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

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.

Keywords: Chemotherapy-induced painful neuropathy; Duloxetine; Neoadjuvant chemotherapy; Neuroprotection.