Skip to main content
Log in

Strontium ranelate analgesia in arthritis models is associated to decreased cytokine release and opioid-dependent mechanisms

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

We investigated the anti-inflammatory activity of strontium ranelate (SR) in arthritis models.

Materials and methods

Rats received 1 mg zymosan (Zy) or saline intra-articularly. Other groups were subjected to anterior cruciate ligament transection in the right knee, as an osteoarthritis (OA) model, or a sham procedure. Joint pain was assessed using the articular incapacitation and paw-pressure tests. Cell influx and cytokines were measured in joint exudates.

Treatment

Groups received either SR (30–300 mg/kg per os) or saline.

Results

SR dose-dependently and significantly inhibited joint pain in both Zy and OA models, while not altering cell influx. Naloxone administration significantly reversed SR analgesia. SR significantly reduced levels of Interleukin-1β and tumor necrosis factor-α in Zy arthritis, whereas those of cytokine-induced neutrophil chemoattractant (CINC)-1 were not altered.

Conclusions

SR provides analgesia in arthritis that is associated to inhibition of the release of inflammatory cytokines into inflamed joints. This effect is abrogated by administration of the opioid antagonist naloxone.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Marie PJ. Strontium ranelate: a dual mode of action rebalancing bone turnover in favour of bone formation. Curr Opin Rheumatol. 2006;18:S11–5.

    Article  PubMed  Google Scholar 

  2. Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD, Cannata J, Balogh A, Lemmel EM, Pors-Nielsen S, Rizzoli R, Genant HK, Reginster JY. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:459–68.

    Article  CAS  PubMed  Google Scholar 

  3. Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C, Devogelaer JP, Curiel MD, Sawicki A, Goemaere S, Sorensen OH, Felsenberg D, Meunier PJ. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab. 2005;90:2816–22.

    Article  CAS  PubMed  Google Scholar 

  4. Carvalho AP, Bezerra MM, Girão VC, Cunha FQ, Rocha FAC. Anti-inflammatory and anti-nociceptive activity of risedronate in experimental pain models in rats and mice. Clin Exp Pharmacol Physiol. 2006;33:601–6.

    Article  CAS  PubMed  Google Scholar 

  5. Bruyere O, Delferriere D, Roux C, Wark JD, Spector T, Devogelaer JP, Brixen K, Adami S, Fechtenbaum J, Kolta S, Reginster JY. Effects of strontium ranelate on spinal osteoarthritis progression. Ann Rheum Dis. 2008;67:335–9.

    Article  CAS  PubMed  Google Scholar 

  6. Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000;289:1504–8.

    Article  CAS  PubMed  Google Scholar 

  7. Edwards JC, Willoughby DA. Demonstration of bone marrow derived cells in synovial lining by means of giant intracellular granules as genetic markers. Ann Rheum Dis. 1982;41:177–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Bresnihan B. The synovial lining cells in chronic arthritis. Br J Rheumatol. 1992;31:433–5.

    Article  CAS  PubMed  Google Scholar 

  9. Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage. 2012;21:16–21.

    Article  PubMed  Google Scholar 

  10. Durand M, Komarova SV, Bhargava A, Trebec-Reynolds DP, Li K, Fiorino C, Maria O, Nabavi N, Manolson MF, Harrison RE, Dixon SJ, Sims SM, Mizianty MJ, Kurgan L, Haroun S, Boire G, Lucena-Fernandes MF, de Brum-Fernandes AJ. Monocytes from patients with osteoarthritis display increased osteoclastogenesis and bone resorption. The in vitro osteoclast differentiation in arthritis Study. Arthritis Rheum. 2013;65:148–58.

    Article  CAS  PubMed  Google Scholar 

  11. Pelletier JP, Kapoor M, Fahmi H, Lajeunesse D, Blesius A, Maillet J, Martel-Pelletier J. Strontium ranelate reduces the progression of experimental dog osteoarthritis by inhibiting the expression of key proteases in cartilage and of IL-1β in the synovium. Ann Rheum Dis. 2013;72:250–7.

    Article  CAS  PubMed  Google Scholar 

  12. Rocha FA, Aragão AG Jr, Oliveira RC, Pompeu MM, Vale MR, Ribeiro RA. Periarthritis promotes gait disturbance in zymosan-induced arthritis in rats. Inflamm Res. 1999;48:485–90.

