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https://www.readbyqxmd.com/read/29343477/role-of-asic3-nav1-7-and-nav1-8-in-electroacupuncture-induced-analgesia-in-a-mouse-model-of-fibromyalgia-pain
#1
Liang-Ta Yen, Yu-Chan Hsu, Jaung-Geng Lin, Ching-Liang Hsieh, Yi-Wen Lin
BACKGROUND: The mechanisms underlying fibromyalgia (FM) pain are not understood. The US Food and Drug Administration has recommended three drugs for treating FM-namely, pregabalin, duloxetine and milnacipran; however, these medications are associated with severe side effects. OBJECTIVE: To create a mouse model of FM pain using dual injections of acidic saline to cause mechanical hyperalgesia and test whether ASIC3, Nav1.7 and Nav1.8 are involved in this process and whether electroacupuncture (EA) can reverse these phenomena...
January 17, 2018: Acupuncture in Medicine: Journal of the British Medical Acupuncture Society
https://www.readbyqxmd.com/read/29335280/mapping-protein-interactions-of-sodium-channel-nav1-7-using-epitope-tagged-gene-targeted-mice
#2
Alexandros H Kanellopoulos, Jennifer Koenig, Honglei Huang, Martina Pyrski, Queensta Millet, Stéphane Lolignier, Toru Morohashi, Samuel J Gossage, Maude Jay, John E Linley, Georgios Baskozos, Benedikt M Kessler, James J Cox, Annette C Dolphin, Frank Zufall, John N Wood, Jing Zhao
The voltage-gated sodium channel NaV1.7 plays a critical role in pain pathways. We generated an epitope-tagged NaV1.7 mouse that showed normal pain behaviours to identify channel-interacting proteins. Analysis of NaV1.7 complexes affinity-purified under native conditions by mass spectrometry revealed 267 proteins associated with Nav1.7 in vivo The sodium channel β3 (Scn3b), rather than the β1 subunit, complexes with Nav1.7, and we demonstrate an interaction between collapsing-response mediator protein (Crmp2) and Nav1...
January 15, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29333591/differential-inhibition-of-nav1-7-and-neuropathic-pain-by-hybridoma-produced-and-recombinant-monoclonal-antibodies-that-target-nav1-7-differential-activities-of-nav1-7-targeting-monoclonal-antibodies
#3
Sangsu Bang, Jiho Yoo, Xingrui Gong, Di Liu, Qingjian Han, Xin Luo, Wonseok Chang, Gang Chen, Sang-Taek Im, Yong Ho Kim, Judith A Strong, Ma-Zhong Zhang, Jun-Ming Zhang, Seok-Yong Lee, Ru-Rong Ji
The voltage-gated Na+ channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody (SVmab) reduces Na+ currents and pain and itch responses in mice. Here, we investigated whether recombinant SVmab (rSVmab) binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltage-sensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1...
January 15, 2018: Neuroscience Bulletin
https://www.readbyqxmd.com/read/29317264/the-genetics-of-chronic-itch-gene-expression-in-the-skin-of-atopic-dermatitis-and-psoriasis-patients-with-severe-itch
#4
Leigh A Nattkemper, Hong Liang Tey, Rodrigo Valdes-Rodriguez, Helen Lee, Nicholas K Mollanazar, Christian Albornoz, Kristen M Sanders, Gil Yosipovitch
To identify itch-related mediators and receptors that are differentially expressed in pruritic skin, we used RNA sequencing to analyze the complete transcriptome in skin from paired itchy, lesional and non-itchy, non-lesional skin biopsies from 25 atopic dermatitis (AD) and 25 psoriasis patients and site-matched biopsies from 30 healthy controls. This analysis identified 18,000 differentially expressed genes common between itchy atopic and psoriatic skin compared to healthy skin. Of those, almost 2,000 genes were differentially expressed between itchy and non-itchy skin in atopic and psoriatic subjects...
