Skip to main content
Log in

Investigation of the effects of therapeutic ultrasound or photobiomodulation and the role of spinal glial cells in osteoarthritis-induced nociception in mice

  • Original Article
  • Published:
Lasers in Medical Science Aims and scope Submit manuscript

Abstract

Pain is the most common symptom of osteoarthritis, and spinal glia is known to contribute to this symptom. Therapeutic ultrasound and laser therapy have been used to effectively treat osteoarthritis, with few adverse effects. Thus, this study aimed to investigate the effects of ultrasound and photobiomodulation on the symptoms and evaluate the participation of spinal glia in osteoarthritis-induced nociception in mice. Male Swiss mice were subjected to osteoarthritis induction with a 0.1-mg intra-articular injection of monosodium iodoacetate. Additionally, the mice received chronic ultrasound or photobiomodulation treatment for 21 days or a single treatment at day 14. Nociception was evaluated using von Frey filaments, and osteoarthritis symptoms were assessed by analysis of gait, joint temperature, and knee joint diameter. The role of spinal microglia and astrocytes on nociception was evaluated via an intrathecal injection of minocycline or fluorocitrate, and the spinal release of IL-1β and TNF-α was assessed by ELISA after chronic treatment with ultrasound or photobiomodulation. Our data showed that both single and chronic treatment with ultrasound or photobiomodulation attenuated the osteoarthritis-induced nociception. No differences in gait, knee joint temperature, or knee joint diameter were found. The intrathecal injection of minocycline and fluorocitrate decreased the osteoarthritis-induced nociception. There was an increase in the spinal levels of TNF-α, which was reverted by chronic ultrasound and laser treatments. These results suggest that osteoarthritis induces nociception and glial activation via spinal release of TNF-α and that the chronic treatment with ultrasound or photobiomodulation decreased nociception and TNF-α release.

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
Fig. 5

Similar content being viewed by others

Data availability

The data and material will be available when requested from the corresponding author.

Code availability

Not applicable.

References

  1. Martel-Pelletier J. Pathophysiology of osteoarthritis. Osteoarthritis Cartilage 2004;A:S31–3. https://doi.org/10.1016/j.joca.2003.10.002

  2. Zhang Y, Jordan JM (2010) Epidemiology of osteoarthritis. Clin Geriatr Med 26(3):355–369. https://doi.org/10.1016/j.cger.2010.03.001

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hunter DJ, McDougall JJ, Keefe FJ (2008) The symptoms of osteoarthritis and the genesis of pain. Rheum Dis Clin North Am 34(3):623–643. https://doi.org/10.1016/j.rdc.2008.05.004

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sagar DR, Burston JJ, Hathway GJ et al (2011) The contribution of spinal glial cells to chronic pain behaviour in the monosodium iodoacetate model of osteoarthritic pain. Mol Pain 7:88. https://doi.org/10.1186/1744-8069-7-88

    Article  PubMed  PubMed Central  Google Scholar 

  5. Woolf CJ (2011) Central sensitization: implications for the diagnosis and treatment of pain. Pain 152:S2-15. https://doi.org/10.1016/j.pain.2010.09.030

    Article  PubMed  Google Scholar 

  6. Latremoliere A, Woolf CJ (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 10(9):895–926. https://doi.org/10.1016/j.jpain.2009.06.012

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ogbonna AC, Clark AK, Gentry C, Hobbs C, Malcangio M (2013) Pain-like behaviour and spinal changes in the monosodium iodoacetate model of osteoarthritis in C57Bl/6 mice. Eur J Pain 17(4):514–526. https://doi.org/10.1002/j.1532-2149.2012.00223.x

    Article  CAS  PubMed  Google Scholar 

  8. Ogbonna AC, Clark AK, Malcangio M (2015) Development of monosodium acetate-induced osteoarthritis and inflammatory pain in ageing mice. Age 37(3):9792. https://doi.org/10.1007/s11357-015-9792-y