    Article  CAS  PubMed  Google Scholar 

  13. de Mel Leite AC, Teotonio MA, Girão VC, Lima Pompeu MM, de Melo Nunes R, Cunha TM, Pinto AC, de Queiroz Cunha F, Rocha FA. Meniscal transection rather than excision increases pain behavior and structural damage in experimental osteoarthritis in mice. Osteoarthritis Cartilage. 2014;22:1878–85.

    Article  Google Scholar 

  14. Castro RR, Cunha FQ, Silva FS Jr, Rocha FA. A quantitative approach to measure joint pain in experimental osteoarthritis-evidence of a role for nitric oxide. Osteoarthritis Cartilage. 2006;14:769–76.

    Article  CAS  PubMed  Google Scholar 

  15. Cunha FQ, Poole S, Lorenzetti BB, Ferreira SH. The pivotal role of tumour necrosis factor alpha in the development of inflammatory hyperalgesia. Br J Pharmacol. 1992;107:660–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Ferreira SH, Lorenzetti BB, Bristow AF, Poole S. Interleukin-1 beta as a potent hyperalgesic agent antagonized by a tripeptide analogue. Nature. 1988;334:698–700.

    Article  CAS  PubMed  Google Scholar 

  17. Bondeson J, Blom AB, Wainwright S, Hughes C, Caterson B, van den Berg WB. The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum. 2010;62:647–57.

    Article  CAS  PubMed  Google Scholar 

  18. Rocha FA, Silva FS Jr, Leite AC, Leite AK, Girão VC, Castro RR, Cunha FQ. Tadalafil analgesia in experimental arthritis involves suppression of intra-articular TNF release. Br J Pharmacol. 2011;164:828–35.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Marie PJ. Strontium ranelate in osteoporosis and beyond: identifying molecular targets in bone cell biology. Mol Interv. 2010;10:305–12.

    Article  CAS  PubMed  Google Scholar 

  20. Guerrero AT, Verri WA Jr, Cunha TM, Silva TA, Rocha FA, Ferreira SH, Cunha FQ, Parada CA. Hypernociception elicited by tibio-tarsal joint flexion in mice: a novel experimental arthritis model for pharmacological screening. Pharmacol Biochem Behav. 2006;84:244–51.

    Article  CAS  PubMed  Google Scholar 

  21. Ferreira SH, Nakamura M. II—Prostaglandin hyperalgesia: the peripheral analgesic activity of morphine, enkephalins and opioid antagonists. Prostaglandins. 1979;18:191–200.

    Article  CAS  PubMed  Google Scholar 

  22. Cunha TM, Roman-Campos D, Lotufo CM, Duarte HL, Souza GR, Verri WA Jr, Funez MI, Dias QM, Schivo IR, Domingues AC, Sachs D, Chiavegatto S, Teixeira MM, Hothersall JS, Cruz JS, Cunha FQ, Ferreira SH. Morphine peripheral analgesia depends on activation of the PI3Kgamma/AKT/nNOS/NO/KATP signaling pathway. Proc Natl Acad Sci USA. 2010;107:4442–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Hurtel-Lemaire AS, Mentaverri R, Caudrillier A, Cournarie F, Wattel A, Kamel S, Terwilliger EF, Brown EM, Brazier M. The calcium-sensing receptor is involved in strontium ranelate-induced osteoclast apoptosis. New insights into the associated signaling pathways. J Biol Chem. 2009;284:575–84.

    Article  CAS  PubMed  Google Scholar 

  24. Stevens CW, Aravind S, Das S, Davis RL. Pharmacological characterization of LPS and opioid interactions at the toll-like receptor 4. Br J Pharmacol. 2013;168:1421–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Grants 302218/2014-9 and 459334/2014-0 from CNPq (Conselho Nacional de Desenvolvimento e Tecnológico—Brasil).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Francisco Airton Castro Rocha.

Additional information

Responsible Editor: Jason J. McDougall.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Melo Nunes, R., Martins, M.R., da Silva Junior, F.S. et al. Strontium ranelate analgesia in arthritis models is associated to decreased cytokine release and opioid-dependent mechanisms. Inflamm. Res. 64, 781–787 (2015). https://doi.org/10.1007/s00011-015-0860-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-015-0860-7

Keywords

Navigation