Brazilian Journal of Pain
https://brjp.org.br/article/doi/10.5935/2595-0118.20210003
Brazilian Journal of Pain
Original Article

The profile of dexamethasone combined with transcranial direct current stimulation in rats submitted to an arthritis model

O perfil da dexametasona combinada com estimulação transcraniana por corrente contínua em ratos submetidos a um modelo de artrite

Gabriela Laste; Bettega Costa Lopes; Liciane Fernandes Medeiros; Felipe Fregni; Wolnei Caumo; Iraci L S Torres

http://dx.doi.org/10.5935/2595-0118.20210003 BrJP, vol.4, n1, p.2-8, 2021
PDF English
PDF Português
SciELO
Downloads: 0
Views: 406

Abstract

BACKGROUND AND OBJECTIVES: To pursue safer and more effective treatments for rheumatoid arthritis, the effect of dexamethasone treatment (DEX, 0.25mg/kg) combined with transcranial direct current stimulation (tDCS) in the behavior and neurochemical parameters of arthritic rats was evaluated.

METHODS: Thirty-six Wistar rats were divided into four groups: control+DEX (CTRL+DEX), arthritis+DEX (RA+DEX), arthritis+DEX+sham-tDCS (RA+DEX+sham-tDCS) and arthritis+DEX+tDCS (RA+DEX+tDCS). The arthritic model (RA) was induced by complete Freund’s adjuvant (CFA) paw administration. Paw edema and mechanical allodynia were assessed by plethysmometer and von Frey apparatus, respectively. Fourteen days after the CFA injection, rats received the treatment for eight days (DEX and/or tDCS). Behavioral parameters were measured with the Open-Field test. ELISA was used to evaluate hippocampal and spinal cord tumor necrosis factor (TNF-α) levels, cerebral cortex and brainstem BDNF levels.

RESULTS: In pre-treatment measurements, arthritic rats presented an increase in joint swelling and mechanical allodynia when compared to the control group, confirming chronic pain establishment. A slight antinociceptive effect of dexamethasone combined with tDCS in the pain model was observed. The pain model significantly induced an increase in the grooming behavior and a reduction in the spinal cord and hippocampal TNF-α levels; these effects were reverted in the sham- and active-tDCS-treated rats. However, no effects of DEX or tDCS were observed in the BDNF levels in the cerebral cortex and brainstem.

CONCLUSION: Despite the small effect observed, tDCS treatment cannot be discarded as a non-pharmacological adjuvant technique for inflammatory chronic pain treatment.

Keywords

Cerebral cortex, Hippocampus, Mechanical allodynia, Spinal cord

Resumo

JUSTIFICATIVA E OBJETIVOS: Para investigar métodos mais seguros e eficazes para o manejo da artrite reumatoide, avaliou-se o efeito do tratamento com dexametasona (DEX, 0,25mg/kg) combinado com estimulação transcraniana por corrente contínua (ETCC) sobre parâmetros comportamentais e bioquímicos de ratos submetidos a um modelo de artrite reumatoide.

MÉTODOS: Trinta e seis ratos Wistar foram alocados em 4 grupos: controle+DEX (CTRL+DEX), artrite+DEX (AR+DEX), artrite+DEX+sham-ETCC (AR+DEX+sham-ETCC) e artrite+DEX+ETCC (AR+DEX+ETCC). O modelo de artrite foi induzido pela administração de complete Freund’s adjuvant (CFA) na pata. Edema na pata e a alodínia mecânica foram avaliadas por pletismômetro e teste de von Frey, respectivamente. 14 dias após injeção de CFA, ratos foram tratados por 8 dias (DEX e/ou ETCC). Atividade locomotora foi avaliada pelo teste do campo aberto. TNF-alfa (hipocampo e medula espinal) e BDNF (córtex e tronco) foram mensurados por ELISA.

RESULTADOS: Nas medições pré-tratamento, ratos com artrite exibiram aumento de o inchaço articular e alodínia mecânica comparados ao grupo controle, confirmando o estabelecimento de modelo de dor crônica. Também se observou discreto efeito antinociceptivo da dexametasona combinada com ETCC no modelo de artrite. O modelo de dor induziu um aumento no comportamento de grooming e reduziu os níveis de TNF-alfa no hipocampo; estes efeitos foram revertidos nos grupos sham- e ETCC ativo. Entretanto, não foram observados efeitos da DEX ou ETCC nos níveis de BDNF no córtex cerebral ou no tronco encefálico.

CONCLUSÃO: Apesar dos discretos efeitos observados, não se pode descartar a ETCC como uma abordagem terapêutica não farmacológica para o manejo da dor crônica inflamatória na artrite reumatoide.

