Involvement of the Sodium Channel Nav1.7 in Paclitaxel-induced Peripheral Neuropathy through ERK1/2 Signaling in Rats

Author(s): Guang Jie Wang, Xi Zhang, Li-De Huang, Yun Xiao*

Journal Name: Current Neurovascular Research

Volume 17 , Issue 3 , 2020

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Background: Paclitaxel treatment is a major cause of chemotherapy-induced peripheral neuropathy. The sodium channel Nav1.7 plays a critical role in pain perception. However, whether Nav1.7 in the dorsal root ganglion (DRG) is involved in paclitaxel-induced peripheral neuropathy remains unclear. Thus, our study aimed to evaluate whether Nav1.7 participates in the pathogenesis of paclitaxel-induced neuropathy.

Methods: Paclitaxel-induced peripheral neuropathy was generated by intraperitoneal administration of paclitaxel on four alternate days.

Results: The results showed that DRG mRNA and protein expression levels of Nav1.7 were upregulated between days 7 and 21 after the administration of paclitaxel. Besides, paclitaxel upregulated extracellular signal-regulated kinase (ERK1/2) phosphorylation in DRG. Intrathecal injection of U0126 (a MEK inhibitor) blocking ERK1/2 phosphorylation blunted up-regulation of Nav1.7 in the DRG and correspondingly attenuated hyperalgesia.

Conclusion: These results indicated that the sodium channel Nav1.7 in the DRG exerted an important function in paclitaxel-induced neuropathy, which was associated with ERK phosphorylation in neurons.

Keywords: Extracellular signal-regulated kinase, dorsal root ganglion, hyperalgesia, paclitaxel-induced peripheral neuropathy, neuron, chemotherapeutic drug.