January 6, 2018: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29311306/mechanism-specific-assay-design-facilitates-the-discovery-of-nav1-7-selective-inhibitors
#5
Tania Chernov-Rogan, Tianbo Li, Gang Lu, Henry Verschoof, Kuldip Khakh, Steven W Jones, Maureen H Beresini, Chang Liu, Daniel F Ortwine, Steven J McKerrall, David H Hackos, Daniel Sutherlin, Charles J Cohen, Jun Chen
Many ion channels, including Nav1.7, Cav1.3, and Kv1.3, are linked to human pathologies and are important therapeutic targets. To develop efficacious and safe drugs, subtype-selective modulation is essential, but has been extremely difficult to achieve. We postulate that this challenge is caused by the poor assay design, and investigate the Nav1.7 membrane potential assay, one of the most extensively employed screening assays in modern drug discovery. The assay uses veratridine to activate channels, and compounds are identified based on the inhibition of veratridine-evoked activities...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29299961/erythromelalgia
#6
Peter Franz Klein-Weigel, Theresa Sophie Volz, Jutta Gisela Richter
Erythromelalgia is a rare syndrome characterized by the intermittent or, less commonly, by the permanent occurrence of extremely painful hyperperfused skin areas mainly located in the distal extremities. Primary erythromelalgia is nowadays considered to be a genetically determined neuropathic disorder affecting SCN9A, SCN10A, and SCN11A coding for NaV1.7, NaV1.8, and NaV1.9 neuronal sodium channels. Secondary forms might be associated with myeloproliferative disorders, connective tissue disease, cancer, infections, and poisoning...
January 4, 2018: VASA. Zeitschrift Für Gefässkrankheiten
https://www.readbyqxmd.com/read/29274816/molecular-determinants-of-loperamide-and-n-desmethyl-loperamide-binding-in-the-herg-cardiac-k-channel
#7
Roy J Vaz, Jiesheng Kang, Yongyi Luo, David Rampe
Abuse of the common anti-diarrheal loperamide is associated with QT interval prolongation as well as development of the potentially fatal arrhythmia torsades de pointes. The mechanism underlying this cardiotoxicity is high affinity inhibition of the human ether-a-go-go-related gene (hERG) cardiac K+ channel. N-Desmethyl loperamide is the major metabolite of loperamide and is a close structural relative of the parent molecule. To date no information is available regarding the affinity of N-desmethyl loperamide for human cardiac ion channels...
December 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29194125/nav1-7-and-pain-contribution-of-peripheral-nerves
#8
Tal Hoffmann, Ohad Sharon, Jürgen Wittmann, Richard W Carr, Alina Vyshnevska, Roberto De, Mohammed A Nassar, Peter W Reeh, Christian Weidner
The sodium channel NaV1.7 contributes to action potential generation and propagation. Loss-of-function mutations in patients lead to congenital indifference to pain, though it remains unclear where on the way from sensory terminals to CNS the signalling is disrupted. We confirm that conditional deletion of NaV1.7 in advillin expressing sensory neurons leads to impaired heat and mechanical nociception in behavioural tests. With single-fiber recordings from isolated skin we found (1) a significantly lower prevalence of heat responsiveness to in normally mechanosensitive C-fibers, although (2) the rare heat responses appeared quite vigorous and (3) heat-induced CGRP release was normal...
November 24, 2017: Pain
https://www.readbyqxmd.com/read/29186022/investigation-of-binding-modes-and-functional-surface-of-scorpion-toxins-anep-to-sodium-channels-1-7
#9
Yongbo Song, Zeyu Liu, Qi Zhang, Chunming Li, Wei Jin, Lili Liu, Jianye Zhang, Jinghai Zhang
The depressant β toxin anti-neuroexcitation peptide (ANEP) from the Chinese scorpion Buthus martensii Karsch has analgesic activity by interacting with receptor site 4 of the voltage-gated sodium channels (VGSCs). Here, with molecular dynamics simulations, we examined the binding modes between ANEP and the site 4 of mice sodium channel 1.7 (mNav1.7), a subtype of VGSCs related to peripheral pain. Homology modeling, molecular mechanics, and molecular dynamics in the biomembrane environment were adopted. The results suggested that ANEP bound to the resting site 4 mainly by amino acid residues in the β2-β3 loop and the 'NC' domains, and the activate site 4 mainly by amino acid residues in the hydrophobic domain of N-groove and residues in the 'pharmacophore'...
November 29, 2017: Toxins
https://www.readbyqxmd.com/read/29176367/rare-nav1-7-variants-associated-with-painful-diabetic-peripheral-neuropathy
#10
Iulia Blesneac, Andreas C Themistocleous, Carl Fratter, Linus J Conrad, Juan D Ramirez, James J Cox, Solomon Tesfaye, Pallai R Shillo, Andrew S C Rice, Stephen J Tucker, David L H Bennett
Diabetic peripheral neuropathy (DPN) is a common disabling complication of diabetes. Almost half of DPN patients develop neuropathic pain for which current analgesic treatments are inadequate. Understanding the role of genetic variability in the development of painful DPN is needed for improved understanding of pain pathogenesis, for better patient stratification in clinical trials and to target therapy more appropriately. Here we examined the relationship between variants in the voltage gated sodium channel Nav1...
