lead to sciatica. Exposed lumbar DRGs were investigated by electrophysiologic techniques. Sham (mineral oil), control (carrier solution), or IL-1β, IL-6, or TNF at doses of 0.5, 1, and 5 ng were applied over the DRG. Baseline discharge rates as well as mechanosensitivity of the DRG and peripheral receptive fields were evaluated over 30 min. Applications of IL-1β at 1 ng resulted in an increase in the discharge rate, 5 ng resulted in an increased mechanosensitivity of the DRG in group II units. Similarly, after 1 ng TNF applications, group II units also showed an increase in mechanosensitivity of DRG and peripheral receptive fields. At low doses IL-1β and TNF sensitization of receptive fields were observed. The responses observed in the group II units indicate that a sub-population of afferent units might have long-term effects modifying the sensory input to the central nervous system. This study provides added evidence to the role of cytokines in modulating afferent activity following inflammation.

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References

  1. Anzai H, Hamba M, Onda A et al. (2002) Epidural application of nucleus pulposus enhances nociresponses of rat dorsal horn neurons. Spine 27(3):E50–E55

    Article  PubMed  Google Scholar 

  2. Aoki Y, Rydevik B, Kikuchi S, Olmarker KJ (2002) Local application of disc-related cytokines on spinal nerve roots. Spine 27(15):1614–1617

    Article  PubMed  Google Scholar 

  3. Bianchi M, Dib B, Panerai AE (1998) Interleukin-1 and nociception in the rat. J Neurosci Res 53:644–650

    Article  Google Scholar 

  4. Burke JG, Watson RW, McCormack D et al (2002) Intervertebral discs which cause low back pain secrete high levels of proinflammatory mediators. J Bone Joint Surg (Br) 84(2):196–201

    Article  CAS  Google Scholar 

  5. Chen CY, Cavanaugh JM, Song Z et al (2003) Effects of nucleus pulposus on nerve root neural activity, mechanosensitivity, axonal morphology and sodium channel. Spine 29(1):17–25

    CAS  Google Scholar 

  6. Cunha FQ, Poole S, Lorenzetti B, Ferreria SH (1992) The pivotal role of tumor necrosis factor alpha in the development of inflammatory hyperalgesia. Br J Pharmacol (107):660–664

    Google Scholar 

  7. Eliav E, Herzberg U, Ruda MA, Bennett GJ (1999) Neuropathic pain from an experimental neuritis of the rat sciatic nerve. Pain 83:169–182

    Article  PubMed  CAS  Google Scholar 

  8. Ferreria SH, Lorenzetti BB, Bristow AF, Poole S (1988) Interleukin 1 beta as a potent hyperalgesic agent antagonized by a tripeptide analogue. Nature 334:698–700

    Article  PubMed  Google Scholar 

  9. Fukuoka H, Kawatani M, Hisamitsu T, Takeshige C (1994) Cutaneous hyperalgesia induced by peripheral injection of interleukin-1 beta in the rat. Brain Res 657(1–2):133–140

    Article  PubMed  CAS  Google Scholar 

  10. Garabedian BS, Poole S, Allchorne A, Winter J, Woolf CJ (1995) Contribution of interleukin 1beta to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia. Br J Pharmacol 115:1265–1275

    PubMed  Google Scholar 

  11. Gronblad M, Virri J, Tolonen J et al (1994) A controlled immunohistochemical study of inflammatory cells in disc herniation tissue. Spine 19(24):2744–2751

    Article  PubMed  CAS  Google Scholar 

  12. Habtemariam A, Gronblad M, Virri J, Seitsalo S, Karaharju E (1998) A comparative immunohistochemical study of inflammatory cells in acute-stage and chronic-stage disc herniations. Spine 23:2159–2166

    Article  PubMed  CAS  Google Scholar 

  13. Harrington JF et al (2000) Herniated lumbar disc material as a source of free glutamate available to affect pain signals through the dorsal root ganglion. Spine 25(8):929–936

    Article  PubMed  CAS  Google Scholar 

  14. Homma Y, Brull SJ, Zhang JM (2002) A comparison of chronic pain behavior following local application of tumor necrosis factor alpha to the normal and mechanically compressed lumbar ganglia in the rat. Pain 95(3):239–246

