Skip to main content

Amitriptyline Downregulates Chronic Inflammatory Response to Biomaterial in Mice


Recent data has signaled that in addition to its therapeutic indications as antidepressant and analgesic, amitriptyline (AM) exerts anti-inflammatory effects in humans and experimental animal models of acute inflammation. We tested the hypothesis that this compound could also modulate the chronic inflammatory process induced by synthetic matrix in mice. Polyether-polyurethane sponge disks were implanted subcutaneously in 9-week-old male C57BL/6 mice. The animals received by oral gavage 5.0 mg/kg of amitriptyline for seven consecutive days in two treatment regimens. In the first series, the treatment was initiated on the day of surgery and the implants removed at day 7 post-implantation. For the assessment of the effect of amitriptyline on chronic inflammation, the treatment was initiated 7 days post-implantation and the sponge discs removed 14 after implantation. The inflammatory markers evaluated, myeloperoxidase - MPO, nitrite content, IL-6, IFN-γ, TNF-α, CXCL1 and CCL2 levels, and NF-κB transcription factor activation were reduced in implants when the treatment began 7 days post-implantation (chronic inflammation). In contrast, only mast cell number, MPO activity and activation of NF-κB pathway decreased when the treatment began soon after implantation (sub-acute inflammation) in 7-day old implants. The anti-inflammatory effects of amitriptyline described here, extend its range of actions as a potential agent able to attenuate long-term inflammatory processes.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7


  1. Xia, Brent T., Nadine Beckmann, Leah K. Winer, Young Kim, Holly S. Goetzman, Rosalie E. Veile, Erich Gulbins, Michael D. Goodman, Vanessa Nomellini, and Charles C. Caldwell. 2019. Amitriptyline treatment mitigates sepsis-induced tumor necrosis factor expression and coagulopathy. Shock 51: 356–363.

    Article  PubMed  CAS  Google Scholar 

  2. Vismari, Luciana, Glaucie J. Alves, Marcelo N. Muscará, and João Palermo-Neto. 2012. A possible role to nitric oxide in the anti-inflammatory effects of amitriptyline. Immunopharmacology and Immunotoxicology 34: 578–585.

    Article  PubMed  CAS  Google Scholar 

  3. Hajhashemi, Valiollah, Hossein Sadeghi, Mohsen Minaiyan, Ahmad Movahedian, and Ardeshir Talebi. 2010. The role of central mechanisms in the anti-inflammatory effect of amitriptyline on carrageenan-induced paw edema in rats. Clinics 65: 1183–1187.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Fattahian, Ehsan, Valiollah Hajhashemi, Mohammad Rabbani, Mohsen Minaiyan, and Parvin Mahzouni. 2016. Anti-inflammatory effect of amitriptyline on ulcerative colitis in normal and reserpine-induced depressed rats. Iranian Journal of Pharmaceutical Research 15: 125–137.

    Article  PubMed  Google Scholar 

  5. Manning, Jennifer, Rebecca Kulbida, Prerana Rai, Lindsay Jensen, Judith Bouma, Sanjay P. Singh, D. O’Malley, and Deniz M. Yilmazer-Hanke. 2014. Amitriptyline is efficacious in ameliorating muscle inflammation and depressive symptoms in the mdx mouse model of Duchenne muscular dystrophy. Experimental Physiology 99: 1370–1386.

    Article  PubMed  CAS  Google Scholar 

  6. Szałach, Łukasz P., Katarzyna A. Lisowska, and Wiesław J. Cubała. 2019. The influence of antidepressants on the immune system. Archivum Immunologiae et Therapiae Experimentalis 67. Springer International Publishing: 143–151.

  7. Ashburn, Ted T., and Karl B. Thor. 2004. Drug repositioning: Identifying and developing new uses for existing drugs. Nature Reviews Drug Discovery 3: 673–683.

    Article  PubMed  CAS  Google Scholar 

  8. Orellano, Laura Alejandra Ariza, Simone Aparecida de Almeida, Luciana Xavier Pereira, Clara Tolentino Machado, Celso Tarso Rodrigues Viana, Silvia Passos Andrade, and Paula Peixoto Campos. 2020. Implant-induced inflammatory angiogenesis is up-regulated in obese mice. Microvascular Research 131. Elsevier Inc: 104014.

