Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Journal of Orthopaedic Science

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.

Conclusion

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Sekiguchi M, Shirasaka M, Konno S, Kikuchi S. Analgesic effect of percutaneously absorbed non-steroidal anti-inflammatory drugs: an experimental study in a rat acute inflammation model. BMC Musculoskelet Dis. 2008;9:1–7.

    Article  Google Scholar 

  2. Guingamp C, Gegout-Pottie P, Philippe L, Terlain B, Netter P, Gillet P. Mono-iodoacetate-induced experimental osteoarthritis: a dose–response study of loss of mobility, morphology, and biochemistry. Arthritis Rheum. 1997;40:1670–9.

    Article  PubMed  CAS  Google Scholar 

  3. Guzman RE, Evans MG, Bove S, Morenko B, Kilgore K. Mono-iodoacetate-induced histologic changes in subchondral bone and articular cartilage of rat femorotibial joints: an animal model of osteoarthritis. Toxicol Pathol. 2003;31:619–24.

    PubMed  CAS  Google Scholar 

  4. Bove SE, Calcaterra SL, Brooker RM, Huber CM, Guzman RE, Juneau PL, Schrier DJ, Kilgore KS. Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. Osteoarthritis Cartilage. 2003;11:821–30.

    Article  PubMed  CAS  Google Scholar 

  5. Smith MD, Triantafillou S, Parker A, Youssef PP, Coleman M. Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J Rheumatol. 1997;24:365–71.

    PubMed  CAS  Google Scholar 

  6. Orita S, Ishikawa T, Miyagi M, Ochiai N, Inoue G, Eguchi Y, Kamoda H, Arai G, Toyone T, Aoki Y, Kubo T, Takahashi K, Ohtori S. Pain-related sensory innervation in monoiodoacetate-induced osteoarthritis in rat knees that gradually develops neuronal injury in addition to inflammatory pain. BMC Musculoskelet Disord. 2011;12:134.

    Article  PubMed  Google Scholar 

  7. Hunt SP, Pini A, Evan G. Induction of c-fos-like protein in spinal cord neurons following sensory stimulation. Nature. 1987;328:632–4.

    Article  PubMed  CAS  Google Scholar 

  8. Menétrey D, Gannon A, Levine JD, Basbaum AI. Expression of c-fos protein in interneurons and projection neurons of the rat spinal cord in response to noxious somatic, articular, and visceral stimulation. J Comp Neurol. 1989;285:177–95.

    Article  PubMed  Google Scholar 

  9. Morgan JI, Curran T. Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. Annu Rev Neurosci. 1991;14:421–51.

    Article  PubMed  CAS  Google Scholar 

  10. Chimoto E, Hagiwara Y, Ando A, Itoi E. Progression of an arthrogenic motion restriction after immobilization in a rat experimental knee model animals. Ups J Med Sci. 2007;112:347–55.

    Article  PubMed  Google Scholar 

  11. Janusz MJ, Bendele AM, Brown KK, Taiwo YO, Hsieh L, Heitmeyer SA. Induction of osteoarthritis in the rat by surgical tear of the meniscus: inhibition of joint damage by a matrix metalloproteinase inhibitor. Osteoarthritis Cartilage. 2002;10:785–91.

    Article  PubMed  CAS  Google Scholar 

  12. Schaible HG. Neurophysiology of nociception and pain reactions in inflammatory joint diseases. Rev Rhum Engl Ed. 1997;64:144S–5S.

    PubMed  CAS  Google Scholar 

  13. Kunkel SL, Wiggins RC, Chensue SW, Larrick J. Regulation of macrophage tumor necrosis factor production by prostaglandin E2. Biochem Biophys Res Commun. 1986;137:404–10.

    Article  PubMed  CAS  Google Scholar 

  14. Tipton DA, Gay DC, DeCoster VA. Effect of a cyclooxygenase-2 inhibitor on interleukin-1beta-stimulated activation of the transcription factor nuclear factor-kappa B in human gingival fibroblasts. J Periodontol. 2007;78:542–9.

    Article  PubMed  CAS  Google Scholar 

  15. Kutuk O, Basaga H. Aspirin inhibits TNFalpha- and IL-1-induced NF-kappaB activation and sensitizes HeLa cells to apoptosis. Cytokine. 2004;25:229–37.

