title: An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways.
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.
authors.affiliation: 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.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Deuis
authors.forename: Katharina
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Andrej A
authors.initials: AA
authors.lastname: Romanovsky
authors.forename: Lourival D
authors.initials: LD
authors.lastname: Possani
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cabot
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
authors.forename: Irina
authors.initials: I
authors.lastname: Vetter
mesh_terms: D015761:4-Aminopyridine / Q000009:adverse effects; D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D003080:Cold Temperature / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006930:Hyperalgesia / Q000139:chemically induced*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D062552:NAV1.3 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D062558:NAV1.9 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D009437:Neuralgia / Q000150:complications* / Q000235:genetics; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D026902:Potassium Channel Blockers / Q000494:pharmacology; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels / Q000172:deficiency; D050051:Transient Receptor Potential Channels / Q000172:deficiency
chemical_list: D000970:Antineoplastic Agents; D062552:NAV1.3 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009944:Organoplatinum Compounds; D026902:Potassium Channel Blockers; C491885:Scn11a protein, mouse; C515216:Scn3a protein, mouse; C491046:Scn8a protein, mouse; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D000077150:Oxaliplatin; D015761:4-Aminopyridine
keywords: Allodynia; Voltage-gated sodium channel