Characterization of Cancer-Induced Nociception in a Murine Model of Breast Carcinoma

  • Amanda Spring de Almeida
  • Flávia Karine Rigo
  • Samira Dal-Toé De Prá
  • Alessandra Marcone Milioli
  • Diéssica Padilha Dalenogare
  • Gabriele Cheiran Pereira
  • Camila dos Santos Ritter
  • Diulle Spat Peres
  • Caren Tatiane de David Antoniazzi
  • Carolina Stein
  • Rafael Noal Moresco
  • Sara Marchesan Oliveira
  • Gabriela TrevisanEmail author
Original Research


Severe and poorly treated pain often accompanies breast cancer. Thus, novel mechanisms involved in breast cancer-induced pain should be investigated. Then, it is necessary to characterize animal models that are reliable with the symptoms and progression of the disease as observed in humans. Explaining cancer-induced nociception in a murine model of breast carcinoma was the aim of this study. 4T1 (104) lineage cells were inoculated in the right fourth mammary fat pad of female BALB/c mice; after this, mechanical and cold allodynia, or mouse grimace scale (MGS) were observed for 30 days. To determine the presence of bone metastasis, we performed the metastatic clonogenic test and measure calcium serum levels. At 20 days after tumor induction, the antinociceptive effect of analgesics used to relieve pain in cancer patients (acetaminophen, naproxen, codeine or morphine) or a cannabinoid agonist (WIN 55,212-2) was tested. Mice inoculated with 4T1 cells developed mechanical and cold allodynia and increased MGS. Bone metastasis was confirmed using the clonogenic assay, and hypercalcemia was observed 20 days after cells inoculation. All analgesic drugs reduced the mechanical and cold allodynia, while the MGS was decreased only by the administration of naproxen, codeine, or morphine. Also, WIN 55,212-2 improved all nociceptive measures. This pain model could be a reliable form to observe the mechanisms of breast cancer-induced pain or to observe the efficacy of novel analgesic compounds.


Allodynia Opioids NSAIDs Cannabinoid Bone metastasis WIN 55,212-2 



Fellowships from the Conselho Nacional de Desenvolvimento Científico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) are also acknowledged. Amanda Spring de Almeida is recipient of a PhD fellowship from CAPES. Gabriela Trevisan is recipient of a fellowship from CNPq [process #306576/2017-1].

Author 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: Amanda Spring de Almeida, Flávia Karine Rigo, Samira Dal-Toé De Prá, Alessandra Marcone Milioli, Diéssica Padilha Dalenogare, Gabriele Cheiran Pereira, Camila dos Santos Ritter, Diulle Spat Peres, Caren Tatiane de David Antoniazzi, Carolina Stein, Rafael Noal Moresco, Sara Marchesan Oliveira, Gabriela Trevisan. (2) Drafting and critically revising the article important intellectual content: Amanda Spring de Almeida, Flávia Karine Rigo, Samira Dal-Toé De Prá, Alessandra Marcone Milioli, Diéssica Padilha Dalenogare, Gabriele Cheiran Pereira, Camila dos Santos Ritter, Diulle Spat Peres, Caren Tatiane de David Antoniazzi, Carolina Stein, Rafael Noal Moresco, Sara Marchesan Oliveira, Gabriela Trevisan. (3) Final article approval: Amanda Spring de Almeida, Flávia Karine Rigo, Samira Dal-Toé De Prá, Alessandra Marcone Milioli, Diéssica Padilha Dalenogare, Gabriele Cheiran Pereira, Camila dos Santos Ritter, Diulle Spat Peres, Caren Tatiane de David Antoniazzi, Carolina Stein, Rafael Noal Moresco, Sara Marchesan Oliveira, Gabriela Trevisan. (4) Acquisition of funding and general supervision of the research group: Rafael Noal Moresco, Sara Marchesan Oliveira, Gabriela Trevisan.


National Research Council of Brazil (CNPq; #422376/2016-7) supported this work.

Compliance with Ethical Standards

The experiments of this manuscript comply with the current laws of the country in which they were performed.

Conflict of interest

The authors declare no potential conflicts of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Amanda Spring de Almeida
    • 1
  • Flávia Karine Rigo
    • 2
  • Samira Dal-Toé De Prá
    • 2
  • Alessandra Marcone Milioli
    • 2
  • Diéssica Padilha Dalenogare
    • 1
  • Gabriele Cheiran Pereira
    • 1
  • Camila dos Santos Ritter
    • 1
  • Diulle Spat Peres
    • 1
  • Caren Tatiane de David Antoniazzi
    • 1
  • Carolina Stein
    • 3
  • Rafael Noal Moresco
    • 3
  • Sara Marchesan Oliveira
    • 4
  • Gabriela Trevisan
    • 1
    • 2
    • 5
    Email author
  1. 1.Programa de Pós-Graduação em FarmacologiaUniversidade Federal de Santa Maria (UFSM)Santa MariaBrazil
  2. 2.Programa de Pós-Graduação em Ciências da SaúdeUniversidade do Extremo Sul Catarinense (Unesc)CriciúmaBrazil
  3. 3.Programa de Pós-Graduação em Ciências FarmacêuticasUniversidade Federal de Santa Maria (UFSM)Santa MariaBrazil
  4. 4.Programa de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaUniversidade Federal de Santa Maria (UFSM)Santa MariaBrazil
  5. 5.Programa de Pós-Graduação em FarmacologiaUniversidade Federal de Santa Maria (UFSM)Santa MariaBrazil

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