title: Spinal release of tumour necrosis factor activates c-Jun N-terminal kinase and mediates inflammation-induced hypersensitivity.
abstract: BACKGROUND
  Mounting evidence points to individual contributions of tumour necrosis factor-alpha (TNF) and the c-Jun N-terminal kinase (JNK) pathway to the induction and maintenance of various pain states. Here we explore the role of spinal TNF and JNK in carrageenan-induced hypersensitivity. As links between TNF and JNK have been demonstrated in vitro, we investigated if TNF regulates spinal JNK activity in vivo.
  
  
  METHODS
  TNF levels in lumbar cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay, spinal TNF gene expression by real-time polymerase chain reaction and TNF protein expression, JNK and c-Jun phosphorylation by western blotting. The role of spinal TNF and JNK in inflammation-induced mechanical and thermal hypersensitivity was assessed by injecting the TNF inhibitor etanercept and the JNK inhibitors SP600125 and JIP-1 intrathecally (i.t.). TNF-mediated regulation of JNK activity was examined by assessing the effect of i.t. etanercept on inflammation-induced spinal JNK activity.
  
  
  RESULTS
  TNF levels were increased in CSF and spinal cord following carrageenan-induced inflammation. While JNK phosphorylation followed the same temporal pattern as TNF, c-jun was only activated at later time points. Intrathecal injection of TNF and JNK inhibitors attenuated carrageenan-induced mechanical and thermal hypersensitivity. TNF stimulation induced JNK phosphorylation in cultured spinal astrocytes and blocking the spinal actions of TNF in vivo by i.t. injection of etanercept reduced inflammation-induced spinal JNK activity.
  
  
  CONCLUSIONS
  Here we show that spinal JNK activity is dependent on TNF and that both TNF and the JNK signalling pathways modulate pain-like behaviour induced by peripheral inflammation.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: D B
authors.initials: DB
authors.lastname: Bas
authors.forename: S
authors.initials: S
authors.lastname: Abdelmoaty
authors.forename: K
authors.initials: K
authors.lastname: Sandor
authors.forename: S
authors.initials: S
authors.lastname: Codeluppi
authors.forename: B
authors.initials: B
authors.lastname: Fitzsimmons
authors.forename: J
authors.initials: J
authors.lastname: Steinauer
authors.forename: X Y
authors.initials: XY
authors.lastname: Hua
authors.forename: T L
authors.initials: TL
authors.lastname: Yaksh
authors.forename: C I
authors.initials: CI
authors.lastname: Svensson
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D004789:Enzyme Activation; D006967:Hypersensitivity / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D010146:Pain / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D013116:Spinal Cord / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases