ACUTE OXALIPLATIN EXPOSURE INDUCES AN HYPEREXCITABLE STATE IN TRPM8-EXPRESSING COLD THERMORECEPTORS

Oxaliplatin (OXA), a drug used in colorectal cancer treatment, causes serious side effects known as chemotherapy-induced peripheral neuropathy (CIPN), characterized by rapid onset of cold and mechanical hypersensitivity. To investigate the role of TRPM8-expressing neurons in acute CIPN, we performed calcium imaging and patch-clamp recordings on TRPM8-BAC-EYFP transgenic mouse cultured DRG neurons following a 1-h incubation with 50 µM OXA. Compared to vehicle (VEH), OXA incubation enhanced calcium signals (n=19-32) in response to cold (from 0.39 ± 0.04 to 0.97 ± 0.24 A.U.), menthol (from 0.69 ± 0.08 to 2.11 ± 0.41 A.U.) and menthol+cold (from 0.44 ± 0.09 to 1.26 ± 0.25 A.U.). In electrophysiological experiments, OXA incubation, compared to VEH, caused a marked hyperexcitability state, including a decrease in rheobase current (from 19.1 ± 4.6 pA to 10.8 ± 1.7 pA) and an increase in the firing frequency to a 200 pA positive current pulse (from 23.5 ± 6.2 Hz to 38.9 ± 7.8 Hz) (n=5-15). Application of TRPM8 agonists also increased the firing frequency response to cold (from 4.2 ± 0.8 Hz to 9.2 ± 2.1 Hz) and menthol+cold (from 8.3 ± 1.2 Hz to 14.4 Hz ± 2.1 Hz) stimulus. Following OXA incubation, the temperature threshold to cooling ramps shifted from 22.2 ± 1.1 ºC to 25.7 ± 1.2 ºC (n=5). Overall, our findings suggest that TRPM8-expressing DRG sensory neurons may play an important role in the acute symptoms of OXA neurotoxicity.
Supported by: “Severo Ochoa” CEX2021-001165-S and Generalitat Valenciana GRISOLIA (CIGRIS/2022/056) and PROMETEO (CIPROM/2024/46) grants.