title: Involvement of peripheral and spinal tumor necrosis factor α in spinal cord hyperexcitability during knee joint inflammation in rats.
abstract: OBJECTIVE
  Tumor necrosis factor α (TNFα) is produced not only in peripheral tissues, but also in the spinal cord. The purpose of this study was to address the potential of peripheral and spinal TNFα to induce and maintain spinal hyperexcitability, which is a hallmark of pain states in the joints during rheumatoid arthritis and osteoarthritis.
  
  
  METHODS
  In vivo recordings of the responses of spinal cord neurons to nociceptive knee input under normal conditions and in the presence of experimental knee joint inflammation were obtained in anesthetized rats. TNFα, etanercept, or antibodies to TNF receptors were applied to either the knee joint or the spinal cord surface.
  
  
  RESULTS
  Injection of TNFα into the knee joint cavity increased the responses of spinal cord neurons to mechanical joint stimulation, and injection of etanercept into the knee joint reduced the inflammation-evoked spinal activity. These spinal effects closely mirrored the induction and reduction of peripheral sensitization. Responses to joint stimulation were also enhanced by spinal application of TNFα, and spinal application of either etanercept or anti-TNF receptor type I significantly attenuated the generation of inflammation-evoked spinal hyperexcitability, which is characterized by widespread pain sensitization beyond the inflamed joint. Spinally applied etanercept did not reduce established hyperexcitability in the acute kaolin/carrageenan model. In antigen-induced arthritis, etanercept decreased spinal responses on day 1, but not on day 3.
  
  
  CONCLUSIONS
  While peripheral TNFα increases spinal responses to joint stimulation, spinal TNFα supports the generation of the full pattern of spinal hyperexcitability. However, established spinal hyperexcitability may be maintained by downstream mechanisms that are independent of spinal TNFα.
authors.affiliation: Jena University Hospital and Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: König
authors.forename: Maxim
authors.initials: M
authors.lastname: Zharsky
authors.forename: Christian
authors.initials: C
authors.lastname: Möller
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Schaible
authors.forename: Andrea
authors.initials: A
authors.lastname: Ebersberger
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000068800:Etanercept; D006930:Hyperalgesia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007074:Immunoglobulin G / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007719:Knee Joint / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009619:Nociceptors / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D010812:Physical Stimulation; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept