title: Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats.
abstract: OBJECTIVE
  During inflammation in the joint, normal joint movements are usually painful. A neuronal mechanism for this form of mechanical hyperalgesia is the persistent sensitization of joint nociceptors to mechanical stimuli. Because tumor necrosis factor (TNF) is a major mediator of joint inflammation, we undertook the present study both to explore the potential of TNF to sensitize joint nociceptors to mechanical stimuli and to address the cellular mechanism involved.
  
  
  METHODS
  In anesthetized rats, action potentials (APs) were recorded from sensory nociceptive Aδ fibers and C fibers supplying the knee joint. We monitored responses to rotation of the knee joint at innocuous and noxious intensities. TNF, etanercept, and a p38 inhibitor were injected into the knee joint, and the cyclooxygenase (COX) inhibitor diclofenac was administered intraperitoneally. APs were also recorded in isolated cultured dorsal root ganglion (DRG) neurons in order to test for changes in neuronal excitability induced by TNF.
  
  
  RESULTS
  A single application of TNF into the normal knee joint caused a significant persistent sensitization of nociceptive sensory fibers to mechanical stimuli applied to the joint. This effect was dose dependent. It was prevented by coadministration of etanercept or by an inhibitor of p38, and it was attenuated by systemic application of a COX inhibitor. Patch clamp recordings from isolated DRG neurons showed a rapid increase in neuronal excitability induced by TNF.
  
  
  CONCLUSIONS
  TNF can induce a long-lasting sensitization of joint nociceptors to mechanical stimuli and thus can induce long-lasting mechanical hyperalgesia in joints. TNF can act directly on neurons, underscoring its role as a sensitizing pain mediator.
authors: Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany.
authors: Frank
authors: F
authors: Richter
authors: Gabriel
authors: G
authors: Natura
authors: Stefan
authors: S
authors: Löser
authors: Katarina
authors: K
authors: Schmidt
authors: Hanna
authors: H
authors: Viisanen
authors: Hans-Georg
authors: HG
authors: Schaible
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002478:Cells, Cultured; D004008:Diclofenac / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000068800:Etanercept; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007074:Immunoglobulin G / Q000494:pharmacology; D007270:Injections, Intra-Articular; D007719:Knee Joint / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor; D013314:Stress, Mechanical; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D004008:Diclofenac; D048051:p38 Mitogen-Activated Protein Kinases; D000068800:Etanercept