    Article  CAS  PubMed  Google Scholar 

  9. Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10(1):23–36. https://doi.org/10.1038/nrn2533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Watkins LR, Milligan ED, Maier SF (2001) Glial activation: a driving force for pathological pain. Trends Neurosci 24(8):450–455. https://doi.org/10.1016/s0166-2236(00)01854-3

    Article  CAS  PubMed  Google Scholar 

  11. Zeng C, Li H, Yang T, Deng ZH, Yang Y, Zhang Y, Ding X, Lei GH (2014) Effectiveness of continuous and pulsed ultrasound for the management of knee osteoarthritis: a systematic review and network meta-analysis. Osteoarthr Cartil 22(8):1090–1099. https://doi.org/10.1016/j.joca.2014.06.028

    Article  CAS  Google Scholar 

  12. Alfredo PP, Bjordal JM, Dreyer SH et al (2012) Efficacy of low level laser therapy associated with exercises in knee osteoarthritis: a randomized double-blind study. Clin Rehabil 26(6):523–533. https://doi.org/10.1177/0269215511425962

    Article  PubMed  Google Scholar 

  13. Hsieh YL (2005) Reduction in induced pain by ultrasound may be caused by altered expression of spinal neuronal nitric oxide synthase-producing neurons. Arch Phys Med Rehabil 86(7):1311–1317. https://doi.org/10.1016/j.apmr.2004.12.035

    Article  PubMed  Google Scholar 

  14. Hsieh YL (2008) Peripheral therapeutic ultrasound stimulation alters the distribution of spinal C-fos immunoreactivity induced by early or late phase of inflammation. Ultrasound Med Biol 34(3):475–486. https://doi.org/10.1016/j.ultrasmedbio.2007.09.007

    Article  PubMed  Google Scholar 

  15. Cidral-Filho FJ, Martins DF, Moré AO, Mazzardo-Martins L, Silva MD, Cargnin-Ferreira E, Santos AR (2013) Light-emitting diode therapy induces analgesia and decreases spinal cord and sciatic nerve tumour necrosis factor-α levels after sciatic nerve crush in mice. Eur J Pain 17(8):1193–1204. https://doi.org/10.1002/j.1532-2149.2012.00280.x

    Article  CAS  PubMed  Google Scholar 

  16. Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16(2):109–110. https://doi.org/10.1016/0304-3959(83)90201-4

    Article  PubMed  Google Scholar 

  17. Pitcher T, Sousa-Valente J, Malcangio M (2016) The monoiodoacetate model of osteoarthritis pain in the mouse. J Vis Exp 111:53746. https://doi.org/10.3791/53746

    Article  Google Scholar 

  18. Hylden JL, Wilcox GL (1980) Intrathecal morphine in mice: a new technique. Eur J Pharmacol 67(2–3):313–316. https://doi.org/10.1016/0014-2999(80)90515-4

    Article  CAS  PubMed  Google Scholar 

  19. Ozgönenel L, Aytekin E, Durmuşoglu G (2009) A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis. Ultrasound Med Biol 35(1):44–49. https://doi.org/10.1016/j.ultrasmedbio.2008.07.009

    Article  PubMed  Google Scholar 

  20. Coradini JG, Mattjie TF, Bernardino GR et al (2014) Comparison of low level laser, ultrasonic therapy and association in joint pain in Wistar rats. Rev Bras Reumatol 54:7–12. https://doi.org/10.1016/j.rbr.2014.01.001

    Article  PubMed  Google Scholar 

  21. Turner TA (1991) Thermography as an aid to the clinical lameness evaluation. Vet Clin North Am Equine Pract 7(2):311–338. https://doi.org/10.1016/s0749-0739(17)30502-3

    Article  CAS  PubMed  Google Scholar 

  22. Makii Y, Asaka M, Setogawa S et al (2018) Alteration of gait parameters in a mouse model of surgically induced knee osteoarthritis. J Orthop Surg 26(2):2309499018768017. https://doi.org/10.1177/2309499018768017