    Article  PubMed  CAS  Google Scholar 

  15. Junger H, Sorkin LS (2000) Nociceptive and inflammatory effects of subcutaneous TNF alpha. Pain 85(1–2):145–151

    Article  PubMed  CAS  Google Scholar 

  16. Kallakuri S, Cavanaugh JM, Takebayashi T, Ozaktay AC et al (2005) The effects of epidural application of allografted nucleus pulposus in rats on cytokine expression, limb withdrawal and nerve root discharge. Eur Spine J 14(10):956–964

    Article  PubMed  Google Scholar 

  17. Kang JD, Georgescu HI, McIntyre-Larkin L, Stefanovic-Racic M, Donaldson WF 3rd, Evans CH (1996) Herniated lumbar intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6 and prostaglandin E2. Spine 21(3):271–277

    Article  PubMed  CAS  Google Scholar 

  18. Kawakami M, Tamaki T, Weinstein JN et al (1996) Pathomechanisms of pain-related behavior produced by allografts of intervertebral disc in the rat. Spine 21(18):2101–2107

    Article  PubMed  CAS  Google Scholar 

  19. Kayama S, Konno S, Olmarker K et al (1996) Incision of the annulus fibrosus induces nerve root morphologic, vascular, and functional changes. An experimental study. Spine 21(22):2539–2543

    Article  PubMed  CAS  Google Scholar 

  20. Kayama S, Olmarker K, Larsson K et al (1998) Cultured, autologous nucleus pulposus cells induce functional changes in spinal nerve roots. Spine 23(20):2155–2158

    Article  PubMed  CAS  Google Scholar 

  21. Kuslich SD, Ulstrom CL, Michael CJ (1991) The tissue origin of low back pain and sciatica: a report of pain response to tissue stimulation during operation on the lumbar spine using local anesthesia. Orthop Clin North Am 22(2):181–187

    PubMed  CAS  Google Scholar 

  22. Liu B, Li H, Brull SJ, Zhang JM (2002) Increased sensitivity of sensory neurons to tumor necrosis factor alpha in rats with chronic compression of the lumbar ganglia. J Neurophysiol 88(3):1393–1399

    PubMed  CAS  Google Scholar 

  23. McCarron RF, Wimpee MW, Hudkins PG et al (1987) The inflammatory effect of nucleus pulposus. A possible element in the pathogenesis of low back pain. Spine 12(8):760–764

    Article  PubMed  CAS  Google Scholar 

  24. Oka T, Oka K, Hosoi M, Hori T (1995) Intracerebroventricular injection of interleukin-6 induces thermal hyperalgesia in rats. Brain Res 692(1–2):123–128

    Article  PubMed  CAS  Google Scholar 

  25. Olmarker K, Larsson K (1998) Tumor necrosis factor alpha and nucleus-pulposus-induced nerve root injury. Spine 23(23):2538–2544

    Article  PubMed  CAS  Google Scholar 

  26. Olmarker K, Myers R (1998) Pathogenesis of sciatic pain: role of herniated nucleus pulposus and deformation of spinal nerve root and dorsal root ganglion. Pain 78:99–105

    Article  PubMed  Google Scholar 

  27. Olmarker K, Rydevik B (2001) Selective inhibition of tumor necrosis factor alpha prevents nucleus pulposus-induced thrombus formation, intraneural edema, and reduction of nerve conduction velocity. Possible implications for future pharmacologic treatment strategies of sciatica. Spine 26(8):863–869

    Article  PubMed  CAS  Google Scholar 

  28. Olmarker K, Nordborg C, Larsson K et al (1996) Ultrastructural changes in spinal nerve roots induced by autologous nucleus pulposus. Spine 21:411–414

    Article  PubMed  CAS  Google Scholar 

  29. Olmarker K, Rydevik B, Nordborg C (1993) Autologous nucleus pulposus induces neurophysiologic and histologic changes in porcine cauda equina nerve roots. Spine 18:1425–1432

    Article  PubMed  CAS  Google Scholar 

  30. Opree A, Kress M (2000) Involvement of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1 beta, and IL-6 but not IL-8 in the development of heat hyperalgesia: effects on heat-evoked calcitonin gene-related peptide release from rat skin. J Neurosci 20(16):6289–6293

