Intervertebral disc herniation: Pathophysiology and emerging therapies

The Intervertebral Disc: Molecular and Structural Studies of the Disc in Health and Disease

Volumn , Issue , 2014, Pages 305-326

  Winkelstein, Beth A ^a   Allen, Kyle D ^b   Setton, Lori A ^c  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b University of Florida   (United States)

^c DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84928692654     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-3-7091-1535-0_19     Document Type: Chapter

References (207)

1. Abe M, Kurihara T, Han W, Shinomiya K, Tanabe T (2002) Changes in expression of voltage-dependent ion channel subunits in dorsal root ganglia of rats with radicular injury and pain. Spine (Phila Pa 1976) 27:1517-1524; discussion 1525
2. Adams MA, Roughley PJ (2006) What is intervertebral disc degeneration, and what causes it? Spine (Phila Pa 1976) 31:2151-2161
3. Ahn SH, Cho YW, Ahn MW, Jang SH, Sohn YK, Kim HS (2002) mRNA expression of cytokines and chemokines in herniated lumbar intervertebral discs. Spine 27(9):911-917
4. Allen KD, Shamji MF, Mata BA, Gabr MA, Sinclair SM, Schmitt DO, Richardson WJ, Setton LA (2011) Kinematic and dynamic gait compensations in a rat model of lumbar radiculopathy and the effects of tumor necrosis factor-alpha antagonism. Arthritis Res Ther 13:R137
5. Allen KD, Mata BA, Gabr MA, Huebner JL, Adams SB Jr, Kraus VB, Schmitt DO, Setton LA (2012) Kinematic and dynamic gait compensations resulting from knee instability in a rat model of osteoarthritis. Arthritis Res Ther 14:R78
6. Aoki K, Rydevik B, Kikuchi S, Olmarker K (2002) Local application of disc-related cytokines on spinal nerve roots. Spine 27: 1614-1617
7. Arai I, Mao GP, Otani K, Konno S, Kikuchi S, Olmarker K (2004) Indomethacin blocks the nucleus pulposus-induced effects on nerve root function. An experimental study in dogs with assessment of nerve conduction and bloodflow following experimental disc herniation. Eur Spine J 13(8):691-694
8. Atcheson SG, Dymeck T (2004) Rapid resolution of chronic sciatica with intravenous infliximab after failed epidural steroid injections. Spine 29:E248-E250
9. Atlas SJ, Keller RB, Wu YA, Deyo RA, Singer DE (2005) Long-term outcomes of surgical and nonsurgical management of lumbar spinal stenosis: 8 to 10 year results from the maine lumbar spine study. Spine (Phila Pa 1976) 30:936-943
10. Awad JN, Moskovich R (2006) Lumbar disc herniations: surgical versus nonsurgical treatment. Clin Orthop Relat Res 443:183-197
11. Bachmeier BE, Nerlich A, Mittermaier N, Weiler C, Lumenta C, Wuertz K, Boos N (2009) Matrix metalloproteinase expression levels suggest distinct enzyme roles during lumbar disc herniation and degeneration. Eur Spine J 18:1573-1586
12. Battie MC, Videman T (2006) Lumbar disc degeneration: epidemiology and genetics. J Bone Joint Surg Am 88(Suppl 2):3-9
13. Battie MC, Videman T, Kaprio J, Gibbons LE, Gill K, Manninen H, Saarela J, Peltonen L (2009) The twin spine study: contributions to a changing view of disc degeneration. Spine J 9:47-59
14. Beare JE, Morehouse JR, DeVries WH, Enzmann GU, Burke DA, Magnuson DS, Whittemore SR (2009) Gait analysis in normal and spinal contused mice using the treadscan system. J Neurotrauma 26:2045-2056
15. Beck KD, Nguyen HX, Galvan MD, Salazar DL, Woodruff TM, Anderson AJ (2010) Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment. Brain 133:433-447
16. Berryman ER, Harris RL, Moalli M, Bagi CM (2009) Digigait quantitation of gait dynamics in rat rheumatoid arthritis model. J Musculoskelet Neuronal Interact 9:89-98
17. Binshtok AM, Wang H, Zimmermann K, Amaya F, Vardeh D, Shi L, Brenner GJ, Ji RR, Bean BP, Woolf CJ, Samad TA (2008) Nociceptors are interleukin-1beta sensors. J Neurosci 28: 14062-14073
18. Bostman OM (1993) Body mass index and height in patients requiring surgery for lumbar intervertebral disc herniation. Spine (Phila Pa 1976) 18:851-854
19. Brisby H, Byrod G, Olmarker K, Miller VM, Aoki Y, Rydevik B (2000) Nitric oxide as a mediator of nucleus pulposus-induced effects on spinal nerve roots. J Orthop Res 18:815-820
20. Brisby H, Olmarker K, Larsson K, Nutu M, Rydevik B (2002) Proinflammatory cytokines in cerebrospinalfluid and serum in patients with disc herniation and sciatica. Eur Spine J 11:62-66
21. Buenaventura RM, Datta S, Abdi S, Smith HS (2009) Systematic review of therapeutic lumbar transforaminal epidural steroid injections. Pain Physician 12:233-251
22. Burke JG, Watson RW, McCormack D, Dowling FE, Walsh MG, Fitzpatrick JM (2002) Intervertebral discs which cause low back pain secrete high levels of proinflammatory mediators. J Bone Joint Surg Br 84:196-201
23. Byrod G, Otani K, Brisby H, Rydevik B, Olmarker K (2000) Methylprednisolone reduces the early vascular permeability increase in spinal nerve roots induced by epidural nucleus pulposus application. J Orthop Res 18:983-987
24. Cao H, Zhang YQ (2008) Spinal glial activation contributes to pathological pain states. Neurosci Biobehav Rev 32:972-983
