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Photobiomodulation Therapy Improves Acute Inflammatory Response in Mice: the Role of Cannabinoid Receptors/ATP-Sensitive K+ Channel/p38-MAPK Signalling Pathway

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Abstract

Although photobiomodulation therapy (PBM) has been applied clinically for the treatment of pain and inflammation, wound healing, sports and soft tissue injuries, as well as to repair injured spinal cords and peripheral nerves, it remains unclear which molecular substrates (receptor) are implicated in the cellular mechanisms of PBM. Here, we reported that PBM (660 nm, 30 mW, 0.06 cm2, 50 J/cm2, plantar irradiation) significantly inhibited carrageenan-induced paw oedema, but not noxious thermal response, through positive modulation to both CB1 and CB2 cannabinoid receptors. The use of CB1 antagonist AM281 or CB2 antagonist AM630 significantly reversed the anti-inflammatory effect of PBM. Analysis of signalling pathway downstream of cannabinoid receptors activation reveals that anti-inflammatory effects of PBM depend, in great extent, on its ability to activate ATP-dependent K+ channels and p38 mitogen-activated protein kinase. Moreover, PBM therapy significantly reduced the levels of pro-inflammatory cytokine IL-6 in both paw and spinal cord, and restored the reduction of the level of anti-inflammatory cytokine IL-10 in spinal cord after carrageenan injection. Unlike the potent cannabinoid receptor agonist (WIN 55212-2), PBM did not exert any CNS-mediated effects in the tetrad assay. Finally, PBM does not reduce inflammation and noxious thermal response induced by LPS and zymosan, a TLR4 and TLR2/dectin-1 ligand, respectively. Thus, cannabinoid receptors and, possibly, the endocannabinoid system, represent an important site of action of PBM that opens the possibility of complementary and nonpsychotropic therapeutic interventions in clinical practice.

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Acknowledgements

We acknowledge grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Apoio a Pesquisa do Estado de Santa Catarina (FAPESC), Programa INCT-INOVAMED (grant 465430/2014-7), Programa de Pós-Graduação em Neurociências (PGN), and Universidade Federal de Santa Catarina (UFSC), all from Brazil. E.C.D.G. and I.S.C. are MSc and PhD students in neuroscience receiving grants from FAPESC. R.R.S. holds a postdoctoral fellowship from CNPq. A.R.S.S and R.C.D. are recipient of a research productivity fellowship from the CNPq.

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Authors and Affiliations

  1. Laboratory of Autoimmunity and Immunopharmacology, Department of Health Sciences, Center Araranguá, Universidade Federal de Santa Catarina, Araranguá, SC, 88906-072, Brazil

    Laís M. S. Neves, Elaine C. D. Gonçalves, Juliana Cavalli, Graziela Vieira, Larissa R. Laurindo, Maíra Cola & Rafael C. Dutra

  2. Laboratory of Assessment and Rehabilitation of the Locomotor Apparatus, Department of Health Sciences, Center Araranguá, Universidade Federal de Santa Catarina, Araranguá, SC, 88905-120, Brazil

    Laís M. S. Neves & Alexandre M. Marcolino

  3. Post-Graduate Program of Neuroscience, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil

    Elaine C. D. Gonçalves, Igor S. Coelho, Adair R. S. Santos & Rafael C. Dutra

  4. Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil

    Róli R. Simões, Igor S. Coelho & Adair R. S. Santos

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  1. Laís M. S. Neves
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  2. Elaine C. D. Gonçalves
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  3. Juliana Cavalli
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Correspondence to Rafael C. Dutra.

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Highlights

• Photobiomodulation therapy improves acute inflammatory response in mice.

• Cannabinoid receptors participate in the immunomodulatory actions of PBM.

• Effects of PBM depend to ATP-dependent K+ channels and p38 MAPK.

• PBM down- and up-regulate cytokines during acute inflammatory response.

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Neves, L.M.S., Gonçalves, E.C.D., Cavalli, J. 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, 5580–5593 (2018). https://doi.org/10.1007/s12035-017-0792-z

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  • DOI: https://doi.org/10.1007/s12035-017-0792-z

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