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

  1. Richard G Webster1,*,
  2. Keith L Brain2,
  3. Richard H Wilson3,
  4. Jean L Grem3,
  5. Angela Vincent1

Article first published online: 29 JAN 2009

DOI: 10.1038/sj.bjp.0706407

Issue

British Journal of Pharmacology

British Journal of Pharmacology

Volume 146, Issue 7, pages 1027–1039, December 2005

Additional Information

How to Cite

Webster, R. G., Brain, K. L., Wilson, R. H., Grem, J. L. and Vincent, A. (2005), Oxaliplatin induces hyperexcitability at motor and autonomic neuromuscular junctions through effects on voltage-gated sodium channels. British Journal of Pharmacology, 146: 1027–1039. doi: 10.1038/sj.bjp.0706407

Author Information

  1. 1

    Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS

  2. 2

    University Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT

  3. 3

    Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, U.S.A.

*Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS. E-mail: richard.webster@imm.ox.ac.uk

Publication History

  1. Issue published online: 29 JAN 2009
  2. Article first published online: 29 JAN 2009
  3. (Received May 17, 2005, Revised July 26, 2005, Accepted August 26, 2005)

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Keywords:

  • Oxaliplatin;
  • neuromyotonia;
  • neurotoxicity;
  • hyperexcitability;
  • carbamazepine;
  • β-pompilidotoxin;
  • voltage-activated Na+ channels;
  • neuromuscular junction

  • 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

View Full Article (HTML) Get PDF (565K)