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Behavioral, Electrophysiological, and Histological Characterization of a New Rat Model for Neoadjuvant Chemotherapy–Induced Neuropathic Pain: Therapeutic Potential of Duloxetine and Allopregnanolone Concomitant Treatment

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Abstract

Neoadjuvant chemotherapy is beneficial against breast cancer, but its toxicity causes painful chemotherapy-induced neuropathy which decreases seriously patients’ quality of life. Development of effective therapy is crucial because current treatments are unsatisfactory. While animal models have previously been produced to test therapeutics against chemotherapy-induced neuropathy, neuropathic pain evoked by the frequently used neoadjuvant-chemotherapy involving sequentially epirubicin and docetaxel has never been modeled. Duloxetine, a serotonin/noradrenalin-reuptake inhibitor, is recommended against chemotherapy-induced neuropathy, but duloxetine exhibits controversial and adverse effects requiring its discontinuation. Here, we firstly produced and characterized a rat model for epirubicin-docetaxel induced painful neuropathy by using behavioral methods including the von Frey filament and the acetone tests that were combined with electrophysiological assessment of peripheral nerve functions and immunohistological analyzes. Using this model, we investigated the possibility to improve duloxetine efficacy and safety by combining its low doses (2 mg/kg/2 days) with the potent neuroprotector allopregnanolone (4 mg/kg/2 days). This concomitant therapy was more effective than separate duloxetine or allopregnanolone treatment to prevent epirubicin-docetaxel induced cold allodynia, mechanical allodynia/hyperalgesia, peripheral nerve functional/electrophysiological, and histological alterations. Interestingly, duloxetine-allopregnanolone concomitant treatment (but not duloxetine) also prevented epirubicin-docetaxel induced Schwann cell dedifferentiation and related macrophage (CD11b/c-positive cells) infiltration in sciatic nerves. Altogether, our results suggest that duloxetine and allopregnanolone concomitant treatment may represent a promising therapeutic option to counteract efficiently painful neuropathy or epirubicin-docetaxel evoked peripheral nerve tissue damages and dysfunctions.

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Data Availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was financially supported by INSERM, CNRS, Université de Strasbourg, and the Association Ti’Toine de Normandie.

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Authors and Affiliations

  1. Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Bâtiment 3 de la Faculté de Médecine, Université de Strasbourg, 11 rue Humann, 67000, Strasbourg, France

    Célia Matta, Laurence Meyer, Ayikoe-Guy Mensah-Nyagan & Omar Taleb

Authors
  1. Célia Matta
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  2. Laurence Meyer
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  3. Ayikoe-Guy Mensah-Nyagan
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  4. Omar Taleb
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Contributions

CM performed behavioral, biochemical, and some of the histological experiments. LM analyzed behavioral data, performed histological experiments on dorsal root ganglia, and contributed to the manuscript editing. OT designed electrophysiological, biochemical, and histological studies; performed experiments; analyzed results; and wrote the manuscript. AGMN designed the whole research project and experimental strategies, analyzed all the data, and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ayikoe-Guy Mensah-Nyagan.

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The authors declare that they have no conflict of interest.

Ethical Statement

Animal care and manipulations were performed according to The European Community Council Directives (2010/63/UE) and under the supervision of authorized investigators. All experiments were performed minimizing the number of animals used and their suffering in accordance with the Alsace Department of Veterinary Public Health Guide for the Care and Use of Laboratory Animals (Agreement number E-67-482-35). A national project authorization was delivered by the French Ministry of Higher Education and Research and by CREMEAS a local ethical committee (Project authorization number APAFIS#9373-201605111128746v2). The experiments also followed the International Association for the Study of Pain ethical guidelines.

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Ayikoe-Guy Mensah-Nyagan and Omar Taleb have equal contribution as last authors.

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Matta, C., Meyer, L., Mensah-Nyagan, AG. et al. Behavioral, Electrophysiological, and Histological Characterization of a New Rat Model for Neoadjuvant Chemotherapy–Induced Neuropathic Pain: Therapeutic Potential of Duloxetine and Allopregnanolone Concomitant Treatment. Neurotox Res 38, 145–162 (2020). https://doi.org/10.1007/s12640-020-00176-2

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