    Google Scholar 

  16. Ohtori S, Takahashi K, Moriya H, Myers RR. TNF-alpha and TNF-alpha receptor type 1 upregulation in glia and neurons after peripheral nerve injury: studies in murine DRG and spinal cord. Spine. 2004;29:1082–8.

    Article  PubMed  Google Scholar 

  17. Pollock J, McFarlane SM, Connell MC, Zehavi U, Vandenabeele P, MacEwan DJ, Scott RH. TNF-alpha receptors simultaneously activate Ca2+ mobilisation and stress kinases in cultured sensory neurones. Neuropharmacol. 2002;42:93–106.

    Article  CAS  Google Scholar 

  18. Orita S, Koshi T, Mitsuka T, Miyagi M, Inoue G, Arai G, Ishikawa T, Hanaoka E, Yamashita K, Yamashita M, Eguchi Y, Toyone T, Takahashi K, Ohtori S. Associations between proinflammatory cytokines in the synovial fluid and radiographic grading and pain-related scores in 47 consecutive patients with osteoarthritis of the knee. BMC Musculoskelet Dis. 2011;12:144.

    Article  CAS  Google Scholar 

  19. Lotz M, Guerne PA. Interleukin-6 induces the synthesis of tissue inhibitor of metalloproteinases-1/erythroid potentiating activity (TIMP-1/EPA). J Biol Chem. 1991;266:2017–20.

    PubMed  CAS  Google Scholar 

  20. Iannone F, Bari CD, Accio FD, Covelli M, Patella V, Bianco GL, Lapadula G. Increased expression of nerve growth factor (NGF) and high affinity NGF receptor (p140 TrkA) in human osteoarthritic chondrocytes. Rheumatology (Oxf). 2002;41:1413–8.

    Article  CAS  Google Scholar 

  21. Pezet S, McMahon SB. Neurotrophins: mediators and modulators of pain. Annu Rev Neurosci. 2006;29:507–38.

    Article  PubMed  CAS  Google Scholar 

  22. Manni L, Lundeberg T, Fiorito S, Bonini S, Vigneti E, Aloe L. Nerve growth factor release by human synovial fibroblasts prior to and following exposure to tumor necrosis factor-alpha, interleukin-1 beta and cholecystokinin-8: the possible role of NGF in the inflammatory response. Clin Exp Rheumatol. 2003;21:617–24.

    Google Scholar 

  23. Carter JL, Lubahn C, Lorton D, Osredkar T, Der TC, Schaller J, Evelsizer S, Flowers S, Ruff N, Reese B, Bellinger DL. Adjuvant-induced arthritis induces c-Fos chronically in neurons in the hippocampus. J Neuroimmunol. 2011;230:85–94.

    Article  PubMed  CAS  Google Scholar 

  24. Takayama B, Kikuchi S, Konno S, Sekiguchi M. An immunohistochemical study of the antinociceptive effect of calcitonin in ovariectomized rats. BMC Musculoskelet Dis. 2008;9:164.

    Article  Google Scholar 

  25. Abbadie C, Besson JM. c-fos expression in rat lumbar spinal cord during the development of adjuvant-induced arthritis. Neuroscience. 1992;48:985–93.

    Article  PubMed  CAS  Google Scholar 

  26. Naranjo JR, Mellström B, Achaval M, Sassone-Corsi P. Molecular pathways of pain: Fos/Jun-mediated activation of a noncanonical AP-1 site in the prodynorphin gene. Neuron. 1991;6:607–17.

    Article  PubMed  CAS  Google Scholar 

  27. Carrive P, Meyer-Carrive I. Changes in formalin-evoked spinal Fos expression and nociceptive behaviour after oral administration of Bufferin A (aspirin) and L-5409709 (ibuprofen + caffeine + paracetamol). Pain. 1997;70:253–66.

    Article  PubMed  CAS  Google Scholar 

  28. Honoré P, Buritova J, Besson JM. Carrageenin-evoked c-Fos expression in rat lumbar spinal cord: the effects of indomethacin. Eur J Pharmacol. 1995;272:249–59.

    Article  PubMed  Google Scholar 

  29. Buritova J, Besson JM. Effects of flurbiprofen and its enantiomers on the spinal c-Fos protein expression induced by noxious heat stimuli in the anaesthetized rat. Eur J Pharmacol. 2000;406:59–67.