  9. Viana, Celso Tarso Rodrigues, Laura Alejandra Ariza Orellano, Luciana Xavier Pereira, Simone Aparecida de Almeida, Letícia Chinait Couto, Marcela Guimarães Takahashi de Lazari, Silvia Passos Andrade, and Paula Peixoto Campos. 2018. Cytokine production is differentially modulated in malignant and non-malignant tissues in ST2-receptor deficient mice. Inflammation 41. Inflammation: 2041–2051.

  10. Belo, Andrezza V., Lucíola S. Barcelos, Mauro M. Teixeira, Mônica A.N.D. Ferreira, and Silvia P. Andrade. 2004. Differential effects of antiangiogenic compounds in neovascularization, leukocyte recruitment, VEGF production, and tumor growth in mice. Cancer Investigation 22: 723–729.

    Article  PubMed  CAS  Google Scholar 

  11. Orellano, L. A.A., S. A. Almeida, P. P. Campos, and S. P. Andrade. 2015. Angiopreventive versus angiopromoting effects of allopurinol in the murine sponge model. Microvascular Research 101. Elsevier Inc.: 118–126.

  12. Marques, Suzane M., Pollyana R. Castro, Paula P. Campos, Celso T.R. Viana, Patricia M. Parreiras, Mônica A.N. Ferreira, and Silvia P. Andrade. 2014. Genetic strain differences in the development of peritoneal fibroproliferative processes in mice. Wound Repair and Regeneration 22: 381–389.

    Article  PubMed  Google Scholar 

  13. Furgała, Anna, Robert Sałat, and Kinga Sałat. 2018. Acute cold allodynia induced by oxaliplatin is attenuated by amitriptyline. Acta Neurobiol Exp 78: 315–321.

    Article  Google Scholar 

  14. Cassini-Vieira, Puebla, Melissa de Carvalho Santuchi, Rafaela Fernandes da Silva, Remo Castro Russo, Fernanda Assis Araújo, Robson Augusto Souza dos Santos, Silvia Passos Andrade, Mauro Martins Teixeira, and Luciola Silva Barcelos. 2018. Lack of interferon-gamma attenuates foreign body reaction to subcutaneous implants in mice. Journal of Biomedical Materials Research - Part A 106: 2243–2250.

    Article  PubMed  CAS  Google Scholar 

  15. Griess, Peter. 1879. Bemerkungen zu der Abhandlung der HH. Weselsky und Benedikt Ueber einige Azoverbindungen. Berichte der Deutschen Chemischen Gesellschaft 12: 426–428.

    Article  Google Scholar 

  16. Castro, Pollyana R., Suzane M. Marques, Celso T.R. Viana, Paula P. Campos, MÔnica A.N.D. Ferreira, Lucíola S. Barcelos, and Silvia P. Andrade. 2014. Deletion of the chemokine receptor CCR2 attenuates foreign body reaction to implants in mice. Microvascular Research 95. Elsevier Inc.: 37–45.

  17. Capettini, L.S.A., S.F. Cortes, J.F. Silva, J.I. Alvarez-Leite, and V.S. Lemos. 2011. Decreased production of neuronal NOS-derived hydrogen peroxide contributes to endothelial dysfunction in atherosclerosis. British Journal of Pharmacology 164: 1738–1748.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Orellano, Laura Alejandra Ariza, Simone Aparecida de Almeida, Luciana Xavier Pereira, Letícia Chinait Couto, Marcela Guimarães Takahashi de Lazari, Celso Tarso Rodrigues Viana, Silvia Passos Andrade, and Paula Peixoto Campos. 2018. Upregulation of foreign body response in obese mice. Obesity 26: 531–539.

    Article  PubMed  CAS  Google Scholar 

  19. Goldenberg, Don, Michael Mayskiy, Christopher Mossey, Robin Ruthazer, and Christopher Schmid. 1996. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis and Rheumatism 39: 1852–1859.

