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

RG Webster, Keith Brain, RH Wilson, JL Grem, A Vincent

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107 Citations (Scopus)
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Abstract

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 hemidiaphragni 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 Ca2+ 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, beta-pompilidotoxin (100 mu M), 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 beta-pompilidotoxin and oxaliplatin suggests that alteration of voltage-gated Na+ channel kinetics is likely to underlie the acute neurotoxic actions of oxaliplatin.
Original languageEnglish
Pages (from-to)1027-1039
Number of pages13
JournalBritish Journal of Pharmacology
Volume146
Issue number7
DOIs
Publication statusPublished - 1 Dec 2005

Keywords

  • hyperexcitability
  • beta-pompilidotoxin
  • neurotoxicity
  • carbamazepine
  • voltage-activated Na+ channels
  • oxaliplatin
  • neuromyotonia
  • neuromuscular junction

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