An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways

Pain. 2013 Sep;154(9):1749-1757. doi: 10.1016/j.pain.2013.05.032. Epub 2013 May 24.


Cold allodynia, pain in response to cooling, occurs during or within hours of oxaliplatin infusion and is thought to arise from a direct effect of oxaliplatin on peripheral sensory neurons. To characterize the pathophysiological mechanisms underlying acute oxaliplatin-induced cold allodynia, we established a new intraplantar oxaliplatin mouse model that rapidly developed long-lasting cold allodynia mediated entirely through tetrodotoxin-sensitive Nav pathways. Using selective inhibitors and knockout animals, we found that Nav1.6 was the key isoform involved, while thermosensitive transient receptor potential channels were not involved. Consistent with a crucial role for delayed-rectifier potassium channels in excitability in response to cold, intraplantar administration of the K(+)-channel blocker 4-aminopyridine mimicked oxaliplatin-induced cold allodynia and was also inhibited by Nav1.6 blockers. Intraplantar injection of the Nav1.6 activator Cn2 elicited spontaneous pain, mechanical allodynia, and enhanced 4-aminopyridine-induced cold allodynia. These findings provide behavioural evidence for a crucial role of Nav1.6 in multiple peripheral pain pathways including cold allodynia.

Keywords: Allodynia; Voltage-gated sodium channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminopyridine / adverse effects
  • Analysis of Variance
  • Animals
  • Antineoplastic Agents / toxicity*
  • Cold Temperature / adverse effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Hyperalgesia / chemically induced*
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NAV1.3 Voltage-Gated Sodium Channel / genetics
  • NAV1.3 Voltage-Gated Sodium Channel / metabolism
  • NAV1.6 Voltage-Gated Sodium Channel / genetics
  • NAV1.6 Voltage-Gated Sodium Channel / metabolism*
  • NAV1.9 Voltage-Gated Sodium Channel / genetics
  • NAV1.9 Voltage-Gated Sodium Channel / metabolism
  • Neuralgia / complications*
  • Neuralgia / genetics
  • Organoplatinum Compounds / toxicity*
  • Oxaliplatin
  • Potassium Channel Blockers / pharmacology
  • TRPA1 Cation Channel
  • TRPM Cation Channels / deficiency
  • Transient Receptor Potential Channels / deficiency


  • Antineoplastic Agents
  • NAV1.3 Voltage-Gated Sodium Channel
  • NAV1.6 Voltage-Gated Sodium Channel
  • NAV1.9 Voltage-Gated Sodium Channel
  • Organoplatinum Compounds
  • Potassium Channel Blockers
  • Scn11a protein, mouse
  • Scn3a protein, mouse
  • Scn8a protein, mouse
  • TRPA1 Cation Channel
  • TRPM Cation Channels
  • TRPM8 protein, mouse
  • Transient Receptor Potential Channels
  • Trpa1 protein, mouse
  • Oxaliplatin
  • 4-Aminopyridine