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

Jennifer R Deuis; Katharina Zimmermann; Andrej A Romanovsky; Lourival D Possani; Peter J Cabot; Richard J Lewis; Irina Vetter

doi:10.1016/j.pain.2013.05.032

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.

Authors

Jennifer R Deuis¹, Katharina Zimmermann, Andrej A Romanovsky, Lourival D Possani, Peter J Cabot, Richard J Lewis, Irina Vetter

Affiliation

¹ School of Pharmacy, The University of Queensland, Woolloongabba, Queensland 4102, Australia Institute for Molecular Biosciences, The University of Queensland, St Lucia, Queensland 4072, Australia Department of Physiology and Pathophysiology, Friedrich-Alexander University of Erlangen-Nuremberg, 91054 Erlangen, Germany Systemic Inflammation Laboratory (FeverLab), Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA Instituto de Biotecnologia, UNAM, Avenida Universidad, 2001, Colonia Chamilpa, Apartado Postal 510-3, Cuernvaca 62210, Mexico.

Abstract

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding