Significance
We found that duloxetine has potent OCT2-inhibitory properties and can diminish excessive accumulation of oxaliplatin into DRG neurons. In addition, pre-treatment of mice with duloxetine prevented OIPN without significantly altering the plasma pharmacokinetics and antitumor properties of oxaliplatin. These results suggest that intentional inhibition of OCT2-mediated transport by duloxetine can be employed as a prevention strategy to ameliorate OIPN without compromising the effectiveness of oxaliplatin-based treatment.