A novel model of paclitaxel-induced peripheral neuropathy produces a clinically relevant phenotype in mice

Abstract

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 cumulative PTX dose. Patients experiencing PIPN may reduce the dosage of chemotherapy or halt treatment due to this 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, this does not mirror the clinical dosing regimen or the patient experience of CIPN. In this study, we conduct a comprehensive and longitudinal behavioral profile of our novel model of PIPN in mice where three consecutive cycles of PTX (4 mg/kg, 4 doses/cycle) are given to mimic the clinical administration. Repeated cycles of PTX caused long-lasting mechanical and cold hypersensitivity in male and female C57Bl/6J mice that mirrors clinical observations of persistent CIPN without causing detrimental effects to rodent overall health, normal rodent behavior, or motor function. Our findings support the use of this translational model to facilitate a better 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.