25. Chang YW, Winkelstein BA (2011) Schwann cell proliferation and macrophage infiltration are evident at day 14 after painful cervical nerve root compression in the rat. J Neurotrauma 28:2429-2438
26. Chaplan SR, Malmberg AB, Yaksh TL (1997) Efficacy of spinal NMDA receptor antagonism in formalin hyperalgesia and nerve injury evoked allodynia in the rat. J Pharmacol Exp Ther 280:829-838
27. Chou R, Huffman LH (2007) Medications for acute and chronic low back pain: A review of the evidence for an American Pain Society/ American College of Physicians clinical practice guideline. Ann Intern Med 147:505-514
28. Cohen SP, Bogduk N, Dragovich A, Buckenmaier CC 3rd, Griffith S, Kurihara C, Raymond J, Richter PJ, Williams N, Yaksh TL (2009) Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica. Anesthesiology 110:1116-1126
29. Colburn RW, Rickman AJ, DeLeo JA (1999) The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp Neurol 157:289-304
30. Cornefjord M, Olmarker K, Otani K, Rydevik B (2001) Effects of diclofenac and ketoprofen on nerve conduction velocity in experimental nerve root compression. Spine (Phila Pa 1976) 26(20):2193-2197
31. Crawley JN (2007) What's wrong with my mouse? Behavioral phenotyping of transgenic and knockout mice. Wiley-Interscience, Hoboken
32. Cuellar JM, Montesano PX, Carstens E (2004) Role of TNF-alpha in sensitization of nociceptive dorsal horn neurons induced by application of nucleus pulposus to L5 dorsal root ganglion in rats. Pain 110:578-587
33. Cuellar JM, Montesano PX, Antognini JF, Carstens E (2005) Application of nucleus pulposus to L5 dorsal root ganglion in rats enhances nociceptive dorsal horn neuronal windup. J Neurophysiol 94:35-48
34. DeLeo JA, Yezierski RP (2001) The role of neuroinflammation and neuroimmune activation in persistent pain. Pain 90:1-6
35. DeLeo JA, Rutkowski MD, Stalder AK, Campbell IL (2000) Transgenic expression of TNF by astrocytes increases mechanical allodynia in a mouse neuropathy model. Neuroreport 11:599-602
36. DeLeo JA, Tanga FY, Tawfik VL (2004) Neuroimmune activation and neuroinflammation in chronic pain and opioid tolerance/hyperalgesia. Neuroscientist 10:40-52
37. Demircan MN, Asir A, Cetinkal A, Gedik N, Kutlay AM, Colak A et al. (2007) Is there any relationship between proinflammatory mediator levels in disc material and myelopathy with cervical disc herniation and spondylosis? A non-randomized, prospective clinical study. Eur Spine J 16(7):983-986
38. Ding XL, Wang YH, Ning LP, Zhang Y, Ge HY, Jiang H, Wang R, Yue SW (2010) Involvement of TRPV4-NO-cGMP-PKG pathways in the development of thermal hyperalgesia following chronic compression of the dorsal root ganglion in rats. Behav Brain Res 208(1):194-201
39. Doita M, Kanatani T, Harada T, Mizuno K (1996) Immunohistologic study of the ruptured intervertebral disc of the lumbar spine. Spine 21:235-241
40. Dyck PJ, Lais AC, Giannini C, Engelstad JK (1990) Structural alterations of nerve during cuff compression. Proc Natl Acad Sci U S A 87:9828-9832
41. Fraser I (2009) Statistics on hospital-based care in the United States. Agency for Healthcare Research and Quality, Rockville
42. Freemont AJ, Watkins A, Le Maitre C, Jeziorska M, Hoyland JA (2002) Current understanding of cellular and molecular events in intervertebral disc degeneration: implications for therapy. J Pathol 196:374-379
43. Frymoyer JW (1988) Back pain and sciatica. N Engl J Med 318:291-300
44. Fumihiko H, Nobuo M, Nobuo H (1996) Changes in responses of wide dynamic range neurons in the spinal dorsal horn after dorsal root or dorsal root ganglion compression. Spine (Phila Pa 1976) 21:1408-1414
45. Gajendran VK, Reuter MW, Golish SR, Hanna LS, Scuderi GJ (2011) Is thefibronectin-aggrecan complex present in cervical disk disease? PM R 3:1030-1034
46. Garfin SR, Cohen MS, Massie JB, Abitbol JJ, Swenson MR, Myers RR, Rydevik BL (1990) Nerve-roots of the cauda equina. The effect of hypotension and acute graded compression on function. J Bone Joint Surg Am 72:1185-1192
47. Genevay S, Stingelin S, Gabay C (2004) Efficacy of etanercept in the treatment of acute, severe sciatica: A pilot study. Ann Rheum Dis 63:1120-1123
48. Gensel JC, Tovar CA, Hamers FP, Deibert RJ, Beattie MS, Bresnahan JC (2006) Behavioral and histological characterization of unilateral cervical spinal cord contusion injury in rats. J Neurotrauma 23:36-54
49. Goupille P, Jayson MI, Valat JP, Freemont AJ (1998) The role of inflammation in disk herniation-associated radiculopathy. Semin Arthritis Rheum 28:60-71
50. Gronblad M, Virri J, Tolonen J, Seitsalo S, Kaapa E, Kankare J, Myllynen P, Karaharju EO (1994) A controlled immunohistochemical study of inflammatory cells in disc herniation tissue. Spine (Phila Pa 1976) 19:2744-2751
51. Guertin AD, Zhang DP, Mak KS, Alberta JA, Kim HA (2005) Microanatomy of axon/glial signaling during Wallerian degeneration. J Neurosci 25:3478-3487
52. Hanai F, Matsui N, Hongo N (1996) Changes in responses of wide dynamic range neurons in the spinal dorsal horn after dorsal root or dorsal root ganglion compression. Spine 21:1408-1414; discussion 1414-1415
