Oxaliplatin-induced neurotoxicity involves TRPM8 in the mechanism of acute hypersensitivity to cold sensation

Oxaliplatin-induced peripheral neurotoxicity (OPN) is commonly associated with peripheral hypersensitivity to cold sensations (CS) but the mechanism is unknown. We hypothesized that the transient receptor potential melastatin 8 (TRPM8), a putative cold and menthol receptor, contributes to oxaliplatin cold hypersensitivity. To determine whether the TRPM8 is involved in acute OPN, varying concentrations of menthol were topically applied to the tongues of healthy subjects (n= 40) and colorectal cancer patients (n= 36) before and after oxaliplatin administration. The minimum concentration of menthol to evoke CS at the menthol application site was determined as the CS detection threshold (CDT). In healthy subjects, the mean CDT was 0.068. Sex and age differences were not found in the CDT. In advanced colorectal cancer patients, the mean CDT significantly decreased from 0.067% to 0.028% (P= 0.0039) after the first course of oxaliplatin infusions, and this marked CS occurred in patients who had grade 1 or less neurotoxicity, and grade 2 neurotoxicity, but not in those with grade 3 neurotoxicity. Further, the mean baseline CDT in oxaliplatin-treated patients was significantly higher than that of chemotherapy-naïve patients and healthy subjects (0.151% vs. 0.066%, P= 0.0225), suggesting that acute sensory changes may be concealed by progressive abnormalities in sensory axons in severe neurotoxicity, and that TRPM8 is subject to desensitization on repeat stimulation. Our study demonstrates the feasibility of undertaking CDT test in a clinical setting to facilitate the identification of early neurotoxicity. Moreover, our results indicate potential TRPM8 involvement in acute OPN.