Palavras-chave

Alodínia, Córtex cerebral, Hipocampo, Medula espinal

References

May A. Chronic pain may change the structure of the brain. Pain. 2008;137(1):7-15.

Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA. 2018;320(13):1369-72.

Wright HL, Mewar D, Bucknall RC, Edwards SW, Moots RJ. Synovial fluid IL-6 concentrations associated with positive response to tocilizumab in an RA patient with failed response to anti-TNF and rituximab. Rheumatology (Oxford). 2015;54(4):743-4.

Majithia V, Geraci SA. Rheumatoid arthritis: diagnosis and management. Am J Med. 2007;120(11):936-9.

Trombetta AC, Meroni M, Cutolo M. Steroids and autoimmunity. Front Horm Res. 2017;48:121-32.

Rana AK, Li Y, Dang Q, Yang F. Monocytes in rheumatoid arthritis: Circulating precursors of macrophages and osteoclasts and, their heterogeneity and plasticity role in RA pathogenesis. Int Immunopharmacol. 2018;65:348-59.

Spezia Adachi LN, Caumo W, Laste G, Fernandes Medeiros L, Ripoll Rozisky J, de Souza A. Reversal of chronic stress-induced pain by transcranial direct current stimulation (tDCS) in an animal model. Brain Res. 2012;1489:17-26.

Laste G, Caumo W, Adachi LN, Rozisky JR, de Macedo IC, Filho PR. After-effects of consecutive sessions of transcranial direct current stimulation (tDCS) in a rat model of chronic inflammation. Exp Brain Res. 2012;221(1):75-83.

Cioato SG, Medeiros LF, Marques Filho PR, Vercelino R, de Souza A, Scarabelot VL. Long-lasting effect of transcranial direct current stimulation in the reversal of hyperalgesia and cytokine alterations induced by the neuropathic pain model. Brain Stimul. 2016;9(2):209-17.

Lopes BC, Medeiros LF, Silva de Souza V, Cioato SG, Medeiros HR, Regner GG. Transcranial direct current stimulation combined with exercise modulates the inflammatory profile and hyperalgesic response in rats subjected to a neuropathic pain model: Long-term effects. Brain Stimul. 2020;13(3):774-82.

Rossato MF, Hoffmeister C, Trevisan G, Bezerra F, Cunha TM, Ferreira J. Monosodium urate crystal interleukin-1β release is dependent on Toll-like receptor 4 and transient receptor potential V1 activation. Rheumatology (Oxford). 2020;59(1):233-42.

Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci USA. 2016;113(29):8284-9.

Stagg CJ, Antal A, Nitsche MA. Physiology of transcranial direct current stimulation. J ECT. 2018;34(3):144-52.

Kubis N. Non-invasive brain stimulation to enhance post-stroke recovery. Front Neural Circuits. 2016;10:56.

Lefaucheur J-P, Antal A, Ayache SS, Benninger DH, Brunelin J, Cogiamanian F. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clin Neurophysiol. 2017;128(1):56-92.

Schoellmann A, Scholten M, Wasserka B, Govindan RB, Krüger R, Gharabaghi A. Anodal tDCS modulates cortical activity and synchronization in Parkinson's disease depending on motor processing. NeuroImage Clin. 2019;22:101689.

Fregni F, Gimenes R, Valle AC, Ferreira MJ, Rocha RR, Natalle L. A randomized, sham-controlled, proof of principle study of transcranial direct current stimulation for the treatment of pain in fibromyalgia. Arthritis Rheumatol. 2006;54(12):3988-98.

Zortea M, Ramalho L, Alves RL, Alves CFDS, Braulio G, Torres ILDS. Transcranial direct current stimulation to improve the dysfunction of descending pain modulatory system related to opioids in chronic non-cancer pain: an integrative review of neurobiology and meta-analysis. Front Neurosci. 2019;13:1218.

Rueger MA, Keuters MH, Walberer M, Braun R, Klein R, Sparing R. Multi-session transcranial direct current stimulation (tDCS) Elicits inflammatory and regenerative processes in the rat brain. PLoS One. 2012;7(8).

Spezia Adachi LN, Quevedo AS, de Souza A, Scarabelot VL, Rozisky JR, de Oliveira C. Exogenously induced brain activation regulates neuronal activity by top-down modulation: conceptualized model for electrical brain stimulation. Exp Brain Res. 2015;233(5):1377-89.

Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: The arrive guidelines for reporting animal research. Animals. 2013;4(1):35-44.

