title: Long-Lasting Activation of the Transcription Factor CREB in Sensory Neurons by Interleukin-1β During Antigen-Induced Arthritis in Rats: A Mechanism of Persistent Arthritis Pain?
abstract: OBJECTIVE
  In spite of successful treatment of immune-mediated arthritis, many patients still experience pain. We undertook this study to investigate whether antigen-induced arthritis (AIA) in rats triggers neuronal changes in sensory neurons that outlast the inflammatory process.
  
  
  METHODS
  We induced unilateral AIA in the knee joint and assessed in sensory neurons the expression of CREB, a transcription factor that regulates genes involved in neuronal plasticity. We tested whether neutralization of the effects of tumor necrosis factor (TNF) by etanercept or infliximab or neutralization of the effects of interleukin-1β (IL-1β) by anakinra influences the up-regulation of phospho-CREB, and we studied the up-regulation of phospho-CREB by IL-1β and TNF in cultured dorsal root ganglion (DRG) neurons.
  
  
  RESULTS
  Unilateral AIA caused bilateral up-regulation of phospho-CREB in lumbar DRG neurons. While inflammation and pain subsided within 21 days, the up-regulation of phospho-CREB still persisted on day 42. At this time point mechanical hyperalgesia at the knee reappeared in the absence of swelling. TNF neutralization during AIA significantly reduced pain-related behavior but did not prevent phospho-CREB up-regulation. In contrast, anakinra, which only reduced thermal hyperalgesia, prevented phospho-CREB up-regulation, suggesting a role of IL-1β in this process. In cultured DRG neurons the application of IL-1β significantly enhanced phospho-CREB.
  
  
  CONCLUSIONS
  Immune-mediated arthritis causes neuroplastic changes in sensory neurons that outlast the inflammatory phase. Such changes may facilitate the persistence or recurrence of pain after remission of arthritis. IL-1β is an important trigger in this process, although its neutralization barely reduced mechanical hyperalgesia during inflammation.
authors.affiliation: Jena University Hospital and Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Gisela
authors.initials: G
authors.lastname: Segond von Banchet
authors.affiliation: Jena University Hospital and Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: König
authors.affiliation: Jena University Hospital and Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Patzer
authors.affiliation: Jena University Hospital and Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Eitner
authors.affiliation: Jena University Hospital and Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Leuchtweis
authors.affiliation: Jena University Hospital and Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ebbinghaus
authors.affiliation: Jena University Hospital and Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Boettger
authors.affiliation: Jena University Hospital and Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Schaible
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D000068800:Etanercept / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation; D006930:Hyperalgesia / Q000235:genetics* / Q000378:metabolism; D000069285:Infliximab / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D009473:Neuronal Plasticity; D010146:Pain / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018501:Antirheumatic Agents; C508137:Creb1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068800:Etanercept