The chemotherapeutic oxaliplatin alters voltage-gated Na(+) channel kinetics on rat sensory neurons.
The chemotherapeutic oxaliplatin causes a sensory-motor neuropathy with predominantly hyperpathic symptoms. The mechanism underlying this hyperexcitability was investigated using rat sensory nerve preparations, dorsal root ganglia and hippocampal neurons. Oxaliplatin resulted in an increase of the amplitude and duration of compound action potentials. It lengthened the refractory period of peripheral nerves suggesting an interaction with voltage-gated Na(+) channels. Application of oxaliplatin to dorsal root ganglion neurons resulted in an increase of the Na(+) current, a block of the maximal amplitude and a shift of the voltage-response relationship towards more negative membrane potentials. The effect was detectable on 13 of 18 tested cells. This observation, together with the absence of any effect on Na(+) currents of hippocampal neurons, suggests that the interaction of oxaliplatin is restricted to one or more channel subtypes. The effect of oxaliplatin could be antagonised by the Na(+) channel blocker carbamazepine which could be used to reduce side effects of oxaliplatin therapy in patients.
Adelsberger
H
H
Zoologisches Institut, Universität München, Luisenstr. 14, 80333, Munich, Germany. adelsberger@zi.biologie.uni-muenchen.de
Quasthoff
S
S
Grosskreutz
J
J
Lepier
A
A
Eckel
F
F
Lersch
C
C
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002220:Carbamazepine / Q000494:pharmacology; D004558:Electric Stimulation; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D013497:Sural Nerve / Q000187:drug effects / Q000502:physiology; D019789:Tetraethylammonium / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology
D009944:Organoplatinum Compounds; D015221:Potassium Channels; D015222:Sodium Channels; D000077150:Oxaliplatin; D002220:Carbamazepine; D013779:Tetrodotoxin; D019789:Tetraethylammonium; D015761:4-Aminopyridine