A Novel Model of Paclitaxel-Induced Peripheral Neuropathy Produces aClinically Relevant Phenotype in Mice

INTRODUCTION: One of the most common adverse side effects of chemotherapeutics is chemotherapy-induced peripheral neuropathy (CIPN). Paclitaxel, a highly effective chemotherapeutic, is associated with a high incidence of paclitaxel-induced peripheral neuropathy (PIPN) that persists for over a year in 64% of patients and worsens with increasing cumulative paclitaxel dose. Patients experiencing PIPN may reduce the dosage of chemotherapy or halt treatment due to pain. Current preclinical models have improved our understanding of PIPN but have been ineffective in generating translational therapeutic options. These models administer a single cycle of PTX to induce a PIPN phenotype of mechanical and cold hypersensitivity that resolves within 28 days. However, these models do not mirror the clinical dosing regimen or generate a PIPN phenotype that reflects the patient experience. We developed a novel model of PIPN in rodents where repeated cycles of PTX are administered to mimic the clinical dosing regimen. Our aim in this study was to conduct a comprehensive and longitudinal behavioral profile of our novel model of PIPN in mice. METHODS: We used our novel model in which three consecutive cycles of PTX (4 mg/kg, 4 doses per cycle) were administered to mimic the clinical dosing regimen in male and female C57Bl/6J mice. We assessed evoked responses, spontaneous behaviors, and normal rodent behaviors throughout PTX administration. RESULTS: Repeated cycles of PTX caused long-lasting mechanical and cold hypersensitivity in male and female mice. PTX administration did not impact overall health, normal rodent behavior, proprioception, or motor function. DISCUSSION: We show that administration of three consecutive PTX cycles generates a clinically relevant phenotype of PIPN, where repeated PTX cycles increase the duration of mechanical and cold hypersensitivity. CONCLUSION: Our findings support the use of this translational model to facilitate an improved understanding of PIPN and the development of effective treatment options. Improved pain management will enable the completion of cancer treatment, decrease health care expenditure, decrease mortality, and improve the quality of life for cancer patients and survivors.