title: Pain-related sensory innervation in monoiodoacetate-induced osteoarthritis in rat knees that gradually develops neuronal injury in addition to inflammatory pain.
abstract: BACKGROUND
  The exact mechanism of knee osteoarthritis (OA)-associated pain is unclear, whereas mixed evidence of inflammatory pain and neuropathic pain has been noted. We aimed to investigate pain-related sensory innervation in a monoiodoacetate (MIA)-induced model of OA.
  
  
  METHODS
  Sixty of seventy female Sprague Dawley rats of six week-old underwent intra-articular MIA and fluorogold (FG) retrograde neurotracer injection into their right (ipsilateral) knee, while their left knees were treated with FG in saline as a control (contralateral knee). Other rats were treated with FG only bilaterally, and used as controls. Rats were evaluated for tactile allodynia using von Frey hairs. Proinflammatory mediators in the knee soft tissues, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and nerve growth factor (NGF), were quantified using ELISAs to evaluate inflammation in the knee after 1, 4, 7, 14, 21, and 28 days post injection. Dorsal root ganglia (DRG) were immunostained for three molecules after 7, 14, 21, and 28 days post injection: calcitonin gene-related peptide (CGRP), a marker of inflammatory pain; and activating transcription factor-3 (ATF3) and growth associated protein-43 (GAP43), as markers for nerve injury and regenerating axons. The distribution of microglia in the spinal cord were also evaluated, because they have been reported to increase in neuropathic pain states. These evaluations were performed up to 28 days postinjection. P < 0.05 was considered significant.
  
  
  RESULTS
  Progressive tactile allodynia and elevated cytokine concentrations were observed in ipsilateral knees. CGRP-immunoreactive (-ir) ipsilateral DRG neurons significantly increased, peaking at 14 days postinjection, while expression of FG-labeled ATF3-ir or ATF3-ir GAP43-ir DRG neurons significantly increased in a time-dependent manner. Significant proliferation of microglia were found with time in the ipsilateral dorsal horn.
  
  
  CONCLUSIONS
  Pain-related characteristics in a MIA-induced rat OA model can originate from an inflammatory pain state induced by the local inflammation initiated by inflammatory cytokines, and that state will be followed by gradual initiation of neuronal injury, which may induce the neuropathic pain state.
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. sumihisa@silver.email.ne.jp
authors.forename: Sumihisa
authors.initials: S
authors.lastname: Orita
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyagi
authors.forename: Nobuyasu
authors.initials: N
authors.lastname: Ochiai
authors.forename: Gen
authors.initials: G
authors.lastname: Inoue
authors.forename: Yawara
authors.initials: Y
authors.lastname: Eguchi
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kamoda
authors.forename: Gen
authors.initials: G
authors.lastname: Arai
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Toyone
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Aoki
authors.forename: Takekazu
authors.initials: T
authors.lastname: Kubo
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takahashi
authors.forename: Seiji
authors.initials: S
authors.lastname: Ohtori
mesh_terms: D000818:Animals; D018771:Arthralgia / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000633:toxicity*; D019807:Iodoacetic Acid / Q000633:toxicity*; D008137:Longitudinal Studies; D009410:Nerve Degeneration / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D020370:Osteoarthritis, Knee / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: D018836:Inflammation Mediators; D019807:Iodoacetic Acid