November 22, 2017: Pain
https://www.readbyqxmd.com/read/29166836/-express-characterisation-of-nav1-7-functional-expression-in-rat-dorsal-root-ganglia-neurons-by-using-an-electrical-field-stimulation-assay
#11
Antoine Fouillet, Jake F Watson, Andrew D Piekarz, Xiaofang Huang, Baolin Li, Birgit Priest, Eric Nisenbaum, Emanuele Sher, Daniel Ursu
No abstract text is available yet for this article.
January 1, 2017: Molecular Pain
https://www.readbyqxmd.com/read/29161016/selective-voltage-gated-sodium-channel-peptide-toxins-from-animal-venom-pharmacological-probes-and-analgesic-drug-development
#12
Ying Wu, Hui Ma, Fan Zhang, Chun-Lei Zhang, Xiaohan Zou, Zhengyu Cao
Voltage-gated sodium channels (Navs) play critical roles in action potential generation and propagation. Nav channelopathy as well as pathological sensitization contribute to allodynia and hyperalgesia. Recent evidence has demonstrated the significant roles of Nav subtypes (Nav1.3, 1.7, 1.8 and 1.9) in nociceptive transduction and therefore these Navs may represent attractive targets for analgesic drug discovery. Animal toxins are structurally diverse peptides that are highly potent yet selective on ion channel subtypes and therefore representing valuable probes to elucidate the structures, gating properties and cellular functions of ion channels...
November 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29139614/human-dental-stem-cell-derived-transgene-free-ipscs-generate-functional-neurons-via-embryoid-body-mediated-and-direct-induction-methods
#13
Ikbale El Ayachi, Jun Zhang, Xiao-Ying Zou, Zongdong Yu, Wei Wei, Kristen M S O'Connell, George T-J Huang
Induced pluripotent stem cells (iPSCs) give rise to neural stem/progenitor cells (NSCs), serving as a good source for neural regeneration. Here, we established transgene-free (TF) iPSCs from dental stem cells (DSCs) and determined their capacity to differentiate into functional neurons in vitro. Generated TF iPSCs from stem cells of apical papilla (SCAP) and dental pulp stem cells (DPSCs) underwent two methods -- embryoid body (EB)-mediated and direct induction, to guide TF-DSC iPSCs along with H9 or H9 Syn-GFP (human embryonic stem cells) into functional neurons in vitro...
November 15, 2017: Journal of Tissue Engineering and Regenerative Medicine
https://www.readbyqxmd.com/read/29122010/expression-of-voltage-gated-sodium-channel-nav1-5-in-non-metastatic-colon-cancer-and-its-associations-with-estrogen-receptor-er-%C3%AE-expression-and-clinical-outcomes
#14
Jianhong Peng, Qingjian Ou, Xiaojun Wu, Rongxin Zhang, Qian Zhao, Wu Jiang, Zhenhai Lu, Desen Wan, Zhizhong Pan, Yujing Fang
BACKGROUND: Voltage-gated sodium channel 1.5 (Nav1.5) potentially promotes the migratory and invasive behaviors of colon cancer cells. Hitherto, the prognostic significance of Nav1.5 expression remains undetermined. The present study aimed to explore the associations of Nav1.5 expression with clinical outcomes and estrogen receptor-β (ER-β) expression in non-metastatic colon cancer patients receiving radical resection. METHODS: A total of 269 consecutive patients with pathologically confirmed stages I-III colon cancer who underwent radical resection were selected...
November 9, 2017: Chinese Journal of Cancer
https://www.readbyqxmd.com/read/29115943/membrane-protein-nav1-7-contributes-to-the-persistent-post-surgical-pain-regulated-by-p-p65-in-dorsal-root-ganglion-drg-of-smir-rats-model
#15
Zhisong Li, Yaru Li, Jing Cao, Xuemin Han, Weihua Cai, Weidong Zang, Jitian Xu, Wei Zhang
BACKGROUND: Persistent post-surgical pain is a difficult clinical problem. In this study, we intend to explore the mechanism underlying the persistent post-surgical pain in SMIR (skin/muscle incision and retraction) rats. METHODS: First of all, the expression of membrane protein Nav1.7 and p-p65 (Phosphorylation of p65) were detected in ipsilateral L4-6 DRGs of SMIR rats by western-blot and immunostaining. Then with ProTx-II (Nav1.7 blocker) or PDTC (p65 inhibitor) were intrathecally injected while the change of Nav1...