    Article  PubMed  CAS  Google Scholar 

  20. Johnson, Bobby L., Teresa C. Rice, Brent T. Xia, Kirsten I. Boone, Ellis A. Green, Erich Gulbins, and Charles C. Caldwell. 2016. Amitriptyline usage exacerbates the immune suppression following burn injury. Shock 46: 541–548.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. O’Neill, Eimear, Billy Kwok, Jennifer S. Day, Thomas J. Connor, and Andrew Harkin. 2016. Amitriptyline protects against TNF-α-induced atrophy and reduction in synaptic markers via a Trk-dependent mechanism. Pharmacology Research and Perspectives 4: 1–15.

    Article  CAS  Google Scholar 

  22. Talley, Nicholas J., G. Richard Locke, Yuri A. Saito, Ann E. Almazar, Ernest P. Bouras, Colin W. Howden, Brian E. Lacy, et al. 2015. Effect of amitriptyline and escitalopram on functional dyspepsia: A multicenter, randomized controlled study. Gastroenterology 149. Elsevier Ltd: 340–349.e2.

  23. Pereira, Luciana Xavier, Celso Tarso Rodrigues Viana, Laura Alejandra Ariza Orellano, Simone Aparecida de Almeida, Marcela Guimarães Takahashi de Lazari, Letícia Chinait Couto, Anilton Cesar Vasconcelos, Silvia Passos Andrade, and Paula Peixoto Campos. 2018. Kinetics of pancreatic tissue proliferation in a polymeric platform in mice. Pancreatology 18: 221–229.

    Article  PubMed  CAS  Google Scholar 

  24. Soehnlein, Oliver, Sabine Steffens, Andrés Hidalgo, and Christian Weber. 2017. Neutrophils as protagonists and targets in chronic inflammation. Nature Reviews Immunology 17. Nature Publishing Group: 248–261.

  25. Stewart, Darryl, and Alistair Nichol. 2018. Inflammation, immunity and allergy. Anaesthesia and Intensive Care Medicine 19. Elsevier Ltd: 534–539. doi:

  26. Medzhitov, Ruslan. 2008. Origin and physiological roles of inflammation. Nature 454: 428–435.

    Article  PubMed  CAS  Google Scholar 

  27. Ahmed, Afsar U. 2011. An overview of inflammation: Mechanism and consequences. Frontiers of Biology in China 6: 274–281.

    Article  CAS  Google Scholar 

  28. Saraswati, Sarita, Abdulqader A. Alhaider, and Abdelgalil M. Abdelgadir. 2018. Costunolide suppresses an inflammatory angiogenic response in a subcutaneous murine sponge model. Apmis 126: 257–266.

    Article  PubMed  CAS  Google Scholar 

  29. Maggio, Nicola, and Andreas Vlachos. 2018. Tumor necrosis factor (TNF) modulates synaptic plasticity in a concentration-dependent manner through intracellular calcium stores. Journal of Molecular Medicine 96. Journal of Molecular Medicine: 1039–1047.

  30. Popa, Calin, Mihai G. Netea, Piet L.C.M. Van Riel, Jos W.M. Van Der Meer, and Anton F.H. Stalenhoef. 2007. The role of TNF-α in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. Journal of Lipid Research 48: 751–752.

    Article  PubMed  CAS  Google Scholar 

  31. Guabiraba, Rodrigo, Remo C. Russo, Amanda M. Coelho, Mônica A.N.D. Ferreira, Gabriel A.O. Lopes, Ariane K.C. Gomes, Silvia P. Andrade, Luciola S. Barcelos, and Mauro M. Teixeira. 2013. Blockade of cannabinoid receptors reduces inflammation, leukocyte accumulation and neovascularization in a model of sponge-induced inflammatory angiogenesis. Inflammation Research 62: 811–821.

    Article  PubMed  CAS  Google Scholar 

  32. Salem, Hesham Aly, and Walaa Wadie. 2017. Effect of niacin on inflammation and angiogenesis in a murine model of ulcerative colitis. Scientific Reports 7. Springer US: 1–8.

  33. Chintakuntlawar, Ashish V., and James Chodosh. 2009. Chemokine CXCL1/KC and its receptor CXCR2 are responsible for neutrophil chemotaxis in adenoviral keratitis. Journal of Interferon and Cytokine Research 29: 657–666.