    PubMed  CAS  Google Scholar 

  31. Ozaktay AC, Cavanaugh JM, Asik I, DeLeo JA, Weinstein JN (2002) Dorsal root sensitivity to interleukin-1 beta, interleukin-6 and tumor necrosis factor in rats. Eur Spine J 11(5):467–475

    Article  PubMed  Google Scholar 

  32. Ozaktay AC, Kallakuri S, Cavanaugh JM (1998) Phospholipase A2 sensitivity of the dorsal root and dorsal root ganglion. Spine (23):1297–1306

    Article  Google Scholar 

  33. Perkins MN, Kelly D (1994) Interleukin-1beta induced desArg9bradykinin-mediated thermal hyperalgesia in the rat. Neuropharm 33:657–660

    Article  CAS  Google Scholar 

  34. Rothoerl RD, Woertgen C, Holzschuh M et al (1998) Is there a clinical correlate to the histologic evidence of inflammation in herniated lumbar disc tissue? Spine (23):1197–1201

    Article  Google Scholar 

  35. Schafers M, Lee DH, Brors D et al (2003) Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor—after spinal nerve ligation. J Neurosci 23(7):3028–3038

    PubMed  CAS  Google Scholar 

  36. Schaible H-G, Schmidt R (1983) Activation of groups III and IV sensory units in medial articular nerve by local mechanical stimulation of knee joint. J Neurophysiol 49(1):35–44

    PubMed  CAS  Google Scholar 

  37. Smyth MJ, Wright V (1958) Sciatica and intervertebral disc. JBJS 40-A(6):1401–1418

    CAS  Google Scholar 

  38. Sorkin LS, Xiao WH, Wagner R et al (1997) Tumor necrosis factor-a induces ectopic activity in nociceptive primary afferent fibers. Neuroscience 81:255–262

    Article  PubMed  CAS  Google Scholar 

  39. Takahashi H, Suguro T, Okajima Y et al (1996) Inflammatory cytokines in the herniated disc of the lumbar spine. Spine (21):218–224

    Article  Google Scholar 

  40. Takebayashi T, Cavanaugh JM, Ozaktay AC, Kallakuri S, Chen CY (2001) Effect of nucleus pulposus on the neural activity of dorsal root ganglion. Spine 26(8):940–945

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors wish to thank Dr. Elaine Hockman, Wayne State University, Research Support Laboratory, for valuable contributions regarding statistical analysis of the data. Supported by the NIH/NIAMS-AR41739 (JMC), AR44757 (JAD), the Orthopedic Research and Education Foundation (JAD) and Bristol-Myers Squibb/Zimmer Foundation (JAD and JNW).

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Authors and Affiliations

  1. Bioengineering Center, Wayne State University, 818 W. Hancock, Detroit, MI, 48201, USA

    A. Cüneyt Özaktay, Srinivasu Kallakuri, Tsuneo Takebayashi & John M. Cavanaugh

  2. Department of Anesthesiology & Intensive Care, Ibn-I Sina Hospital, University of Ankara, School of Medicine, Sihhiye, Ankara, Turkey

    Ibrahim Asik

  3. Department of Anesthesiology and Pharmacology, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, HB7125, Lebanon, NH, 03756, USA

    Joyce A. DeLeo

  4. Department of Orthopedic Surgery, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, HB7125, Lebanon, NH, 03756, USA

    James N. Weinstein

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  1. A. Cüneyt Özaktay
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  2. Srinivasu Kallakuri
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  3. Tsuneo Takebayashi
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  4. John M. Cavanaugh
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  5. Ibrahim Asik
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  6. Joyce A. DeLeo
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  7. James N. Weinstein
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Correspondence to A. Cüneyt Özaktay.

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Özaktay, A.C., Kallakuri, S., Takebayashi, T. et al. Effects of interleukin-1 beta, interleukin-6, and tumor necrosis factor on sensitivity of dorsal root ganglion and peripheral receptive fields in rats. Eur Spine J 15, 1529–1537 (2006). https://doi.org/10.1007/s00586-005-0058-8

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  • DOI: https://doi.org/10.1007/s00586-005-0058-8

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