53. Hart LG, Deyo RA, Cherkin DC (1995) Physician office visits for low back pain. Frequency, clinical evaluation, and treatment patterns from a US national survey. Spine (Phila Pa 1976) 20: 11-19
54. Hashizume H, DeLeo JA, Colburn RW, Weinstein JN (2000a) Spinal glial activation and cytokine expression after lumbar root injury in the rat. Spine (Phila Pa 1976) 25:1206-1217
55. Hashizume H, Rutkowski MD, Weinstein JN, DeLeo JA (2000b) Central administration of methotrexate reduces mechanical allodynia in an animal model of radiculopathy/sciatica. Pain 87(2):159-169
56. Hashizume H, Kawakami M, Yoshida M, Okada M, Enyo Y, Inomata Y (2007) Sarpogrelate hydrochloride, a 5-HT2a receptor antagonist, attenuates neurogenic pain induced by nucleus pulposus in rats. Spine (Phila Pa 1976) 32:315-320
57. Heliovaara M (1987a) Body height, obesity, and risk of herniated lumbar intervertebral disc. Spine (Phila Pa 1976) 12:469-472
58. Heliovaara M (1987b) Occupation and risk of herniated lumbar intervertebral disc or sciatica leading to hospitalization. J Chronic Dis 40:259-264
59. Heliovaara M, Impivaara O, Sievers K, Melkas T, Knekt P, Korpi J, Aromaa A (1987a) Lumbar disc syndrome in Finland. J Epidemiol Community Health 41:251-258
60. Heliovaara M, Knekt P, Aromaa A (1987b) Incidence and risk factors of herniated lumbar intervertebral disc or sciatica leading to hospitalization. J Chronic Dis 40:251-258
61. Hogan QH (2007) Role of decreased sensory neuron membrane calcium currents in the genesis of neuropathic pain. Croat Med J 48:9-21
62. Hou SX, Tang JG, Chen HS, Chen J (2003) Chronic inflammation and compression of the dorsal root contribute to sciatica induced by the intervertebral disc herniation in rats. Pain 105:255-264
63. Hu SJ, Xing JL (1998) An experimental model for chronic compression of dorsal root ganglion produced by intervertebral foramen stenosis in the rat. Pain 77:15-23
64. Huang KY, Lin RM, Chen WY, Lee CL, Yan JJ, Chang MS (2008) IL-20 may contribute to the pathogenesis of human intervertebral disc herniation. Spine 33(19):2034-2040
65. Hubbard RD, Winkelstein BA (2005) Transient cervical nerve root compression in the rat induces bilateral forepaw allodynia and spinal glial activation: mechanical factors in painful neck injuries. Spine (Phila Pa 1976) 30:1924-1932
66. Hubbard RD, Winkelstein BA (2008) Dorsal root compression produces myelinated axonal degeneration near the biomechanical thresholds for mechanical behavioral hypersensitivity. Exp Neurol 212:482-489
67. Hubbard RD, Chen Z, Winkelstein BA (2008a) Transient cervical nerve root compression modulates pain: load thresholds for allodynia and sustained changes in spinal neuropeptide expression. J Biomech 41:677-685
68. Hubbard RD, Quinn KP, Martinez JJ, Winkelstein BA (2008b) The role of graded nerve root compression on axonal damage, neuropeptide changes, and pain-related behaviors. Stapp Car Crash J 52:33-58
69. Hubbard RD, Martinez JJ, Burdick JA, Winkelstein BA (2009) Controlled release of GDNF reduces nerve root-mediated behavioral hypersensitivity. J Orthop Res 27:120-127
70. Hwang PY, Allen KD, Shamji MF, Jing L, Mata BA, Gabr MA, Huebner JL, Kraus VB, Richardson WJ, Setton LA (2012) Changes in midbrain pain receptor expression, gait and behavioral sensitivity in a rat model of radiculopathy. Open Orthop J 6:383-391. PubMed Central PMCID: PMC3434701
71. Igarashi T, Kikuchi S, Shubayev V, Myers RR (2000) 2000 Volvo Award winner in Basic Science Studies: exogenous tumor necrosis factor-alpha mimics nucleus pulposus-induced neuropathology. Molecular, histologic, and behavioral comparisons in rats. Spine 25:2975-2980
72. Inoue K (2006) The function of microglia through purinergic receptors: neuropathic pain and cytokine release. Pharmacol Ther 109: 210-226
73. Jancalek R, Dubovy P (2007) An experimental animal model of spinal root compression syndrome: an analysis of morphological changes of myelinated axons during compression radiculopathy and after decompression. Exp Brain Res 179:111-119
74. Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413:203-210
75. Kajander KC, Pollock CH, Berg H (1996) Evaluation of hindpaw position in rats during chronic constriction injury (CCI) produced with different suture materials. Somatosens Mot Res 13:95-101
76. Kallakuri S, Takebayashi T, Ozaktay AC, Chen C, Yang S, Wooley PH, Cavanaugh JM (2005) The effects of epidural application of allografted nucleus pulposus in rats on cytokine expression, limb withdrawal and nerve root discharge. Eur Spine J 14:956-964
77. Kanayama M, Hashimoto T, Shigenobu K, Yamane S (2003) Efficacy of serotonin receptor blocker for symptomatic lumbar disc herniation. Clin Orthop Relat Res (411):159-165
78. Kang JD, Stefanovic-Racic M, McIntyre LA, Georgescu HI, Evans CH (1997) Toward a biochemical understanding of human intervertebral disc degeneration and herniation. Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix metalloproteinases. Spine 22(10):1065-1073
79. Karppinen J, Korhonen T, Malmivaara A, Paimela L, Kyllonen E, Lindgren KA, Rantanen P, Tervonen O, Niinimaki J, Seitsalo S, Hurri H (2003) Tumor necrosis factor-alpha monoclonal antibody, infliximab, used to manage severe sciatica. Spine 28:750-753; discussion 753-754
