title: Repeated intra-articular injections of acidic saline produce long-lasting joint pain and widespread hyperalgesia.
abstract: BACKGROUND
  Synovial fluid in inflamed joint shows a drop in pH, which activates proton-gated ion channels in nociceptors. No studies have ever tried to develop and characterize acid-induced joint pain.
  
  
  METHODS
  Rats were injected intra-articularly with pH 4.0 acidic saline twice, 5 days apart. Pain-related behaviour tests including weight-bearing asymmetry, paw withdrawal threshold and knee compression threshold were conducted. To clarify the roles of proton-gated ion channels, rats were injected intra-articularly with selective antagonists for ASIC1a, ASIC3 and TRPV1 on day 5 (before the second injection) or on day 14. Underlying peripheral and central pain mechanisms were evaluated using joint histology, interleukin-1β concentrations in the synovium, single-fibre recording of the knee afferent and expression of phosphorylated cyclic adenosine monophosphate-responsive element-binding protein (p-CREB) in the spinal dorsal horn.
  
  
  RESULTS
  Repeated injections of acidic saline induced weight-bearing asymmetry, decrease in paw withdrawal threshold and knee compression threshold bilaterally, which lasted until day 28. Early administration of ASIC3 antagonist reduced the bilateral and long-lasting hyperalgesia. Neither articular degeneration nor synovial inflammation was observed. C-fibre of the knee afferent was activated by acidic saline, which was attenuated by pre-injection of ASIC3 antagonist. p-CREB expression was transiently up-regulated bilaterally on day 6, but not on day 14.
  
  
  CONCLUSIONS
  We developed and characterized a model of acid-induced long-lasting bilateral joint pain. Peripheral ASIC3 and spinal p-CREB played important roles for the development of hyperalgesia. This animal model gives insights into the mechanisms of joint pain, which is helpful in developing better pain treatments.
authors.affiliation: Department of Orthopaedic Surgery, Kochi Medical School, Kochi University, Nankoku, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Sugimura
authors.forename: M
authors.initials: M
authors.lastname: Ikeuchi
authors.forename: M
authors.initials: M
authors.lastname: Izumi
authors.forename: T
authors.initials: T
authors.lastname: Kawano
authors.forename: K
authors.initials: K
authors.lastname: Aso
authors.forename: T
authors.initials: T
authors.lastname: Kato
authors.forename: T
authors.initials: T
authors.lastname: Ushida
authors.forename: M
authors.initials: M
authors.lastname: Yokoyama
authors.forename: T
authors.initials: T
authors.lastname: Tani
mesh_terms: D062565:Acid Sensing Ion Channels / Q000378:metabolism; D000143:Acids; D000818:Animals; D018771:Arthralgia / Q000139:chemically induced* / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced*; D007270:Injections, Intra-Articular; D053583:Interleukin-1beta / Q000378:metabolism; D007473:Ion Channels / Q000037:antagonists & inhibitors; D007596:Joints / Q000187:drug effects / Q000473:pathology; D008297:Male; D009475:Neurons, Afferent / Q000473:pathology; D010147:Pain Measurement / Q000187:drug effects; D020671:Posterior Horn Cells / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride; D013583:Synovial Membrane / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D016474:Weight-Bearing
chemical_list: C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D000143:Acids; C568268:Asic1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D053583:Interleukin-1beta; D007473:Ion Channels; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D012965:Sodium Chloride