title: IκB kinase β inhibitor downregulates pain-related neuropeptide production in the sensory neurons innervating injured lumbar intervertebral discs in the dorsal root ganglia of rats.
abstract: BACKGROUND
  Nuclear factor-κB (NF-κB) is an essential gene transcriptional regulator of inflammatory cytokines, and it plays important roles in numerous conditions, including inflammatory and neuropathic pain, especially when discogenic pain is involved. Phosphorylation of IκB protein through IκB kinase (IKK) is the first step in the activation of NF-κB activation and the upregulation of NF-κB-responsive genes.
  
  
  OBJECTIVE
  To investigate whether IKK inhibition alters the properties of pain-related neuropeptides in the rat lumbar degenerative intervertebral disc (IVD) model.
  
  
  METHODS
  Retrograde neurotracing and immunofluorescent investigation of pain-related neuropeptide (calcitonin gene-related peptide [CGRP]) in the sensory innervation of injured lumbar IVD in rat dorsal root ganglia (DRGs).
  
  
  METHODS
  Forty female Sprague-Dawley rats were equally divided into four groups: naive, sham, and two agent-treated groups (vehicle [saline] group and anti-IKKβ [IMD-0560, IKKβ inhibitor] group). The L5-L6 IVDs of the agent-treated rats were exposed and injured by repeated punctures. The retrograde neurotracer Fluoro-Gold (FG) and corresponding treatment agents were intradiscally applied. In the sham group, FG alone was applied onto uninjured IVDs. One week later, L1-L3 DRGs were harvested and immunolabeled for CGRP as a pain marker. The proportions of FG-labeled CGRP-immunoreactive (-ir) DRG neurons were assessed.
  
  
  RESULTS
  Fluoro-Gold-labeled DRG neurons were almost equally prevalent at each DRG level. The proportions of FG-labeled CGRP-ir DRG neurons in the two agent-treated groups were significantly increased in comparison with those in the naive and the sham groups (p<.05) and were significantly decreased in the anti-IKKβ group in comparison with that in the vehicle group (p<.05).
  
  
  CONCLUSIONS
  The neuropeptide CGRP as a pain marker was upregulated in DRG neurons innervating the injured IVDs, and intradiscal inhibition of IKKβ significantly suppressed CGRP production in the DRG neurons innervating the rat IVD, suggesting the possible analgesic effect of IKKβ inhibition in discogenic pain.
authors: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. sorita@chiba-u.jp
authors: Sumihisa
authors: S
authors: Orita
authors: Masayuki
authors: M
authors: Miyagi
authors: Sayako
authors: S
authors: Kobori
authors: Takefumi
authors: T
authors: Gemba
authors: Tetsuhiro
authors: T
authors: Ishikawa
authors: Gen
authors: G
authors: Inoue
authors: Tomoaki
authors: T
authors: Toyone
authors: Yasuchika
authors: Y
authors: Aoki
authors: Yawara
authors: Y
authors: Eguchi
authors: Kazuhisa
authors: K
authors: Takahashi
authors: Seiji
authors: S
authors: Ohtori
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007403:Intervertebral Disc / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D008159:Lumbar Vertebrae; D016328:NF-kappa B / Q000378:metabolism; D010146:Pain / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001549:Benzamides; C503742:N-(2,5-bis(trifluoromethyl)phenyl)-5-bromo-2-hydroxybenzamide; D016328:NF-kappa B; D051550:I-kappa B Kinase; D015740:Calcitonin Gene-Related Peptide