80. Kasimcan O, Kaptan H (2010) Efficacy of gabapentin for radiculopathy caused by lumbar spinal stenosis and lumbar disk hernia. Neurol Med Chir (Tokyo) 50:1070-1073
81. Kawakami M, Weinstein JN, Chatani K, Spratt KF, Meller ST, Gebhart GF (1994a) Experimental lumbar radiculopathy. Behavioral and histologic changes in a model of radicular pain after spinal nerve root irritation with chromic gut ligatures in the rat. Spine (Phila Pa 1976) 19:1795-1802
82. Kawakami M, Weinstein JN, Spratt KF, Chatani K, Traub RJ, Meller ST, Gebhart GF (1994b) Experimental lumbar radiculopathy. Immunohistochemical and quantitative demonstrations of pain induced by lumbar nerve root irritation of the rat. Spine (Phila Pa 1976) 19:1780-1794
83. Kawakami M, Matsumoto T, Kuribayashi K, Tamaki T (1999) mRNA expression of interleukins, phospholipase A2, and nitric oxide synthase in the nerve root and dorsal root ganglion induced by autologous nucleus pulposus in the rat. J Orthop Res 17:941-946
84. Kawakami M, Matsumoto T, Tamaki T (2001) Roles of thromboxane A2 and leukotriene B4 in radicular pain induced by herniated nucleus pulposus. J Orthop Res 19(3):472-477
85. Kawakami M, Hashizume H, Nishi H, Matsumoto T, Tamaki T, Kuribayashi K (2003) Comparison of neuropathic pain induced by the application of normal and mechanically compressed nucleus pulposus to lumbar nerve roots in the rat. J Orthop Res 21:535-539
86. Kobayashi S, Yoshizawa H, Yamada S (2004a) Pathology of lumbar nerve root compression. Part 1: intraradicular inflammatory changes induced by mechanical compression. J Orthop Res 22:170-179
87. Kobayashi S, Yoshizawa H, Yamada S (2004b) Pathology of lumbar nerve root compression. Part 2: morphological and immunohistochemical changes of dorsal root ganglion. J Orthop Res 22:180-188
88. Kobayashi S, Baba H, Uchida K, Kokubo Y, Kubota C, Yamada S, Suzuki Y, Yoshizawa H (2005a) Effect of mechanical compression on the lumbar nerve root: localization and changes of intraradicular inflammatory cytokines, nitric oxide, and cyclooxygenase. Spine 30:1699-1705
89. Kobayashi S, Kokubo Y, Uchida K, Yayama T, Takeno K, Negoro K, Nakajima H, Baba H, Yoshizawa H (2005b) Effect of lumbar nerve root compression on primary sensory neurons and their central branches: changes in the nociceptive neuropeptides substance P and somatostatin. Spine (Phila Pa 1976) 30:276-282
90. Kobayashi S, Meir A, Baba H, Uchida K, Hayakawa K (2005c) Imaging of intraneural edema by using gadolinium-enhanced MR imaging: experimental compression injury. AJNR Am J Neuroradiol 26:973-980
91. Kobayashi S, Sasaki S, Shimada S, Kaneyasu M, Mizukami Y, Kitade I, Ogawa M, Kawahara H, Baba H, Yoshizawa H (2005d) Changes of calcitonin gene-related peptide in primary sensory neurons and their central branch after nerve root compression of the dog. Arch Phys Med Rehabil 86:527-533
92. Kobayashi S, Uchida K, Kokubo Y, Takeno K, Yayama T, Miyazaki T, Nakajima H, Nomura E, Mwaka E, Baba H (2008) Synapse involvement of the dorsal horn in experimental lumbar nerve root compression: A light and electron microscopic study. Spine (Phila Pa 1976) 33:716-723
93. Komori H, Shinomiya K, Nakai O, Yamaura I, Takeda S, Furuya K (1996) The natural history of herniated nucleus pulposus with radiculopathy. Spine (Phila Pa 1976) 21:225-229
94. Korhonen T, Karppinen J, Paimela L, Malmivaara A, Lindgren KA, Jarvinen S, Niinimaki J, Veeger N, Seitsalo S, Hurri H (2005) The treatment of disc herniation-induced sciatica with infliximab: results of a randomized, controlled, 3-month follow-up study. Spine 30:2724-2728
95. Korhonen T, Karppinen J, Paimela L, Malmivaara A, Lindgren KA, Bowman C, Hammond A, Kirkham B, Jarvinen S, Niinimaki J, Veeger N, Haapea M, Torkki M, Tervonen O, Seitsalo S, Hurri H (2006) The treatment of disc-herniation-induced sciatica with infliximab: one-year follow-up results offirst ii, a randomized controlled trial. Spine 31:2759-2766
96. Le Maitre CL, Freemont AJ, Hoyland JA (2005) The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. Arthritis Res Ther 7(4):R732-R745
97. Le Maitre CL, Hoyland JA, Freemont AJ (2007) Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1beta and TNFalpha expression profile. Arthritis Res Ther 9:R77
98. Lindenlaub T, Teuteberg P, Hartung T, Sommer C (2000) Effects of neutralizing antibodies to TNF-alpha on pain-related behavior and nerve regeneration in mice with chronic constriction injury. Brain Res 866:15-22
99. Loupasis GA, Stamos K, Katonis PG, Sapkas G, Korres DS, Hartofilakidis G (1999) Seven-to 20-year outcome of lumbar discectomy. Spine (Phila Pa 1976) 24:2313-2317
100. Marriott I (2004) The role of tachykinins in central nervous system inflammatory responses. Front Biosci 9:2153-2165
101. Maves TJ, Pechman PS, Gebhart GF, Meller ST (1993) Possible chemical contribution from chromic gut sutures produces disorders of pain sensation like those seen in man. Pain 54:57-69
102. McCarron RF, Wimpee MW, Hudkins PG, Laros GS (1987) The inflammatory effect of nucleus pulposus. A possible element in the pathogenesis of low-back pain. Spine (Phila Pa 1976) 12: 760-764
