Brazilian Journal of Anesthesiology
Brazilian Journal of Anesthesiology
Original Investigation

Therapeutic ultrasound ameliorates hyperalgesia and edema on CFA-induced persistent inflammatory response in mice

Mariana Rodrigues, Rafael I. Barbosa, Lais M.S. Neves, Heloyse U. Kuriki, Elaine C.D. Gonçalves, Adair R.S. Santos, Rafael C. Dutra, Alexandre M. Marcolino

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The present study investigated the effects of pulsed and continuous ultrasound (USP and USC) in edema and hyperalgesia after chronic inflammatory process induced by Complete Freund's Adjuvant-CFA and analyzing the relationship of the application frequency of ultrasound, in pro- and anti-inflammatory cytokine production.

Forty-five animals were divided into 9 groups; all animals from groups 2 to 9 were subjected to a persistent inflammation model induced by CFA in mice. We report the effects and the underlying action mechanisms of USP and USC in the animals which were irradiated two, three or five times a week on the left hind paw. The analyses performed in this study were: evaluation of hind paw edema through the plethysmometer, evaluation of thermal hyperalgesia through withdrawal test using a water container at 44.5°C (± 0.5°C), and the plantar region of the left paw which was removed for analysis of cytokines.

Our results showed that USP and USC consistently reduced paw edema, and pulsed ultrasound showed a higher significant effect than the continuous mode. Moreover, groups with irradiation frequency of five times a week presented an inhibition of the edema, and groups with frequency of three or two times a week reduced mainly hyperalgesia, in comparison with the control group. The beneficial effects of the US then seem to be associated with upregulation of anti- and pro-inflammatory mediators, such as IL-10 and IL-6, respectively.

This study provided evidence that ultrasound constitutes an important non-pharmacological intervention for the management of inflammatory and pain states.


Inflammatory mediators;  Edema;  Ultrasonic therapy;  Pain management;  Rehabilitation;  Electrophysical agents  


1 NT Ashley, ZM Weil, RJ. Nelson Inflammation: Mechanisms, costs, and natural variation Annu Rev Ecol Evol Syst, 43 (2012), pp. 385-406

2 LJ. Rather Disturbance of function (functio laesa): the legendary fifth cardinal sign of inflammation, added by Galen to the four cardinal signs of Celsus Bull New York Acad Med J Urban Heal, 47 (1971), pp. 303-322

3 R Guirro, C Abib, C. Maximo Os efeitos fisiologicos da crioterapia: uma revisao Fisioterapia Pesquisa, 6 (1999), pp. 164-170

4 A Cipriano, DB Almeida, J. Vall Profile of chronic pain patients seen in a pain outpatient setting of a major Southern Brazil’ city Most, 12 (2011), pp. 297-300

5 JHS Picavet, JSAG. Schouten Musculoskeletal pain in the Netherlands: prevalences, consequences and risk groups, the DMC(3)-study Pain, 102 (2003), pp. 167-178

6 CC Chan, S Boyce, C Brideau, et al. Pharmacology of a selective cyclooxygenase-2 inhibitor, L-745,337: A novel nonsteroidal anti-inflammatory agent with an ulcerogenic sparing effect in rat and nonhuman primate stomach J Pharmacol Exp Ther, 274 (1995), pp. 1531-1537

7 RP Gomes, E Bressan, TM Silva, MS Gevaerd, CR Tonussi, SC. Domenech Effects of one minute and ten minutes of walking activity in rats with arthritis induced by complete Freund's adjuvant on pain and edema symptoms Rev Bras Reumatol, 54 (2014), pp. 83-89

8 Y Zhang, A Shaffer, J Portanova, K Seibert, PC. Isakson Inhibition of cyclooxygenase-2 rapidly reverses inflammatory hyperalgesia and prostaglandin E2 production J Pharmacol Exp Ther, 283 (1997), pp. 1069-1075

9 A. Wright Recent concepts in the neurophysiology of pain Man Ther, 4 (1999), pp. 196-202

10 Ricardo G, et al. Efeitos do ultra-som terapêutico em edema traumático agudo em patas de ratos. 2005;3:27-35.

11 A. Cunha, N.A Da, Parizotto, B.De. Campos Vidal The effect of therapeutic ultrasound on repair of the achilles tendon (Tendo calcaneus) of the rat Ultrasound Med Biol, 27 (2001) (2001), pp. 1691-1696

12 A Wiltink, PJ Nijweide, WA Oosterbaan, RT Hekkenberg, PJM. Helders Effect of therapeutic ultrasound on endochondral ossification Ultrasound Med Biol, 21 (1995), pp. 121-127

13 WH de Brito Vieira, KA Aguiar, KM Silva, PM Canela, FS Silva, BJ. Abreu Overview of ultrasound usage trends in orthopedic and sports physiotherapy Crit Ultrasound J, 4 (2012), pp. 1-8

14 ASA Levy, O Simon, J Shelly, M. Gardener 6-Shogaol reduced chronic inflammatory response in the knees of rats treated with complete Freund's adjuvant BMC Pharmacol, 6 (2006), pp. 1-8

