Top

Published in:

01-10-2006 | Original Article

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

Authors: A. Cüneyt Özaktay, Srinivasu Kallakuri, Tsuneo Takebayashi, John M. Cavanaugh, Ibrahim Asik, Joyce A. DeLeo, James N. Weinstein

Published in: European Spine Journal | Issue 10/2006

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.

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–E55CrossRefPubMed

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

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

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):196–201CrossRef

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

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

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

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

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):133–140CrossRefPubMed

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 115:1265–1275PubMed

11.

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

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 23:2159–2166CrossRefPubMed

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):929–936CrossRefPubMed

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):239–246CrossRefPubMed

15.

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

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):956–964CrossRefPubMed

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):271–277CrossRefPubMed

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):2101–2107CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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):181–187PubMed

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):1393–1399PubMed

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):760–764PubMedCrossRef

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):123–128CrossRefPubMed

25.

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

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 78:99–105CrossRefPubMed

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 CrossRefPubMed

28.

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

29.

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

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):6289–6293PubMed

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):467–475CrossRefPubMed

32.

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

33.

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

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):1197–1201CrossRef

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):3028–3038PubMed

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):35–44PubMed

37.

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

38.

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

39.

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

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):940–945CrossRefPubMed

Title: Effects of interleukin-1 beta, interleukin-6, and tumor necrosis factor on sensitivity of dorsal root ganglion and peripheral receptive fields in rats
Authors: A. Cüneyt Özaktay
Srinivasu Kallakuri
Tsuneo Takebayashi
John M. Cavanaugh
Ibrahim Asik
Joyce A. DeLeo
James N. Weinstein
Publication date: 01-10-2006
Publisher: Springer-Verlag
Published in: European Spine Journal / Issue 10/2006
Print ISSN: 0940-6719
Electronic ISSN: 1432-0932
DOI: https://doi.org/10.1007/s00586-005-0058-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 10/2006

Comment on the article: a study of clinical predictors of lumbar provocation discography (M. Laslett et al.)

Clinical predictors of lumbar provocation discography: a study of clinical predictors of lumbar provocation discography

German Spine Congress

A preliminary study of reliability of impedance measurement to detect iatrogenic initial pedicle perforation (in the porcine model)

Announcements October 2006

Multidirectional flexibility analysis of anterior and posterior lumbar artificial disc reconstruction: in vitro human cadaveric spine model