    Article  PubMed  CAS  Google Scholar 

  34. Kaufmann, Manuel, Michael Schlossbauer, Ute Hubauer, Stefan Stadler, Marcus Fischer, Stefan Wallner, Julian Hupf, Markus Zimmermann, Evelyn Orso, Florian Zeman, Andreas Luchner, Lars Maier, and Carsten Jungbauer. 2020. N-acety-b-D-glucosaminidase: A potential biomarker for early detection of acute kidney injury in acute chest pain. Nephrology 25: 135–143.

    Article  PubMed  CAS  Google Scholar 

  35. Avula, M. N., A. N. Rao, L. D. McGill, D. W. Grainger, and F. Solzbacher. 2014. Foreign body response to subcutaneous biomaterial implants in a mast cell-deficient Kitw-Sh murine model. Acta Biomaterialia 10. Acta Materialia Inc.: 1856–1863. doi:

  36. Hayden, Matthew S., and Sankar Ghosh. 2012. NF-κB, the first quarter-century: Remarkable progress and outstanding questions. Genes and Development 26: 203–234.

    Article  PubMed  CAS  Google Scholar 

  37. Lawrence, Toby. 2009. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harbor Perspectives in Biology 1: 1–11.

    Article  CAS  Google Scholar 

  38. Gurgel, José Alves, Roberto César Pereira Lima-Júnior, Cristiano Oliveira Rabelo, Breno Bezerra Gomes Pinho Pessoa, Gerly Anne Castro Brito, and Ronaldo Albuquerque Ribeiro. 2013. Amitriptyline, clomipramine, and maprotiline attenuate the inflammatory response by inhibiting neutrophil migration and mast cell degranulation. Revista Brasileira de Psiquiatria 35: 387–392.

    Article  PubMed  Google Scholar 

  39. Clemons, Anthony, Magdalini Vasiadi, Duraisamy Kempuraj, Taxiarchis Kourelis, Gregory Vandoros, and Theoharis C. Theoharides. 2011. Amitriptyline and prochlorperazine inhibit proinflammatory mediator release from human mast cells: Possible relevance to chronic fatigue syndrome. Journal of Clinical Psychopharmacology 31: 385–387.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Kandil, Esraa A., Noha F. Abdelkader, Bahia M. El-Sayeh, and Samira Saleh. 2016. Imipramine and amitriptyline ameliorate the rotenone model of Parkinson’s disease in rats. Neuroscience 332. IBRO: 26–37. doi:

  41. Xia, Brent T., Nadine Beckmann, Leah K. Winer, Amanda M. Pugh, Timothy A. Pritts, Vanessa Nomellini, Erich Gulbins, and Charles C. Caldwell. 2019. Amitriptyline reduces inflammation and mortality in a murine model of sepsis. Cellular Physiology and Biochemistry 52: 565–579.

    Article  PubMed  CAS  Google Scholar 

  42. Meiners, Jana, Vittoria Palmieri, Robert Klopfleisch, Jana Fabienne Ebel, Lukasz Japtok, Fabian Schumacher, Ayan Mohamud Yusuf, Katrin A. Becker, Julia Zöller, Matthias Hose, Burkhard Kleuser, Dirk M. Hermann, Richard N. Kolesnick, Jan Buer, Wiebke Hansen, and Astrid M. Westendorf. 2019. Intestinal acid sphingomyelinase protects from severe pathogen-driven colitis. Frontiers in Immunology 10: 1–14.

    Article  CAS  Google Scholar 

Download references


The western blots images shown in this work were obtained using Typhoon™ FLA 9000 scanner equipment in the Centro de Aquisição e Processamento de Imagens (CAPI-ICB/UFMG).


The Brazilian Research Support from FAPEMIG and CNPq funded this project (grant number: APQ-01140-13 and 448853/2014-0).

Author information

Authors and Affiliations



All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Karina Scheuermann, Laura Alejandra Ariza Orellano, Luciano Santos Aggum Capettini, Silvia Passos Andrade, and Paula Peixoto Campos. The first draft of the manuscript was written by Paula Peixoto Campos and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Paula Peixoto Campos.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Scheuermann, K., Orellano, L.A.A., Viana, C.T.R. et al. Amitriptyline Downregulates Chronic Inflammatory Response to Biomaterial in Mice. Inflammation 44, 580–591 (2021).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • amitriptyline
  • anti-inflammatory
  • sponge model
  • chronic inflammation