15 G. ter Haar Therapeutic applications of ultrasound Prog Biophys Mol Biol, 93 (2007), pp. 111-129

16 NP du Sert, V Hurst, A Ahluwalia, et al. The arrive guidelines 2.0: Updated guidelines for reporting animal research PLoS Biol, 18 (2020), pp. 1-12

17 H. Kang Sample size determination and power analysis using the G*Power software J Educ Eval Health Prof, 18 (2021), pp. 1-12

18 RC Dutra, KABS Silva, AF Bento, et al. Euphol, a tetracyclic triterpene produces antinociceptive effects in inflammatory and neuropathic pain: The involvement of cannabinoid system Neuropharmacology, 63 (2012), pp. 593-605

19 RS Abd El-Rahman, GM Suddek, NM Gameil, HA El-Kashef Protective potential of MMR vaccine against complete Freund's adjuvant-induced inflammation in rats Inflammopharmacology, 19 (2011), pp. 343-348

20 GRF Bertolini, TS da Silva, AP Ciena, EL. Artifon Comparação do ultrassom pulsado e contínuo no reparo tendíneo de ratos Fisioter Pesqui, 19 (2012), pp. 242-247

21 JB Canever, LC Fontanela, KG Hendler, et al. Viability of transverse rectus abdominis musculocutaneous flap treated with photobiomodulation and therapeutic ultrasound: an experimental model Lasers Med Sci, 37 (2022), pp. 461-470

22 YL. Hsieh Effects of ultrasound and diclofenac phonophoresis on inflammatory pain relief: Suppression of inducible nitric oxide synthase in arthritic rats Phys Ther, 86 (2006), pp. 39-49

23 Chung J, Min B, Baik EJ. Resolution of arthritis-associated. 2016;96:808-17.

24 LMS Neves, ECD Gonçalves, J Cavalli, et al. Photobiomodulation therapy improves acute inflammatory response in mice: the role of cannabinoid receptors/ATP-sensitive K+ Channel/p38-MAPK Signalling Pathway Mol Neurobiol, 55 (2018), pp. 5580-5593

25 TS Farcic, CS Baldan, CG Cattapan, NA Parizotto, SMA João, RA Casarotto, et al. Treatment time of ultrasound therapy interferes with the organization of collagen fibers in rat tendons Brazilian J Phys Ther, 17 (2013), pp. 263-271

26 J-I Chung, S Barua, BH Choi, B-H Min, H-C Han, EJ Baik, et al. Anti-inflammatory effect of low intensity ultrasound (LIUS) on complete Freund's adjuvant-induced arthritis synovium Osteoarthr Cartil, 20 (2012), pp. 314-322

27 SK Maiti, N Kumar, GR Singh, M Hoque, R Singh Ultrasound therapy in tendinous injury healing in goats J Vet Med Ser A Physiol Pathol Clin Med, 53 (2006), pp. 249-258

28 JG Coradini, TF Mattjie, GR Bernardino, et al. Comparação entre o laser de baixa potaência, ultrassom terapaêutico e associação, na dor articular em ratos wistar Rev Bras Reumatol, 54 (2014), pp. 7-12

29 F Tascioglu, S Kuzgun, O Armagan, G Ogutler Short-term effectiveness of ultrasound therapy in knee osteoarthritis J Int Med Res, 38 (2010), pp. 1233-1242

30 LS. Maximo, et al. Fisioterapia e pesquisa Revista de Fisioterapia da Universidade de Sao Paulo, 5, Curso de Fisioterapia da Faculdade de Medicina da USP (1998)

31 Van Miert ASJPAM. Van. Present concepts on the inflammatory modulators with special reference to cytokines. 2002;26:111-26.

32 T Wei, TZ Guo, WW Li, WS Kingery, JD. Clark Acute versus chronic phase mechanisms in a rat model of CRPS J. Neuroinflammation., 13 (2016), pp. 1-15

33 T Tanaka, M Narazaki, K Masuda, T. Kishimoto Regulation of IL-6 in immunity and diseases Adv Exp Med Biol, 941 (2016), pp. 79-88

34 T Tanaka, M Narazaki, T. Kishimoto IL-6 in inflammation, immunity, and disease Cold Spring Harb Perspect Biol, 6 (2014), Article a016295

35 E Lin, SE Calvano, SF. Lowry Inflammatory cytokines and cell response in surgery Surgery, 127 (2000), pp. 117-126

36 C Hung, P Huang, J Tzeng, J Wang, Y. Chen Research Report (2022)

37 S Ruohonen, M Khademi, M Jagodic, H-S Taskinen, T Olsson, M Röyttä, et al. Cytokine responses during chronic denervation J Neuroinflammation, 2 (2005), pp. 1-11

38 CMB de Oliveira, RK Sakata, AM Issy, LR Gerola, Salomão R.Citocinas e Dor Rev Bras Anestesiol, 61 (2011), pp. 255-265

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