103. Mixter CG, Blumgart HL, Berlin DD (1934) Total ablation of the thyroid for angina pectoris and congestive heart failure: results of eighteen months' experience. Ann Surg 100:570-577
104. Moalem G, Tracey DJ (2006) Immune and inflammatory mechanisms in neuropathic pain. Brain Res Rev 51:240-264
105. Moore RJ, Vernon-Roberts B, Fraser RD, Osti OL, Schembri M (1996) The origin and fate of herniated lumbar intervertebral disc tissue. Spine 21:2149-2155
106. Morishita Y, Hida S, Naito M, Arimizu J, Matsushima U, Nakamura A (2006) Measurement of the local pressure of the intervertebral foramen and the electrophysiologic values of the spinal nerve roots in the vertebral foramen. Spine (Phila Pa 1976) 31:3076-3080
107. Mosconi T, Kruger L (1996) Fixed-diameter polyethylene cuffs applied to the rat sciatic nerve induce a painful neuropathy: ultrastructural morphometric analysis of axonal alterations. Pain 64:37-57
108. Mulleman D, Mammou S, Griffoul I, Watier H, Goupille P (2006a) Pathophysiology of disk-related low back pain and sciatica. II. Evidence supporting treatment with TNF-alpha antagonists. Joint Bone Spine 73:270-277
109. Mulleman D, Mammou S, Griffoul I, Watier H, Goupille P (2006b) Pathophysiology of disk-related sciatica. I-Evidence supporting a chemical component. Joint Bone Spine 73:151-158
110. Murata Y, Onda A, Rydevik B, Takahashi K, Olmarker K (2004a) Distribution and appearance of tumor necrosis factor-alpha in the dorsal root ganglion exposed to experimental disc herniation in rats. Spine (Phila Pa 1976) 29:2235-2241
111. Murata Y, Onda A, Rydevik B, Takahashi K, Olmarker K (2004b) Selective inhibition of tumor necrosis factor-alpha prevents nucleus pulposus-induced histologic changes in the dorsal root ganglion. Spine 29:2477-2484
112. Myers RR, Yamamoto T, Yaksh TL, Powell HC (1993) The role of focal nerve ischemia and wallerian degeneration in peripheral nerve injury producing hyperesthesia. Anesthesiology 78: 308-316
113. Nakamae T, Ochi M, Olmarker K (2011) Pharmacological inhibition of tumor necrosis factor may reduce pain behavior changes induced by experimental disc puncture in the rat: an experimental study in rats. Spine (Phila Pa 1976) 36:E232-E236
114. Nicholson KJ, Quindlen JC, Winkelstein BA (2011) Development of a duration threshold for modulating evoked neuronal responses after nerve root compression injury. Stapp Car Crash J 55:1-24
115. Nicholson KJ, Guarino BB, Winkelstein BA (2012) Transient nerve root compression load and duration differentially mediate behavioral sensitivity and associated spinal astrocyte activation and mGLuR5 expression. Neuroscience 209:187-195
116. Nilsson E, Nakamae T, Olmarker K (2011) Pain behavior changes following disc puncture relate to nucleus pulposus rather than to the disc injury per se: an experimental study in rats. Open Orthop J 5:72-77
117. Nygaard OP, Mellgren SI, Osterud B (1997) The inflammatory properties of contained and noncontained lumbar disc herniation. Spine 22(21):2484-2488
118. Obata K, Tsujino H, Yamanaka H, Yi D, Fukuoka T, Hashimoto N, Yonenobu K, Yoshikawa H, Noguchi K (2002) Expression of neurotrophic factors in the dorsal root ganglion in a rat model of lumbar disc herniation. Pain 99:121-132
119. Obata K, Yamanaka H, Dai Y, Mizushima T, Fukuoka T, Tokunaga A, Noguchi K (2004) Activation of extracellular signal-regulated protein kinase in the dorsal root ganglion following inflammation near the nerve cell body. Neuroscience 126:1011-1021
120. O'Donnell JL, O'Donnell AL (1996) Prostaglandin E2 content in herniated lumbar disc disease. Spine 21(14):1653-1655; discussion 1655-1656
121. Ohtori S, Takahashi K, Aoki Y, Doya H, Ozawa T, Saito T, Moriya H (2004) Spinal neural cyclooxygenase-2 mediates pain caused in a rat model of lumbar disk herniation. J Pain 5(7):385-391
122. Olmarker K (2001) Radicular pain-recent pathophysiologic concepts and therapeutic implications. Schmerz 15:425-429
123. Olmarker K (2008) Puncture of a lumbar intervertebral disc induces changes in spontaneous pain behavior: an experimental study in rats. Spine 33:850-855
124. Olmarker K, Larsson K (1998) Tumor necrosis factor alpha and nucleuspulposus-induced nerve root injury. Spine (Phila Pa 1976) 23:2538-2544
125. 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
126. Olmarker K, Rydevik B (1991) Pathophysiology of sciatica. Orthop Clin North Am 22:223-234
127. 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 26:863-869
128. Olmarker K, Rydevik B, Holm S (1989) Edema formation in spinal nerve roots induced by experimental, graded compression. An experimental study on the pig cauda equina with special reference to differences in effects between rapid and slow onset of compression. Spine (Phila Pa 1976) 14:569-573
129. Olmarker K, Rydevik B, Nordborg C (1993) Autologous nucleus pulposus induces neurophysiologic and histologic changes in porcine cauda equina nerve roots. Spine (Phila Pa 1976) 18:1425-1432
130. Olmarker K, Byrod G, Cornefjord M, Nordborg C, Rydevik B (1994) Effects of methylprednisolone on nucleus pulposus-induced nerve root injury. Spine (Phila Pa 1976) 19:1803-1808