    Article  Google Scholar 

  23. Jacobs BY, Kloefkorn HE, Allen KD (2014) Gait analysis methods for rodent models of osteoarthritis. Curr Pain Headache Rep 18(10):456. https://doi.org/10.1007/s11916-014-0456-x

    Article  PubMed  PubMed Central  Google Scholar 

  24. Johnson VL, Hunter DJ (2014) The epidemiology of osteoarthritis. Best Pract Res Clin Rheumatol 28(1):5–15. https://doi.org/10.1016/j.berh.2014.01.004

    Article  PubMed  Google Scholar 

  25. Guzman RE, Evans MG, Bove S, Morenko B, Kilgore K (2003) Mono-iodoacetate-induced histologic changes in subchondral bone and articular cartilage of rat femorotibial joints: an animal model of osteoarthritis. Toxicol Pathol 31(6):619–624. https://doi.org/10.1080/01926230390241800

    Article  CAS  PubMed  Google Scholar 

  26. van der Kraan PM, Vitters EL, van de Putte LB, van den Berg WB (1989) Development of osteoarthritic lesions in mice by “metabolic” and “mechanical” alterations in the knee joints. Am J Pathol 135(6):1001–1014

    PubMed  PubMed Central  Google Scholar 

  27. Jia L, Wang Y, Chen J, Chen W (2016) Efficacy of focused low-intensity pulsed ultrasound therapy for the management of knee osteoarthritis: A randomized, double blind, placebo-controlled trial. Sci Rep 6:1–9. https://doi.org/10.1038/srep35453

    Article  CAS  Google Scholar 

  28. Johns LD (2002) Nonthermal effects of therapeutic ultrasound: The frequency resonance hypothesis. J Athl Train 37:293–299

    PubMed  PubMed Central  Google Scholar 

  29. Chen YW, Tzeng JI, Huang PC, Hung CH, Shao DZ, Wang JJ (2015) Therapeutic ultrasound suppresses neuropathic pain and upregulation of substance P and neurokinin-1 receptor in rats after peripheral nerve injury. Ultrasound Med Biol 41(1):143–150. https://doi.org/10.1016/j.ultrasmedbio.2014.07.022

    Article  CAS  PubMed  Google Scholar 

  30. Hung CH, Huang PC, Tzeng JI, Wang JJ, Chen YW (2016) Therapeutic ultrasound and treadmill training suppress peripheral nerve injury-induced pain in rats. Phys Ther 96(10):1545–1553. https://doi.org/10.2522/ptj.20140379

    Article  PubMed  Google Scholar 

  31. Leong DJ, Zhang H, Xu L et al (2013) Therapeutic ultrasound: Osteoarthritis symptom-modification and potential for disease modification. J Surgery 1(2):5

    Google Scholar 

  32. Tsui PH, Wang SH, Huang CC (2005) In vitro effects of ultrasound with different energies on the conduction properties of neural tissue. Ultrasonics 43(7):560–565. https://doi.org/10.1016/j.ultras.2004.12.003

    Article  PubMed  Google Scholar 

  33. Pan H, Zhou Y, Izadnegahdar O, Cui J, Deng CX (2005) Study of sonoporation dynamics affected by ultrasound duty cycle. Ultrasound Med Biol 31(6):849–856. https://doi.org/10.1016/j.ultrasmedbio.2005.03.014

    Article  PubMed  Google Scholar 

  34. da Silva Junior EM, Mesquita-Ferrari RA, França CM et al (2017) Modulating effect of low intensity pulsed ultrasound on the phenotype of inflammatory cells. Biomed Pharmacother 96:1147–1153. https://doi.org/10.1016/j.biopha.2017.11.108

    Article  CAS  PubMed  Google Scholar 

  35. Straub SJ, Johns LD, Howard SM (2008) Variability in effective radiating area at 1 MHz affects ultrasound treatment intensity. Phys Ther 88(1):50–57. https://doi.org/10.2522/ptj.20060358

