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

• Published in: British journal of pharmacology 2005-12, Vol.146 (7), p.1027-1039
• Main Authors: Webster, Richard G, Brain, Keith L, Wilson, Richard H, Grem, Jean L, Vincent, Angela
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Animals; Antineoplastic Agents - pharmacology; Autonomic Nervous System - drug effects; Autonomic Nervous System - physiology; Biological and medical sciences; Calcium - metabolism; carbamazepine; hyperexcitability; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; neuromuscular junction; Neuromuscular Junction - drug effects; Neuromuscular Junction - physiology; neuromyotonia; neurotoxicity; Organoplatinum Compounds - pharmacology; Oxaliplatin; Pharmacology. Drug treatments; Potassium Channels - physiology; Sodium Channels - drug effects; Sodium Channels - physiology; Synaptic Transmission - drug effects; Vas Deferens - innervation; voltage‐activated Na+ channels; β‐pompilidotoxin
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0706407

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. 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 Ca2+ concentration in nerve terminal varicosities were observed, and recovery after stimuli trains was unaffected. 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. 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. British Journal of Pharmacology (2005) 146, 1027–1039. doi:10.1038/sj.bjp.0706407