Use of
chemotherapy drug
oxaliplatin is associated with painful
peripheral neuropathy that is exacerbated by cold. Remodeling of
ion channels including TRP channels in dorsal root ganglion (DRG) neurons contribute to the sensory
hypersensitivity following
oxaliplatin treatment in animal models. However, it has not been studied if TRP channels and membrane depolarization of DRG neurons serve as the initial ionic/membrane drives (such as within an hour) that contribute to the development of
oxaliplatin-induced
neuropathic pain. In the current study, we studied in mice (1) in vitro acute effects of
oxaliplatin on the membrane excitability of IB4+ and IB4- subpopulations of DRG neurons using a perforated patch clamping, (2) the preventative effects of a membrane-hyperpolarizing drug
retigabine on
oxaliplatin-induced sensory
hypersensitivity, and (3) the preventative effects of TRP channel antagonists on the
oxaliplatin-induced membrane hyperexcitability and sensory
hypersensitivity. We found (1) IB4+ and IB4- subpopulations of small DRG neurons displayed previously undiscovered, substantially different membrane excitability, (2)
oxaliplatin selectively depolarized IB4- DRG neurons, (3) pretreatment of
retigabine largely prevented
oxaliplatin-induced sensory
hypersensitivity, (4) antagonists of TRPA1 and TRPM8 channels prevented
oxaliplatin-induced membrane depolarization, and (5) the antagonist of TRPM8 largely prevented
oxaliplatin-induced sensory
hypersensitivity. These results suggest that
oxaliplatin depolarizes IB4- neurons through TRPM8 channels to drive the development of
neuropathic pain and targeting the initial drives of TRPM8 and/or membrane depolarization may prevent
oxaliplatin-induce
neuropathic pain.