131. Olmarker K, Brisby H, Yabuki S, Nordborg C, Rydevik B (1997) The effects of normal, frozen, and hyaluronidase-digested nucleus pulposus on nerve root structure and function. Spine 22:471-475; discussion 476
132. Olmarker K, Iwabuchi M, Larsson K, Rydevik B (1998) Walking analysis of rats subjected to experimental disc herniation. Eur Spine J 7:394-399
133. Olmarker K, Storkson R, Berge OG (2002) Pathogenesis of sciatic pain: A study of spontaneous behavior in rats exposed to experimental disc herniation. Spine 27:1312-1317
134. Olmarker K, Nutu M, Storkson R (2003) Changes in spontaneous behavior in rats exposed to experimental disc herniation are blocked by selective TNF-alpha inhibition. Spine 28:1635-1641; discussion 1642
135. Onda A, Hamba M, Yabuki S, Kikuchi S (2002) Exogenous tumor necrosis factor-alpha induces abnormal discharges in rat dorsal horn neurons. Spine (Phila Pa 1976) 27:1618-1624; discussion 1624
136. Onda A, Murata Y, Rydevik B, Larsson K, Kikuchi S, Olmarker K (2004) Infliximab attenuates immunoreactivity of brain-derived neurotrophic factor in a rat model of herniated nucleus pulposus. Spine 29:1857-1861
137. Onda A, Murata Y, Rydevik B, Larsson K, Kikuchi S, Olmarker K (2005) Nerve growth factor content in dorsal root ganglion as related to changes in pain behavior in a rat model of experimental lumbar disc herniation. Spine (Phila Pa 1976) 30:188-193
138. Otani K, Arai I, Mao GP, Konno S, Olmarker K, Kikuchi S (1997) Experimental disc herniation: evaluation of the natural course. Spine (Phila Pa 1976) 22:2894-2899
139. 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 11:467-475
140. Ozaktay AC, Kallakuri S, Takebayashi T, Cavanaugh JM, Asik I, DeLeo JA, Weinstein JN (2006) Effects of interleukin-1 beta, interleukin-6, and tumor necrosis factor on sensitivity of dorsal root ganglion and peripheral receptivefields in rats. Eur Spine J 15:1529-1537
141. Park JB, Chang H, Kim YS (2002) The pattern of interleukin-12 and T-helper types 1 and 2 cytokine expression in herniated lumbar disc tissue. Spine (Phila Pa 1976) 27(19):2125-2128
142. Pedowitz RA, Garfin SR, Massie JB, Hargens AR, Swenson MR, Myers RR, Rydevik BL (1992) Effects of magnitude and duration of compression on spinal nerve root conduction. Spine (Phila Pa 1976) 17:194-199
143. Piesla MJ, Leventhal L, Strassle BW, Harrison JE, Cummons TA, Lu P, Whiteside GT (2009) Abnormal gait, due to inflammation but not nerve injury, reflects enhanced nociception in preclinical pain models. Brain Res 1295:89-98
144. Ramer LM, Richter MW, Roskams AJ, Tetzlaff W, Ramer MS (2004) Peripherally-derived olfactory ensheathing cells do not promote primary afferent regeneration following dorsal root injury. Glia 47:189-206
145. Ricci JA, Stewart WF, Chee E, Leotta C, Foley K, Hochberg MC (2006) Back pain exacerbations and lost productive time costs in United States workers. Spine (Phila Pa 1976) 31:3052-3060
146. Roberts S, Evans H, Trivedi J, Menage J (2006) Histology and pathology of the human intervertebral disc. J Bone Joint Surg Am 88(Suppl 2):10-14
147. Robinson I, Meert TF (2005) Stability of neuropathic pain symptoms in partial sciatic nerve ligation in rats is affected by suture material. Neurosci Lett 373:125-129
148. Rothman SM, Winkelstein BA (2007) Chemical and mechanical nerve root insults induce differential behavioral sensitivity and glial activation that are enhanced in combination. Brain Res 1181:30-43
149. Rothman SM, Winkelstein BA (2010) Cytokine antagonism reduces pain and modulates spinal astrocytic reactivity after cervical nerve root compression. Ann Biomed Eng 38(8):2563-2576
150. Rothman SM, Kreider RA, Winkelstein BA (2005) Spinal neuropeptide responses in persistent and transient pain following cervical nerve root injury. Spine (Phila Pa 1976) 30:2491-2496
151. Rothman SM, Guarino BB, Winkelstein BA (2009a) Spinal microglial proliferation is evident in a rat model of painful disc herniation both in the presence of behavioral hypersensitivity and following minocycline treatment sufficient to attenuate allodynia. J Neurosci Res 87:2709-2717
152. Rothman SM, Huang Z, Lee KE, Weisshaar CL, Winkelstein BA (2009b) Cytokine mRNA expression in painful radiculopathy. J Pain 10(1):90-99
153. Rothman SM, Nicholson KJ, Winkelstein BA (2010) Time-dependent mechanics and measures of glial activation and behavioral sensitivity in a rodent model of radiculopathy. J Neurotrauma 27: 803-814
154. Rutkowski MD, Winkelstein BA, Hickey WF, Pahl JL, DeLeo JA (2002) Lumbar nerve root injury induces central nervous system neuroimmune activation and neuroinflammation in the rat: relationship to painful radiculopathy. Spine (Phila Pa 1976) 27:1604-1613
155. Rydevik B (1994) Sciatica and herniated disk. Current aspects of pathophysiology and pain mechanisms. Nord Med 109:74-76
156. Rydevik B, Brown MD, Lundborg G (1984) Pathoanatomy and pathophysiology of nerve root compression. Spine (Phila Pa 1976) 9:7-15