    Article  PubMed  Google Scholar 

  36. Rayegani SM, Raeissadat SA, Heidari S, Moradi-Joo M. Safety and effectiveness of low-level laser therapy in patients with knee osteoarthritis: A systematic review and meta-analysis. J Lasers Med Sci 2017;8(1):S12-S19. https://doi.org/10.15171/jlms.2017.s3

  37. de Freitas LF, Hamblin MR (2016) Proposed mechanisms of photobiomodulation or low-level light therapy. IEEE J Sel Top Quantum Electron 22(3):7000417. https://doi.org/10.1109/JSTQE.2016.2561201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cotler HB, Chow RT, Hamblin MR, Carroll J. The use of low level laser therapy (LLLT) for musculoskeletal pain. MOJ Orthop Rheumatol 2015;2(5):00068. https://doi.org/10.15406/mojor.2015.02.00068

  39. Chow RT, David MA, Armati PJ (2007) 830 nm laser irradiation induces varicosity formation, reduces mitochondrial membrane potential and blocks fast axonal flow in small and medium diameter rat dorsal root ganglion neurons: implications for the analgesic effects of 830 nm laser. J Peripher Nerv Syst 12(1):28–39. https://doi.org/10.1111/j.1529-8027.2007.00114.x

    Article  PubMed  Google Scholar 

  40. Chow R, Armati P, Laakso EL, Bjordal JM, Baxter GD (2011) Inhibitory effects of laser irradiation on peripheral mammalian nerves and relevance to analgesic effects: a systematic review. Photomed Laser Surg 29(6):365–381. https://doi.org/10.1089/pho.2010.2928

    Article  PubMed  Google Scholar 

  41. Andrade P, Visser-Vandewalle V, Hoffmann C, Steinbusch HWM, Daemen MA et al (2011) Role of TNF-alpha during central sensitization in preclinical studies. Neurol Sci 32:757. https://doi.org/10.1007/s10072-011-0599-z

    Article  PubMed  PubMed Central  Google Scholar 

  42. Bove SE, Calcaterra SL, Brooker RM et al (2003) Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. Osteoarthr Cartil 11(11):821–830. https://doi.org/10.1016/s1063-4584(03)00163-8

    Article  CAS  Google Scholar 

  43. Favero M, Ramonda R, Goldring MB, Goldring SR, Punzi L (2015) Early knee osteoarthritis RMD Open 1(1):e000062. https://doi.org/10.1136/rmdopen-2015-000062

    Article  PubMed  Google Scholar 

  44. Hsieh YL, Chen HY, Yang CC (2018) Early intervention with therapeutic low-intensity pulsed ultrasound in halting the progression of post-traumatic osteoarthritis in a rat model. Ultrasound Med Biol 44(12):2637–2645. https://doi.org/10.1016/j.ultrasmedbio.2018.08.007

    Article  PubMed  Google Scholar 

  45. Wang P, Liu C, Yang X et al (2014) Effects of low-level laser therapy on joint pain, synovitis, anabolic, and catabolic factors in a progressive osteoarthritis rabbit model. Lasers Med Sci 29(6):1875–1885. https://doi.org/10.1007/s10103-014-1600-x

    Article  PubMed  Google Scholar 

Download references

Funding

This work was supported by Fundação de Amparo à Pesquisa do Estado de Minas (FAPEMIG), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) [Grant 001].

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Giovane Galdino.

Ethics declarations

Ethics approval

The experiments were approved by the Animal Care and Use Committee at the Federal University of Alfenas, in Alfenas, Minas Gerais, Brazil (protocol number 49/2017).

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Malta, I., Moraes, T., Elisei, L. et al. Investigation of the effects of therapeutic ultrasound or photobiomodulation and the role of spinal glial cells in osteoarthritis-induced nociception in mice. Lasers Med Sci 37, 1687–1698 (2022). https://doi.org/10.1007/s10103-021-03418-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10103-021-03418-7

Keywords

Navigation