title: ISSLS prize winner: disc dynamic compression in rats produces long-lasting increases in inflammatory mediators in discs and induces long-lasting nerve injury and regeneration of the afferent fibers innervating discs: a pathomechanism for chronic discogenic low back pain.
abstract: METHODS
  Animal model of intravertebral disc (IVD) degeneration.
  
  
  OBJECTIVE
  To examine production of inflammatory mediators in IVDs and neuropeptides in dorsal root ganglia (DRGs) in rat models of IVD compression and injury.
  
  
  BACKGROUND
  Sensory nerve fibers in IVDs and inflammatory mediator responses have been verified in animal models of IVD injury. However, the IVD injury in animals incompletely models degenerated human IVDs causing discogenic low back pain, because human IVDs are also subject to compression.
  
  
  METHODS
  Experimental groups (controls, IVD injury, IVD compression, and their combination) of Sprague Dawley rats were prepared. Fluoro-Gold (FG; Fluorochrome, Denver, CO) was applied into coccygeal IVDs. Inflammatory mediators in IVDs, including nerve growth factor, tumor necrosis factor α, interleukin 1β, and interleukin 6, were quantified using enzyme-linked immunosorbent assays. DRGs were immunostained for calcitonin gene-related peptide, activating transcription factor 3, and growth-associated phosphoprotein 43.
  
  
  RESULTS
  The upregulation of inflammatory mediators was transient in the IVD injury group but delayed and long-lasting in the IVD compression group. When the IVD injury and compression were combined, the upregulation of inflammatory mediators was long-lasting through 8 weeks. The proportion of calcitonin gene-related peptide-immunoreactive neurons among Fluoro-Gold-labeled neurons remained significantly higher in the IVD injury, compression, and combination groups than in the controls. In contrast, increases in the proportions of activating transcription factor 3-immunoreactive or growth-associated phosphoprotein 43-immunoreactive neurons in the IVD injury group animals were transient but long-lasting in the compression and combination groups compared with controls.
  
  
  CONCLUSIONS
  Disc injury in rats produces persistent increases in neuropeptides in DRGs but only transient increases in inflammatory mediators in IVDs. On the contrary, disc compression in rats produces a long-lasting increase in inflammatory mediators in IVDs and neuropeptides in DRGs. Moreover, disc compression induces persistent nerve injury and regeneration of the afferent fibers innervating IVDs.
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. masayuki008@aol.com
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyagi
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kamoda
authors.forename: Miyako
authors.initials: M
authors.lastname: Suzuki
authors.forename: Kenichi
authors.initials: K
authors.lastname: Murakami
authors.forename: Masataka
authors.initials: M
authors.lastname: Shibayama
authors.forename: Sumihisa
authors.initials: S
authors.lastname: Orita
authors.forename: Yawara
authors.initials: Y
authors.lastname: Eguchi
authors.forename: Gen
authors.initials: G
authors.lastname: Arai
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sakuma
authors.forename: Gou
authors.initials: G
authors.lastname: Kubota
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Oikawa
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ozawa
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Aoki
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Toyone
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takahashi
authors.forename: Gen
authors.initials: G
authors.lastname: Inoue
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kawakami
authors.forename: Seiji
authors.initials: S
authors.lastname: Ohtori
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000818:Animals; D001363:Awards and Prizes; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D059350:Chronic Pain / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D019922:GAP-43 Protein / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007403:Intervertebral Disc / Q000294:innervation / Q000378:metabolism* / Q000473:pathology; D055959:Intervertebral Disc Degeneration / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D017116:Low Back Pain / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology; D009416:Nerve Regeneration; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009475:Neurons, Afferent / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat; D019922:GAP-43 Protein; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D009479:Neuropeptides; D014409:Tumor Necrosis Factor-alpha; D015740:Calcitonin Gene-Related Peptide