157. Rydevik BL, Pedowitz RA, Hargens AR, Swenson MR, Myers RR, Garfin SR (1991) Effects of acute, graded compression on spinal nerve root function and structure. An experimental study of the pig cauda equina. Spine (Phila Pa 1976) 16:487-493
158. Saab CY, Waxman SG, Hains BC (2008) Alarm or curse? The pain of neuroinflammation. Brain Res Rev 58:226-235
159. Saal JS (1995) The role of inflammation in lumbar pain. Spine (Phila Pa 1976) 20:1821-1827
160. Saal JS, Franson RC, Dobrow R, Saal JA (1990) High levels of inflammatory phospholipase A2 activity in lumbar disc herniations. Spine 15:674-678
161. Sapunar D, Ljubkovic M, Lirk P, McCallum JB, Hogan QH (2005) Distinct membrane effects of spinal nerve ligation on injured and adjacent dorsal root ganglion neurons in rats. Anesthesiology 103:360-376
162. Sasaki N, Kikuchi S, Konno S, Sekiguchi M, Watanabe K (2007) Anti-TNF-alpha antibody reduces pain-behavioral changes induced by epidural application of nucleus pulposus in a rat model depending on the timing of administration. Spine (Phila Pa 1976) 32: 413-416
163. Schafers M, Svensson CI, Sommer C, Sorkin LS (2003) Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci 23(7):2517-2521
164. Schafers M, Marziniak M, Sorkin LS, Yaksh TL, Sommer C (2004) Cyclooxygenase inhibition in nerve-injury-and TNF-induced hyperalgesia in the rat. Exp Neurol 185(1):160-168
165. Sekiguchi Y, Kikuchi S, Myers RR, Campana WM (2003) ISSLS prize winner: erythropoietin inhibits spinal neuronal apoptosis and pain following nerve root crush. Spine (Phila Pa 1976) 28:2577-2584
166. Sekiguchi M, Otoshi K, Kikuchi S, Konno S (2011) Analgesic effects of prostaglandin E2 receptor subtype EP1 receptor antagonist: experimental study of application of nucleus pulposus. Spine 36(22):1829-1834
167. Sekiguchi M, Konno S, Kikuchi S (2008) The effects of a 5-HT2A receptor antagonist on bloodflow in lumbar disc herniation: application of nucleus pulposus in a canine model. Eur Spine J 17:307-313
168. Sekiguchi M, Sekiguchi Y, Konno S, Kobayashi H, Homma Y, Kikuchi S (2009) Comparison of neuropathic pain and neuronal apoptosis following nerve root or spinal nerve compression. Eur Spine J 18:1978-1985
169. Shamji MF, Whitlatch L, Friedman AH, Richardson WJ, Chilkoti A, Setton LA (2008) An injectable and in situ-gelling biopolymer for sustained drug release following perineural administration. Spine (Phila Pa 1976) 33:748-754
170. Shamji MF, Allen KD, So S, Jing L, Adams SB Jr, Schuh R, Huebner J, Kraus VB, Friedman AH, Setton LA, Richardson WJ (2009) Gait abnormalities and inflammatory cytokines in an autologous nucleus pulposus model of radiculopathy. Spine (Phila Pa 1976) 34:648-654
171. Shamji MF, Setton LA, Jarvis W, So S, Chen J, Jing L, Bullock R, Isaacs RE, Brown C, Richardson WJ (2010) Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues. Arthritis Rheum 62:1974-1982
172. Skouen J, Brisby H, Otani K, Olmarker K, Rosengren L, Rydevik B (1999) Protein markers in cerebrospinalfluid in experimental nerve root injury. A study of slow-onset chronic compression effects or the biochemical effects of nucleus pulposus on sacral nerve roots. Spine 24:2195-2200
173. Sommer C, Schmidt C, George A, Toyka KV (1997) A metalloprotease-inhibitor reduces pain associated behavior in mice with experimental neuropathy. Neurosci Lett 237(1):45-48
174. Sommer C, Schafers M, Marziniak M, Toyka KV (2001) Etanercept reduced hyperalgesia in experimental painful neuropathy. J Peripher Nerv Syst 6:67-72
175. Song XJ, Wang ZB, Gan Q, Walters ET (2006) cAMP and cGMP contribute to sensory neuron hyperexcitability and hyperalgesia in rats with dorsal root ganglia compression. J Neurophysiol 95(1):479-492
176. Specchia N, Pagnotta A, Toesca A, Greco F (2002) Cytokines and growth factors in the protruded intervertebral disc of the lumbar spine. Eur Spine J 11:145-151
177. Staal JB, de Bie R, de Vet HC, Hildebrandt J, Nelemans P (2008) Injection therapy for subacute and chronic low-back pain. Cochrane Database Syst Rev (3):CD001824
178. Stoll G, Jander S (1999) The role of microglia and macrophages in the pathophysiology of the CNS. Prog Neurobiol 58:233-247
179. Stoll G, Muller HW (1999) Nerve injury, axonal degeneration and neural regeneration: basic insights. Brain Pathol 9:313-325
180. Suter MR, Wen YR, Decosterd I, Ji RR (2007) Do glial cells control pain? Neuron Glia Biol 3:255-268
181. Suzuki M, Inoue G, Gemba T, Watanabe T, Ito T, Koshi T, Yamauchi K, Yamashita M, Orita S, Eguchi Y, Ochiai N, Kishida S, Takaso M, Aoki Y, Takahashi K, Ohtori S (2009) Nuclear factor-kappa B decoy suppresses nerve injury and improves mechanical allodynia and thermal hyperalgesia in a rat lumbar disc herniation model. Eur Spine J 18(7):1001-1007
182. Takahashi H, Suguro T, Okazima Y, Motegi M, Okada Y, Kakiuchi T (1996) Inflammatory cytokines in the herniated disc of the lumbar spine. Spine (Phila Pa 1976) 21(2):218-224
183. Takahashi N, Yabuki S, Aoki Y, Kikuchi S (2003) Pathomechanisms of nerve root injury caused by disc herniation: an experimental study of mechanical compression and chemical irritation. Spine (Phila Pa 1976) 28:435-441