November 7, 2017: BMC Anesthesiology
https://www.readbyqxmd.com/read/29106681/common-missense-variant-of-scn9a-gene-is-associated-with-pain-intensity-in-patients-with-chronic-pain-from-disc-herniation
#16
Mateusz Kurzawski, Marcin Rut, Violetta Dziedziejko, Krzysztof Safranow, Anna Machoy-Mokrzynska, Marek Drozdzik, Monika Bialecka
Objective: Lumbar intervertebral disk herniation (LDH) is considered one of the major risk factors for lower back pain, mainly caused by irritation of a spinal nerve or its root. One of the genes related to pain perception is SCN9A, which encodes the voltage gated sodium channel NaV1.7, a key molecule involved in peripheral pain processing. It had been presented before that a common polymorphism within SCN9A (rs6746030: G > A, R1150W) might influence nociception in the general population...
November 2, 2017: Pain Medicine: the Official Journal of the American Academy of Pain Medicine
https://www.readbyqxmd.com/read/29094728/enhancing-inactivation-rather-than-reducing-activation-of-nav1-7-channels-by-a-clinically-effective-analgesic-cnv1014802
#17
Yue-Ming Zheng, Wan-Fu Wang, Yan-Fen Li, Yong Yu, Zhao-Bing Gao
The Nav1.7 channel represents a promising target for pain relief. In the recent decades, a number of Nav1.7 channel inhibitors have been developed. According to the effects on channel kinetics, these inhibitors could be divided into two major classes: reducing activation or enhancing inactivation. To date, however, only several inhibitors have moved forward into phase 2 clinical trials and most of them display a less than ideal analgesic efficacy, thus intensifying the controversy regarding if an ideal candidate should preferentially affect the activation or inactivation state...
November 2, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29063143/the-nav1-7-blocker-protoxin-ii-reduces-burn-injury-induced-spinal-nociceptive-processing
#18
Jose Vicente Torres-Pérez, Pavel Adamek, Jiri Palecek, Marcela Vizcaychipi, Istvan Nagy, Angelika Varga
Controlling pain in burn-injured patients poses a major clinical challenge. Recent findings suggest that reducing the activity of the voltage-gated sodium channel Nav1.7 in primary sensory neurons could provide improved pain control in burn-injured patients. Here, we report that partial thickness scalding-type burn injury on the rat paw upregulates Nav1.7 expression in primary sensory neurons 3 h following injury. The injury also induces upregulation in phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB), a marker for nociceptive activation in primary sensory neurons...
October 23, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/29029933/highly-potent-and-selective-nav1-7-inhibitors-for-use-as-intravenous-agents-and-chemical-probes
#19
R Ian Storer, Andy Pike, Nigel A Swain, Aristos J Alexandrou, Bruce M Bechle, David C Blakemore, Alan D Brown, Neil A Castle, Matthew S Corbett, Neil J Flanagan, David Fengas, M Scott Johnson, Lyn H Jones, Brian E Marron, C Elizabeth Payne, David Printzenhoff, David J Rawson, Colin R Rose, Thomas Ryckmans, Jianmin Sun, Jonathan W Theile, Rubben Torella, Elaine Tseng, Joseph S Warmus
The discovery and selection of a highly potent and selective NaV1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A proposed protein-ligand binding mode for this compound is also provided to rationalise the high levels of potency and selectivity over inhibition of related sodium channels. To further support the proposed binding mode, potent conjugates are described which illustrate the potential for development of chemical probes to enable further target evaluation...
November 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28990532/a-novel-scn9a-mutation-f826y-in-primary-erythromelalgia-alters-the-excitability-of-nav1-7
#20
B Wu, Y Zhang, H Tang, Mei Yang, Hai Long, Gaoxing Shi, Jianguang Tang, Xiaoliu Shi
Primary erythromelalgia (PE) is a dominant inherited disorder characterized by recurrent pain, redness, and warmth of the extremities that is caused by gain-of-function mutations in the voltage-gated sodium channel Nav1.7. We investigated a three-generation Chinese Han family with PE. The proband is a 15-year old girl presented with skin ulcers, recurrent burning pain, warmth, and redness of the lower extremities that are refractory to all kinds of reported medications. The other two patients presented with similar symptoms but with far less severity that naturally remitted near their forties...
October 9, 2017: Current Molecular Medicine
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