title: Percutaneously absorbed NSAIDs attenuate local production of proinflammatory cytokines and suppress the expression of c-Fos in the spinal cord of a rodent model of knee osteoarthritis.
abstract: BACKGROUND
  Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in clinical situations to reduce inflammation and pain. Percutaneous administration is one of the routes mainly used in Japan to deal with the pain from acute injuries, to chronic pain such as chronic low back pain and osteoarthritis (OA). There have been no studies that report the effect of percutaneous administration of NSAIDs on chronic pain in animal models. This study aimed to investigate the effect of percutaneously absorbed NSAIDs on a rodent model of OA.
  
  
  METHODS
  OA was induced with an intra-articular injection of monoiodoacetate into the right knees (left knee was treated with saline, normal control) of female Sprague-Dawley rats. Physical evaluation, diameter, and the range of motion (ROM) of the knee joint, as well as pain-related behavior, were evaluated. Animals were killed and perfused 7 days after the intra-articular injection, and then local tissue from the knee [for cytokine assay: tumor necrosis factor (TNF)-α, interleukin (IL)-6, and nerve growth factor (NGF)] and spinal cord (immunostained for c-Fos protein reflecting neuronal excitation) were evaluated (n = 7 each). Twenty-eight days after the injection, the other rats were then divided into three groups and were identified by a plaster tape containing an NSAID or a vehicle applied to their OA (ipsilateral) knees: a vehicle-treated group, a loxoprofen-treated (lox) group, and a ketoprofen-treated (ket) group. The behavior elicited by von Frey hairs, inflammatory cytokines, and c-Fos protein at 0, 8, and 24 h after tape application were evaluated (n = 7 each). The plaster tapes contained corresponding NSAIDs used in clinical settings: lox 2.8 mg and ket 1.1 mg. Three of the OA animals were histologically evaluated.
  
  
  RESULTS
  As the OA progressed, the ipsilateral knee joint showed OA-like appearance physically and histologically. The knee diameter increased and ROM decreased significantly (P < 0.05), showing histological OA-like cartilage degeneration. Pain threshold decreased significantly according to OA progression (P < 0.05). NSAID application significantly improved the threshold 24 h after application in both the lox and ket groups (P < 0.05) without any significant difference between groups. Cytokine concentrations and c-Fos were significantly suppressed in both lox and ket groups (P < 0.05). Lox suppressed TNF-α and NGF more than ket, whereas ket suppressed IL-6 more.
  
  
  CONCLUSIONS
  Suppression of proinflammatory cytokines and c-Fos expression by clinically used NSAIDs suggests that their percutaneous administration may have an analgesic effect for treating chronic pain at a molecular level.
authors: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. sumihisa@silver.email.ne.jp
authors: Sumihisa
authors: S
authors: Orita
authors: Tetsuhiro
authors: T
authors: Ishikawa
authors: Masayuki
authors: M
authors: Miyagi
authors: Nobuyasu
authors: N
authors: Ochiai
authors: Gen
authors: G
authors: Inoue
authors: Yawara
authors: Y
authors: Eguchi
authors: Hiroto
authors: H
authors: Kamoda
authors: Gen
authors: G
authors: Arai
authors: Miyako
authors: M
authors: Suzuki
authors: Yoshihiro
authors: Y
authors: Sakuma
authors: Yasuhiro
authors: Y
authors: Oikawa
authors: Tomoaki
authors: T
authors: Toyone
authors: Yasuchika
authors: Y
authors: Aoki
authors: Kazuhisa
authors: K
authors: Takahashi
authors: Seiji
authors: S
authors: Ohtori
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016207:Cytokines / Q000096:biosynthesis* / Q000187:drug effects; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007150:Immunohistochemistry; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012869:Skin Absorption; D013116:Spinal Cord / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D016760:Proto-Oncogene Proteins c-fos