title: Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current.
abstract: Infusion of the chemotherapeutic agent oxaliplatin leads to an acute and a chronic form of peripheral neuropathy. Acute oxaliplatin neuropathy is characterized by sensory paresthesias and muscle cramps that are notably exacerbated by cooling. Painful dysesthesias are rarely reported for acute oxaliplatin neuropathy, whereas a common symptom of chronic oxaliplatin neuropathy is pain. Here we examine the role of the sodium channel isoform Na(V)1.6 in mediating the symptoms of acute oxaliplatin neuropathy. Compound and single-action potential recordings from human and mouse peripheral axons showed that cooling in the presence of oxaliplatin (30-100 μM; 90 min) induced bursts of action potentials in myelinated A, but not unmyelinated C-fibers. Whole-cell patch-clamp recordings from dissociated dorsal root ganglion (DRG) neurons revealed enhanced tetrodotoxin-sensitive resurgent and persistent current amplitudes in large, but not small, diameter DRG neurons when cooled (22 °C) in the presence of oxaliplatin. In DRG neurons and peripheral myelinated axons from Scn8a(med/med) mice, which lack functional Na(V)1.6, no effect of oxaliplatin and cooling was observed. Oxaliplatin significantly slows the rate of fast inactivation at negative potentials in heterologously expressed mNa(V)1.6r in ND7 cells, an effect consistent with prolonged Na(V) open times and increased resurgent and persistent current in native DRG neurons. This finding suggests that Na(V)1.6 plays a central role in mediating acute cooling-exacerbated symptoms following oxaliplatin, and that enhanced resurgent and persistent sodium currents may provide a general mechanistic basis for cold-aggravated symptoms of neuropathy.
authors.affiliation: Institute of Physiology, Ludwig-Maximilians University, 80336 Munich, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Sittl
authors.forename: Angelika
authors.initials: A
authors.lastname: Lampert
authors.forename: Tobias
authors.initials: T
authors.lastname: Huth
authors.forename: E Theresa
authors.initials: ET
authors.lastname: Schuy
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Link
authors.forename: Johannes
authors.initials: J
authors.lastname: Fleckenstein
authors.forename: Christian
authors.initials: C
authors.lastname: Alzheimer
authors.forename: Peter
authors.initials: P
authors.lastname: Grafe
authors.forename: Richard W
authors.initials: RW
authors.lastname: Carr
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001369:Axons; D005727:Ganglia, Spinal / Q000166:cytology / Q000502:physiology; D006801:Humans; D051379:Mice; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000502:physiology; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced*; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D009944:Organoplatinum Compounds; C100681:SCN8A protein, human; D015222:Sodium Channels; D000077150:Oxaliplatin