Mechanical allodynia triggered by cold exposure in mice with the Scn11a p.R222S mutation: a novel model of drug therapy
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ORIGINAL ARTICLE
Mechanical allodynia triggered by cold exposure in mice with the Scn11a p.R222S mutation: a novel model of drug therapy for neuropathic pain related to NaV1.9 Yosuke Matsubara 1,2 & Hiroko Okuda 3 & Kouji H. Harada 3 & Shohab Youssefian 2 & Akio Koizumi 3,4 Received: 18 May 2020 / Accepted: 15 September 2020 # The Author(s) 2020
Abstract Mutations within the SCN11A gene which encodes the voltage-gated sodium channel NaV1.9 mainly expressed in small fiber sensory neurons have been associated with neuropathic disorders; however, suitable medications have not been fully investigated. To develop drug therapies against NaV1.9-related neuropathic pain, we aimed to establish a novel model using mice carrying the Scn11a p.R222S mutation initially identified in patients with familial episodic limb pain that is characterized by paroxysmal pain induced by fatigue or bad weather conditions. We investigated the influence of cold exposure (4 °C, overnight) on the behavioral and biochemical phenotypes of Scn11a p.R222S mutant (R222S) and wild type C57BL/6N (WT) mice. We also tested the effects of acetaminophen (125, 250 mg/kg, perorally, p.o.) and traditional Japanese medicine, goshajinkigan (0.5 or 1.0 g/kg, p.o.), which are analgesic drugs prescribed to patients with neuropathic pain, in this model of cold-induced mechanical allodynia in R222S mice. Cold-exposed R222S mice exhibited enhanced mechanical allodynia and thermal hypersensitivity compared with WT mice. The decrease of the mechanical withdrawal threshold in R222S mice was reversible 24 h after housing at room temperature. There was no significant change in the levels of interleukin-1β, interleukin-6, tumor necrosis factor-α, or interferon-γ in the plasma or spinal cords of WT and R222S mice after cold exposure. Both acetaminophen (250 mg/kg) and goshajinkigan (1.0 g/kg) significantly attenuated mechanical allodynia in R222S mice. The model of cold-induced mechanical allodynia in mice with the Scn11a p.R222S mutation is novel and useful for evaluating analgesic drugs for intractable neuropathies related to NaV1.9. Keywords NaV1.9 . Familial episodic limb pain . Neuropathic pain . Acetaminophen . Goshajinkigan . Kampo
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00210-020-01978-z) contains supplementary material, which is available to authorized users. * Yosuke Matsubara [email protected] 1
Tsumura Kampo Research Laboratories, Tsumura & Co., Ibaraki, Japan
2
Laboratory of Molecular Biosciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
3
Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
4
Social Health Medicine Welfare Laboratory, Public Interest Incorporated Association Kyoto Hokenkai, Kyoto, Japan
Voltage-gated sodium channels (NaVs) are a family of sodium ion channel proteins that play a crucial role in the electrical excitability of nerve systems and cardiac and skeletal muscles. N
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