Mielke S, Sparreboom A, Mross K. Peripheral neuropathy: A persisting challenge in paclitaxel-based regimes. Eur J Cancer 2006; 42(1): 24-30.
[] [PMID: 16293411]
Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol 2002; 249(1): 9-17.
[] [PMID: 11954874]
Dougherty PM, Cata JP, Cordella JV, Burton A, Weng HR. Taxol-induced sensory disturbance is characterized by preferential impairment of myelinated fiber function in cancer patients. Pain 2004; 109(1-2): 132-42.
[] [PMID: 15082135]
Loprinzi CL, Maddocks-Christianson K, Wolf SL, et al. The Paclitaxel acute pain syndrome: Sensitization of nociceptors as the putative mechanism. Cancer J 2007; 13(6): 399-403.
[] [PMID: 18032978]
Jaggi AS, Singh N. Mechanisms in cancer-chemotherapeutic drugs-induced peripheral neuropathy. Toxicology 2012; 291(1-3): 1-9.
[] [PMID: 22079234]
Okubo K, Takahashi T, Sekiguchi F, et al. Inhibition of T-type calcium channels and hydrogen sulfide-forming enzyme reverses paclitaxel-evoked neuropathic hyperalgesia in rats. Neuroscience 2011; 188: 148-56.
[] [PMID: 21596106]
Ward SJ, McAllister SD, Kawamura R, Murase R, Neelakantan H, Walker EA. Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT(1A) receptors without diminishing nervous system function or chemotherapy efficacy. Br J Pharmacol 2014; 171(3): 636-45.
[] [PMID: 24117398]
Gold MS, Gebhart GF. Nociceptor sensitization in pain pathogenesis. Nat Med 2010; 16(11): 1248-57.
[] [PMID: 20948530]
Zhang H, Dougherty PM. Enhanced excitability of primary sensory neurons and altered gene expression of neuronal ion channels in dorsal root ganglion in paclitaxel-induced peripheral neuropathy. Anesthesiology 2014; 120(6): 1463-75.
[] [PMID: 24534904]
Hara T, Chiba T, Abe K, et al. Effect of paclitaxel on transient receptor potential vanilloid 1 in rat dorsal root ganglion. Pain 2013; 154(6): 882-9.
[] [PMID: 23602343]
Zhao M, Isami K, Nakamura S, Shirakawa H, Nakagawa T, Kaneko S. Acute cold hypersensitivity characteristically induced by oxaliplatin is caused by the enhanced responsiveness of TRPA1 in mice. Mol Pain 2012; 8: 55.
[] [PMID: 22839205]
Miyano K, Tang HB, Nakamura Y, Morioka N, Inoue A, Nakata Y. Paclitaxel and vinorelbine, evoked the release of substance P from cultured rat dorsal root ganglion cells through different PKC isoform-sensitive ion channels. Neuropharmacology 2009; 57(1): 25-32.
[] [PMID: 19376141]
Drenth JP, Waxman SG. Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. J Clin Invest 2007; 117(12): 3603-9.
[] [PMID: 18060017]
Fertleman CR, Baker MD, Parker KA, et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron 2006; 52(5): 767-74.
[] [PMID: 17145499]
Jarecki BW, Piekarz AD, Jackson JO II, Cummins TR. Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents. J Clin Invest 2010; 120(1): 369-78.
[] [PMID: 20038812]
Faber CG, Lauria G, Merkies IS, et al. Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci USA 2012; 109(47): 19444-9.
[] [PMID: 23115331]
Cummins TR, Howe JR, Waxman SG. Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel. J Neurosci 1998; 18(23): 9607-19.
[] [PMID: 9822722]
Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. From genes to pain: Na v 1.7 and human pain disorders. Trends Neurosci 2007; 30(11): 555-63.
[] [PMID: 17950472]
Rush AM, Cummins TR, Waxman SG. Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. J Physiol 2007; 579(Pt 1): 1-14.
[] [PMID: 17158175]
Black JA, Liu S, Tanaka M, Cummins TR, Waxman SG. Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain 2004; 108(3): 237-47.
[] [PMID: 15030943]
Chattopadhyay M, Mata M, Fink DJ. Continuous delta-opioid receptor activation reduces neuronal voltage-gated sodium channel (NaV1.7) levels through activation of protein kinase C in painful diabetic neuropathy. J Neurosci 2008; 28(26): 6652-8.
[] [PMID: 18579738]
Chattopadhyay M, Mata M, Fink DJ. Vector-mediated release of GABA attenuates pain-related behaviors and reduces Na(V)1.7 in DRG neurons. Eur J Pain 2011; 15(9): 913-20.
[] [PMID: 21486703]
Liu C, Cao J, Ren X, Zang W. Nav1.7 protein and mRNA expression in the dorsal root ganglia of rats with chronic neuropathic pain. Neural Regen Res 2012; 7(20): 1540-4.
[PMID: 25657691]
Impey S, Obrietan K, Storm DR. Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 1999; 23(1): 11-4.
[] [PMID: 10402188]
Ji RR, Baba H, Brenner GJ, Woolf CJ. Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci 1999; 2(12): 1114-9.
[] [PMID: 10570489]
Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Zhang YQ. Protein kinases as potential targets for the treatment of pathological pain. Handb Exp Pharmacol 2007; (177): 359-89.
[PMID: 17087130]
Zhuang ZY, Wen YR, Zhang DR, et al. A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 2006; 26(13): 3551-60.
[] [PMID: 16571763]
Reyes-Gibby CC, Wang J, Yeung SJ, Shete S. Informative gene network for chemotherapy-induced peripheral neuropathy. BioData Min 2015; 8: 24.
[] [PMID: 26269716]
Yang Y, Chengyuan W. Guidelines on the basic outcome data from International Association for the Study of Pain. Clin J Pain 2007; 23(6): 549.
[] [PMID: 17575497]
Kawakami K, Chiba T, Katagiri N, et al. Paclitaxel increases high voltage-dependent calcium channel current in dorsal root ganglion neurons of the rat. J Pharmacol Sci 2012; 120(3): 187-95.
[] [PMID: 23090716]
Shi XD, Fu D, Xu JM, Zhang YL, Dai RP. Activation of spinal ERK1/2 contributes to mechanical allodynia in a rat model of postoperative pain. Mol Med Rep 2013; 7(5): 1661-5.
[] [PMID: 23450427]
Wang LN, Yao M, Yang JP, et al. Cancer-induced bone pain sequentially activates the ERK/MAPK pathway in different cell types in the rat spinal cord. Mol Pain 2011; 7: 48.
[] [PMID: 21722369]
Xia Z, Xiao Y, Wu Y, Zhao B. Sodium channel Nav1.7 expression is upregulated in the dorsal root ganglia in a rat model of paclitaxel-induced peripheral neuropathy. Springerplus 2016; 5(1): 1738.
[] [PMID: 27777872]
Lee JH, Park CK, Chen G, et al. A monoclonal antibody that targets a NaV1.7 channel voltage sensor for pain and itch relief. Cell 2014; 157(6): 1393-404.
[] [PMID: 24856969]
Minett MS, Falk S, Santana-Varela S, et al. Pain without nociceptors? Nav1.7-independent pain mechanisms. Cell Rep 2014; 6(2): 301-12.
[] [PMID: 24440715]
Stamboulian S, Choi JS, Ahn HS, et al. ERK1/2 mitogen-activated protein kinase phosphorylates sodium channel Na(v)1.7 and alters its gating properties. J Neurosci 2010; 30(5): 1637-47.
[] [PMID: 20130174]
Zhuang ZY, Gerner P, Woolf CJ, Ji RR. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 2005; 114(1-2): 149-59.
[] [PMID: 15733640]
Sun H, Ren K, Zhong CM, et al. Nerve injury-induced tactile allodynia is mediated via ascending spinal dorsal column projections. Pain 2001; 90(1-2): 105-11.
[] [PMID: 11166976]
Li Y, Zhang H, Kosturakis AK, et al. MAPK signaling downstream to TLR4 contributes to paclitaxel-induced peripheral neuropathy. Brain Behav Immun 2015; 49: 255-66.
[] [PMID: 26065826]

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Article Details

Year: 2020
Published on: 28 September, 2020
Page: [267 - 274]
Pages: 8
DOI: 10.2174/1567202617666200514113441
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