    Article  PubMed  CAS  Google Scholar 

  30. Delcroix JD, Valletta JS, Wu C, Hunt SJ, Kowal AS, Mobley WC. NGF signaling in sensory neurons: evidence that early endosomes carry NGF retrograde signals. Neuron. 2003;39:69–84.

    Article  PubMed  CAS  Google Scholar 

  31. Michael GJ, Averill S, Nitkunan A, Rattray M, Bennett DL, Yan Q, Priestley JV. Nerve growth factor treatment increases brain-derived neurotrophic factor selectively in TrkA-expressing dorsal root ganglion cells and in their central terminations within the spinal cord. J Neurosci. 1997;17:8476–90.

    PubMed  CAS  Google Scholar 

  32. Kerr BJ, Bradbury EJ, Bennett DL, Trivedi PM, Dassan P, French J, Shelton DB, McMahon SB, Thompson SW. Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord. J Neurosci. 1999;19:5138–48.

    PubMed  CAS  Google Scholar 

  33. Orita S, Ohtori S, Nagata M, Horii M, Yamashita M, Yamauchi K, Inoue G, Suzuki M, Eguchi Y, Kamoda H, Arai G, Ishikawa T, Miyagi M, Ochiai N, Kishida S, Takaso M, Aoki Y, Takahashi K. Inhibiting nerve growth factor or its receptors downregulates calcitonin gene-related peptide expression in rat lumbar dorsal root ganglia innervating injured intervertebral discs. J Orthop Res. 2010;28:1614–20.

    Article  PubMed  CAS  Google Scholar 

  34. Buritova J, Honoré P, Besson JM. Ketoprofen produces profound inhibition of spinal c-Fos protein expression resulting from an inflammatory stimulus but not from noxious heat. Pain. 1996;67:379–89.

    Article  PubMed  CAS  Google Scholar 

  35. Panfil C, Makowska A, Ellrich J. Brainstem and cervical spinal cord Fos immunoreactivity evoked by nerve growth factor injection into neck muscles in mice. Cephalalgia. 2006;26:128–35.

    Article  PubMed  CAS  Google Scholar 

  36. Sugimoto M, Kojima T, Asami M, Iizuka Y, Matsuda K. Inhibition of prostaglandin production in the inflammatory tissue by loxoprofen-Na, an anti-inflammatory prodrug. Biochem Pharmacol. 1991;42:2363–8.

    Article  PubMed  CAS  Google Scholar 

  37. Ferreira-gomes J, Adães S, Castro-lopes JM. Assessment of movement-evoked pain in osteoarthritis by the knee-bend and catwalk tests: a clinically relevant study. J Pain. 2008;9:945–54.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Miho Sekiguchi, M.D., Ph.D. (Department of Orthopaedic Surgery, Fukushima School of Medicine, Fukushima, Japan) for technical advice.

Conflict of interest

None of the authors have any conflicts of interest or disclosures in relation to this work.

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Sumihisa Orita, Tetsuhiro Ishikawa, Masayuki Miyagi, Nobuyasu Ochiai, Gen Inoue, Yawara Eguchi, Hiroto Kamoda, Gen Arai, Miyako Suzuki, Yoshihiro Sakuma, Yasuhiro Oikawa, Kazuhisa Takahashi & Seiji Ohtori

  2. Department of Anesthesiology, School of Medicine, University of California, San Diego, La Jolla, San Diego, CA, USA

    Sumihisa Orita

  3. Teikyo University Chiba Medical Center, Chiba, Japan

    Tomoaki Toyone

  4. Toho University Sakura Medical Center, Chiba, Japan

    Yasuchika Aoki

Authors
  1. Sumihisa Orita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tetsuhiro Ishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masayuki Miyagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nobuyasu Ochiai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gen Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yawara Eguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroto Kamoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gen Arai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Miyako Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoshihiro Sakuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yasuhiro Oikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tomoaki Toyone
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yasuchika Aoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kazuhisa Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Seiji Ohtori
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sumihisa Orita.

Additional information

S. Orita, T. Ishikawa, and M. Miyagi equally contributed to this work.

About this article

Cite this article

Orita, S., Ishikawa, T., Miyagi, M. et al. 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. J Orthop Sci 17, 77–86 (2012). https://doi.org/10.1007/s00776-011-0175-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00776-011-0175-7

Keywords

Search

Navigation