Oxaliplatin induces hyperexcitability at motor and autonomic neuromuscular junctions through effects on voltage-gated sodium channels

1 Oxaliplatin, an effective cytotoxic treatment in combination with 5-fluorouracil for colorectal cancer, is associated with sensory, motor and autonomic neurotoxicity. Motor symptoms include hyperexcitability while autonomic effects include urinary retention, but the cause of these side-effects is unknown. We examined the effects on motor nerve function in the mouse hemidiaphragm and on the autonomic system in the vas deferens. 2 In the mouse diaphragm, oxaliplatin (0.5 mM) induced multiple endplate potentials (EPPs) following a single stimulus, and was associated with an increase in spontaneous miniature EPP frequency. In the vas deferens, spontaneous excitatory junction potential frequency was increased after 30 min exposure to oxaliplatin; no changes in resting Ca ²⁺ concentration in nerve terminal varicosities were observed, and recovery after stimuli trains was unaffected. 3 In both tissues, an oxaliplatin-induced increase in spontaneous activity was prevented by the voltage-gated Na ⁺ channel blocker tetrodotoxin (TTX). Carbamazepine (0.3 mM) also prevented multiple EPPs and the increase in spontaneous activity in both tissues. In diaphragm, β-pompilidotoxin (100 μM), which slows Na ⁺ channel inactivation, induced multiple EPPs similar to oxaliplatin's effect. By contrast, blockers of K ⁺ channels (4-aminopyridine and apamin) did not replicate oxaliplatin-induced hyperexcitability in the diaphragm. 4 The prevention of hyperexcitability by TTX blockade implies that oxaliplatin acts on nerve conduction rather than by effecting repolarisation. The similarity between β-pompilidotoxin and oxaliplatin suggests that alteration of voltage-gated Na ⁺ channel kinetics is likely to underlie the acute neurotoxic actions of oxaliplatin.