Role of TRPM8 in the mechanism of acute hyperexcitability to cold sensation associated with oxaliplatin-induced neurotoxicity.

Abstract

e13580 Background: Oxaliplatin is commonly associated with peripheral neurotoxicity, particularly cold-induced paresthesia. However, the mechanisms that lead to these enhanced cold sensations in oxaliplatin-treated patients are unknown. Menthol induces cold sensations by interacting with the peripheral cold receptor, transient receptor potential melastatin 8 (TRPM8). Therefore, we hypothesized that TRPM8 may be involved in the mechanisms of acute oxaliplatin-induced peripheral neurotoxicity. Methods: To test this hypothesis, varying concentrations of L-menthol (from 0.0005 % to 0.5 %) were topically applied to the tongues of healthy subjects and colorectal cancer patients before and after they were treated with oxaliplatin and then the cold sensations were examined. All subjects experienced a cold sensation at the menthol application site and the intensity of the cold sensation detection threshold (CDT) was obtained. The CDT was calculated based on the menthol concentration. Results: In healthy subjects, the mean (± SD) CDT was 0.07 (± 0.025) %, and the CDT was not less than 0.005%. In colorectal cancer patients, CDT significantly decreased from 0.069 (± 0.043) % to 0.031 (± 0.023) % (p = 0.0058) after the patients received oxaliplatin infusions, and this enhanced cold sensation also occurred (from 0.186 [± 0.048] % to 0.077 [± 0.026] %; p = 0.0014) in patients who had previously received oxaliplatin (median, 320 mg/m2; range, 170-2,450 mg/m2). Conclusions: These findings indicate that TRPM8 is involved in acute hyperexcitability to cold sensation and contributes to acute oxaliplatin-induced neurotoxicity. Furthermore, these results indicate that TRPM8 is a potential target to understand the oxaliplatin-induced neurotoxicity as well as a good candidate for a prognostic marker of neurotoxicity severity score, although the methodology using menthol has not been firmly established.