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Nociception in a Progressive Multiple Sclerosis Model in Mice Is Dependent on Spinal TRPA1 Channel Activation

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Abstract

Central neuropathic pain is a common untreated symptom in progressive multiple sclerosis (PMS) and is associated with poor quality of life and interference with patients’ daily activities. The neuroinflammation process and mitochondrial dysfunction in the PMS lesions generate reactive species. The transient potential receptor ankyrin 1 (TRPA1) has been identified as one of the major mechanisms that contribute to neuropathic pain signaling and can be activated by reactive compounds. Thus, the goal of our study was to evaluate the role of spinal TRPA1 in the central neuropathic pain observed in a PMS model in mice. We used C57BL/6 female mice (20–30 g), and the PMS model was induced by the experimental autoimmune encephalomyelitis (EAE) using mouse myelin oligodendrocyte glycoprotein (MOG35–55) antigen and CFA (complete Freund’s adjuvant). Mice developed progressive clinical score, with motor impairment observed after 15 days of induction. This model induced mechanical and cold allodynia and heat hyperalgesia which were measured up to 14 days after induction. The hypersensitivity observed was reduced by the administration of selective TRPA1 antagonists (HC-030031 and A-967079, via intrathecal and intragastric), antioxidants (α-lipoic acid and apocynin, via intrathecal and intragastric), and TRPA1 antisense oligonucleotide (via intrathecal). We also observed an increase in TRPA1 mRNA levels, NADPH oxidase activity, and 4-hydroxinonenal (a TRPA1 agonist) levels in spinal cord samples of PMS-EAE induced animals. In conclusion, these results support the hypothesis of the TRPA1 receptor involvement in nociception observed in a PMS-EAE model in mice.

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Funding

Fellowships from the Conselho Nacional de Desenvolvimento Científico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) are received. Fellowship from the Camila Ritter from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (process #88882.427871/2019-01). Gabriela Trevisan is recipient of a fellowship from CNPq (process #306576/2017-1; https://doi.org/10.13039/501100003593), L’ORÉAL—ABC—UNESCO Para Mulheres na Ciência, 2016 and Prêmio Capes de Teses—Ciências Biológicas II, CAPES, 2014 (process #23038.006930/2014/59; https://doi.org/10.13039/501100002322).

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Authors and Affiliations

  1. Graduated Program in Pharmacology, Federal University of Santa Maria (UFSM), Avenida Roraima, Santa Maria, RS, 97105-900, Brazil

    Camila Ritter, Diéssica Padilha Dalenogare, Amanda Spring de Almeida, Vitória Loreto Pereira, Gabriele Cheiran Pereira, Caren Tatiane Antoniazzi, Sabrina Qader Kudsi & Gabriela Trevisan

  2. Graduated Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria (UFSM), Santa Maria, RS, 97105-900, Brazil

    Maria Fernanda Pessano Fialho & Sara Marchesan Oliveira

  3. Graduated Program in Pharmacology, Federal University of Santa Catarina (UFSC), Florianopolis, SC, 88040-900, Brazil

    Débora Denardin Lückemeyer & Juliano Ferreira

Authors
  1. Camila Ritter
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  2. Diéssica Padilha Dalenogare
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Contributions

All the authors discussed the results, commented on the manuscript, and approved this final version.

1) Substantial contributions to conception and design, data acquisition, analysis, and interpretation: Camila Ritter, Diéssica Padilha Dalenogare, Amanda Spring de Almeida, Vitória Loreto Pereira, Gabriele Cheiran Pereira, Maria Fernanda Pessano Fialho, Débora Denardin Lückemeyer, Caren Tatiane Antoniazzi, Sabrina Qader Kudsi, Juliano Ferreira, Sara Marchesan Oliveira, and Gabriela Trevisan.

2) Drafting and critically revising the article important intellectual content: Camila Ritter, Diéssica Padilha Dalenogare, Amanda Spring de Almeida, Vitória Loreto Pereira, Gabriele Cheiran Pereira, Maria Fernanda Pessano Fialho, Débora Denardin Lückemeyer, Caren Tatiane Antoniazzi, Sabrina Qader Kudsi, Juliano Ferreira, Sara Marchesan Oliveira, and Gabriela Trevisan.

3) Final article approval: Camila Ritter, Diéssica Padilha Dalenogare, Amanda Spring de Almeida, Vitória Loreto Pereira, Gabriele Cheiran Pereira, Maria Fernanda Pessano Fialho, Débora Denardin Lückemeyer, Caren Tatiane Antoniazzi, Sabrina Qader Kudsi, Juliano Ferreira, Sara Marchesan Oliveira, and Gabriela Trevisan.

4) Acquisition of funding and general supervision of the research group: Juliano Ferreira, Sara Marchesan Oliveira, and Gabriela Trevisan.

Corresponding author

Correspondence to Gabriela Trevisan.

Ethics declarations

The experimental procedures were approved by the Ethics Committee on Animal Use of UFSM and were carried out in accordance with Brazilian Animal Welfare Standards (protocol #7218010817/2017). The experimental protocols followed the guidelines of Animal Research Reporting In Vivo Experiments (ARRIVE) [35]. Also, experiments were performed using the current ethical guidelines for the investigation of experimental pain in conscious animals, and the minimum necessary number of animals and the intensity of noxious stimuli were used to demonstrate the consistent effects of the treatments [36].

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Ritter, C., Dalenogare, D.P., de Almeida, A.S. et al. Nociception in a Progressive Multiple Sclerosis Model in Mice Is Dependent on Spinal TRPA1 Channel Activation. Mol Neurobiol 57, 2420–2435 (2020). https://doi.org/10.1007/s12035-020-01891-9

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