184. Takamori Y, Arimizu J, Izaki T, Naito M, Kobayashi T (2011) Combined measurement of nerve root bloodflow and electrophysiological values: intraoperative straight-leg-raising test for lumbar disc herniation. Spine (Phila Pa 1976) 36:57-62
185. Tobinick EL, Britschgi-Davoodifar S (2003) Perispinal TNF-alpha inhibition for discogenic pain. Swiss Med Wkly 133:170-177
186. Tokunaga S, Yamanokuchi K, Yabuki A, Fujiki M, Misumi K (2010) Cartilage oligomeric matrix protein in canine spinal cord appears in the cerebrospinalfluid associated with intervertebral disc herniation. Spine (Phila Pa 1976) 35:4-9
187. Uceyler N, Tscharke A, Sommer C (2008) Early cytokine gene expression in mouse CNS after peripheral nerve lesion. Neurosci Lett 436(2):259-264
188. van der Windt DAWM, Simons E, Riphagen II, Ammendolia C, Verhagen AP, Laslett M, Devillé W, Deyo RA, Bouter LM, de Vet HCW, Aertgeerts B (2010) Physical examination for lumbar radiculopathy due to disc herniation in patients with low-back pain. Cochrane Database Syst Rev (2):CD007431
189. Van Zundert J, Harney D, Joosten EA, Durieux ME, Patijn J, Prins MH, Van Kleef M (2006) The role of the dorsal root ganglion in cervical radicular pain: diagnosis, pathophysiology, and rationale for treatment. Reg Anesth Pain Med 31:152-167
190. Verri WA Jr, Cunha TM, Parada CA, Poole S, Cunha FQ, Ferreira SH (2006) Hypernociceptive role of cytokines and chemokines: targets for analgesic drug development? Pharmacol Ther 112:116-138
191. Vrinten DH, Hamers FF (2003) 'Catwalk' automated quantitative gait analysis as a novel method to assess mechanical allodynia in the rat; a comparison with von Frey testing. Pain 102:203-209
192. Weiler C, Nerlich AG, Bachmeier BE, Boos N (2005) Expression and distribution of tumor necrosis factor alpha in human lumbar intervertebral discs: A study in surgical specimen and autopsy controls. Spine (Phila Pa 1976) 30:44-53; discussion 54
193. Weiler C, Lopez-Ramos M, Mayer HM, Korge A, Siepe CJ, Wuertz K, Weiler V, Boos N, Nerlich AG (2011) Histological analysis of surgical lumbar intervertebral disc tissue provides evidence for an association between disc degeneration and increased body mass index. BMC Res Notes 4:497
194. Weinstein JN, Lurie JD, Tosteson TD, Skinner JS, Hanscom B, Tosteson AN, Herkowitz H, Fischgrund J, Cammisa FP, Albert T, Deyo RA (2006a) Surgical vs nonoperative treatment for lumbar disk herniation: The spine patient outcomes research trial (sport) observational cohort. JAMA 296:2451-2459
195. Weinstein JN, Tosteson TD, Lurie JD, Tosteson AN, Hanscom B, Skinner JS, Abdu WA, Hilibrand AS, Boden SD, Deyo RA (2006b) Surgical vs nonoperative treatment for lumbar disk herniation: The spine patient outcomes research trial (sport): A randomized trial. JAMA 296:2441-2450
196. Weisshaar CL, Winer JP, Guarino BB, Janmey PA, Winkelstein BA (2011) The potential for salmonfibrin and thrombin to mitigate pain subsequent to cervical nerve root injury. Biomaterials 32(36):9738-9746
197. Whishaw IQ, Kolb B (2005) The behavior of the laboratory rat: A handbook with tests. Oxford University Press, Oxford/New York
198. Willburger RE, Wittenberg RH (1994) Prostaglandin release from lumbar disc and facet joint tissue. Spine (Phila Pa 1976) 19(18): 2068-2070
199. Winkelstein BA, DeLeo JA (2004) Mechanical thresholds for initiation and persistence of pain following nerve root injury: mechanical and chemical contributions at injury. J Biomech Eng 126: 258-263
200. Winkelstein BA, Rutkowski MD, Sweitzer SM, Pahl JL, DeLeo JA (2001a) 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 439(2):127-139
201. Winkelstein BA, Rutkowski MD, Weinstein JN, DeLeo JA (2001b) Quantification of neural tissue injury in a rat radiculopathy model: comparison of local deformation, behavioral outcomes, and spinal cytokine mRNA for two surgeons. J Neurosci Methods 111: 49-57
202. Winkelstein BA, Weinstein JN, DeLeo JA (2002) The role of mechanical deformation in lumbar radiculopathy: an in vivo model. Spine (Phila Pa 1976) 27:27-33
203. Xu J, Pollock CH, Kajander KC (1996) Chromic gut suture reduces calcitonin-gene-related peptide and substance P levels in the spinal cord following chronic constriction injury in the rat. Pain 64: 503-509
204. Yabuki S, Kawaguchi Y, Nordborg C, Kikuchi S, Rydevik B, Olmarker K (1998) Effects of lidocaine on nucleus pulposus-induced nerve root injury: A neurophysiologic and histologic study of the pig cauda equina. Spine 23:2383-2389
205. Yamamoto T, Nozaki-Taguchi N (1995) Role of cholecystokinin-B receptor in the maintenance of thermal hyperalgesia induced by unilateral constriction injury to the sciatic nerve in the rat. Neurosci Lett 202:89-92
206. Yildirim K, Deniz O, Gureser G, Karatay S, Ugur M, Erdal A, Senel K (2009) Gabapentin monotherapy in patients with chronic radiculopathy: The efficacy and impact on life quality. J Back Musculoskelet Rehabil 22:17-20
207. Zanella JM, Burright EN, Hildebrand K, Hobot C, Cox M, Christoferson L, McKay WF (2008) Effect of etanercept, a tumor necrosis factoralpha inhibitor, on neuropathic pain in the rat chronic constriction injury model. Spine (Phila Pa 1976) 33(3):227-234