Koch DA, Silva RB, de Souza AH, Leite CE, Nicoletti NF, Campos MM. Efficacy and gastrointestinal tolerability of ML3403, a selective inhibitor of p38 MAP kinase and CBS-3595, a dual inhibitor of p38 MAP kinase and phosphodiesterase 4 in CFA-induced arthritis in rats. Rheumatology. 2014;53(3):425-32.

Laste G, Ripoll Rozisky J, de Macedo IC, Souza Dos Santos V, Custódio De Souza IC, Caumo W. Spinal cord brain-derived neurotrophic factor levels increase after dexamethasone treatment in male rats with chronic inflammation. Neuroimmunomodulation. 2013;20(2):119-25.

Vivancos GG, Verri Jr WA, Cunha TM, Schivo IR, Parada CA, Cunha FQ. An electronic pressure-meter nociception paw test for rats. Braz J Med Biol Res. 2004;37(3):391-9.

Chen Y, Boettger MK, Reif A, Schmitt A, Üçeyler N, Sommer C. Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice. Mol Pain. 2010;6:13.

Helyes Z, Szabó A, Németh J, Jakab B, Pintér E, Bánvölgyi A. Antiinflammatory and analgesic effects of somatostatin released from capsaicin-sensitive sensory nerve terminals in a Freund's adjuvant-induced chronic arthritis model in the rat. Arthritis Rheum. 2004;50(5):1677-85.

Millan MJ. The induction of pain: an integrative review. Progr Neurobiol. 1999;57(1):1-164.

Wang Y, Zhao R, Gu Z, Dong C, Guo G, Li L. Effects of glucocorticoids on osteoporosis in rheumatoid arthritis: a systematic review and meta-analysis. Osteoporos Int. 2020;31(8):1401-9.

Oliveira PG, Brenol CV, Edelweiss MI, Meurer L, Brenol JCT, Xavier RM. Subcutaneous inflammation (panniculitis) in tibio-tarsal joint of rats inoculated with complete Freund's adjuvant. Clin Exp Med. 2007;7(4):184-7.

Laste G, Souza ICC, Santos VSD, Caumo W, Torres ILS. Histopathological changes in three variations of wistar rat adjuvant-induced arthritis model. Int J Pharmaceutical Res Schol. 2014;3(2):780-90.

Zhang L, Berta T, Xu Z-Z, Liu T, Park JY, Ji RR. TNF-α contributes to spinal cord synaptic plasticity and inflammatory pain: distinct role of TNF receptor subtypes 1 and 2. Pain. 2011;152(2):419-27.

Park CK, Lü N, Xu ZZ, Liu T, Serhan CN, Ji RR. Resolving TRPV1- and TNF-α-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J Neurosci. 2011;31(42):15072-85.

Can M, Gul S, Bektas S, Hanci V, Acikgoz S. Effects of dexmedetomidine or methylprednisolone on inflammatory responses in spinal cord injury. Acta Anaesthesiol Scand. 2009;53(8):1068-72.

Parent AJ, Beaudet N, Beaudry H, Bergeron J, Bérubé P, Drolet G. Increased anxiety-like behaviors in rats experiencing chronic inflammatory pain. Behavl Brain Rese. 2012;229(1):160-7.

Seibenhener ML, Wooten MC. Use of the open field maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp. 2015.

Filho PR, Vercelino R, Cioato SG, Medeiros LF, de Oliveira C, Scarabelot VL. Transcranial direct current stimulation (tDCS) reverts behavioral alterations and brainstem BDNF level increase induced by neuropathic pain model: long-lasting effect. Progr Neuropsychopharmacol Biol Psychiatry. 2016;64:44-51.

Caparroz-Assef SM, Bersani-Amado CA, Kelmer-Bracht AM, Bracht A, Ishii-Iwamoto EL. The metabolic changes caused by dexamethasone in the adjuvant-induced arthritic rat. Mol Cell Biochem. 2007;302(1-2):87-98.

Lurie S, Kuhn C, Bartolome J, Schanberg S. Differential sensitivity to dexamethasone suppression in an animal model of the DST. Biol Psychiatry. 1989;26(1):26-34.

Earp JC, Pyszczynski NA, Molano DS, Jusko WJ. Pharmacokinetics of dexamethasone in a rat model of rheumatoid arthritis. Biopharm Drug Dispos. 2008;29(6):366-72.

Submitted date:
09/17/2020

Accepted date:
12/16/2020

60873693a953956be559b263 brjp Articles
2595-3192 (Electronic) 2595-0118 (Printed)
BrJP ©2024 All rights reserved.

BrJP

Share this page
Page Sections