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https://www.readbyqxmd.com/read/29752399/common-coding-variants-in-scn10a-are-associated-with-the-nav1-8-late-current-and-cardiac-conduction
#1
Vincenzo Macri, Jennifer A Brody, Dan E Arking, William J Hucker, Xiaoyan Yin, Honghuang Lin, Robert W Mills, Moritz F Sinner, Steven A Lubitz, Ching-Ti Liu, Alanna C Morrison, Alvaro Alonso, Ning Li, Vadim V Fedorov, Paul M Janssen, Joshua C Bis, Susan R Heckbert, Elena V Dolmatova, Thomas Lumley, Colleen M Sitlani, L Adrienne Cupples, Sara L Pulit, Christopher Newton-Cheh, John Barnard, Jonathan D Smith, David R Van Wagoner, Mina K Chung, Gus J Vlahakes, Christopher J O'Donnell, Jerome I Rotter, Kenneth B Margulies, Michael P Morley, Thomas P Cappola, Emelia J Benjamin, Donna Muzny, Richard A Gibbs, Rebecca D Jackson, Jared W Magnani, Caroline N Herndon, Stephen S Rich, Bruce M Psaty, David J Milan, Eric Boerwinkle, Peter J Mohler, Nona Sotoodehnia, Patrick T Ellinor
BACKGROUND: Genetic variants at the SCN5A / SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized. METHODS: We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue...
May 2018: Circulation. Genomic and precision medicine
https://www.readbyqxmd.com/read/29722437/the-opioid-oxycodone-use-dependently-inhibits-the-cardiac-sodium-channel-nav1-5
#2
Jannis E Meents, Krisztina Juhasz, Sonja Stölzle-Feix, Vera Peuckmann-Post, Roman Rolke, Angelika Lampert
BACKGROUND AND PURPOSE: Oxycodone is a potent semi-synthetic opioid that is commonly used for the treatment of severe acute and chronic pain. However, treatment with oxycodone can lead to cardiac electrical changes, such as long-QT syndrome, potentially inducing sudden cardiac arrest. Here, we investigate whether the cardiac side effects of oxycodone can be explained by modulation of the cardiac sodium channel Nav1.5. EXPERIMENTAL APPROACH: Heterologously expressed Nav1...
May 3, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29686617/a-chimeric-nav1-8-channel-expression-system-based-on-hek293t-cell-line
#3
Xi Zhou, Yunxiao Zhang, Dongfang Tang, Songping Liang, Ping Chen, Cheng Tang, Zhonghua Liu
Among the nine voltage-gated sodium channel (NaV) subtypes, NaV1.8 is an attractive therapeutic target for pain. The heterologous expression of recombinant NaV1.8 currents is of particular importance for its electrophysiological and pharmacological studies. However, NaV1.8 expresses no or low-level functional currents when transiently transfected into non-neuronal cell lines. The present study aims to explore the molecular determinants limiting its functional expression and accordingly establish a functional NaV1...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29677019/mu-opioid-receptors-in-nociceptive-afferents-produce-a-sustained-suppression-of-hyperalgesia-in-chronic-pain
#4
Amie Severino, Wenling Chen, Joshua K Hakimian, Brigitte L Kieffer, Claire Gaveriaux-Ruff, Wendy Walwyn, Juan Carlos Marvizon
The latent sensitization model of chronic pain reveals that recovery from some types of long-term hyperalgesia is an altered state in which nociceptive sensitization persists but is suppressed by the ongoing activity of analgesic receptors such as µ-opioid receptors (MORs). To determine whether these MORs are the ones present in nociceptive afferents, we bred mice expressing Cre-recombinase under the Nav1.8 channel promoter (Nav1.8cre) with MOR-floxed mice (flMOR). These Nav1.8cre/flMOR mice had reduced MOR expression in primary afferents, as revealed by quantitative PCR, in situ hybridization and immunofluorescence colocalization with the neuropeptide CGRP...
April 17, 2018: Pain
https://www.readbyqxmd.com/read/29572558/modulation-of-sodium-channels-as-pharmacological-tool-for-pain-therapy-highlights-and-gaps
#5
REVIEW
Nilufar Foadi
Voltage-gated sodium channels are crucially involved in the transduction and transmission of nociceptive signals and pathological pain states. In the past decades, a lot of effort has been spent examining and characterizing biophysical properties of the different sodium channels and their role in signaling pathways. Several gains of function mutations of the sodium channels Nav1.7, Nav1.8, and Nav1.9 are associated with pain disorders. Due to their critical role in nociceptive pathways voltage-gated sodium channels are regarded interesting targets for pharmacological pain treatment...
March 23, 2018: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/29554219/prrt2-controls-neuronal-excitability-by-negatively-modulating-na-channel-1-2-1-6-activity
#6
Floriana Fruscione, Pierluigi Valente, Bruno Sterlini, Alessandra Romei, Simona Baldassari, Manuela Fadda, Cosimo Prestigio, Giorgia Giansante, Jacopo Sartorelli, Pia Rossi, Alicia Rubio, Antonio Gambardella, Thierry Nieus, Vania Broccoli, Anna Fassio, Pietro Baldelli, Anna Corradi, Federico Zara, Fabio Benfenati
Proline-rich transmembrane protein 2 (PRRT2) is the causative gene for a heterogeneous group of familial paroxysmal neurological disorders that include seizures with onset in the first year of life (benign familial infantile seizures), paroxysmal kinesigenic dyskinesia or a combination of both. Most of the PRRT2 mutations are loss-of-function leading to haploinsufficiency and 80% of the patients carry the same frameshift mutation (c.649dupC; p.Arg217Profs*8), which leads to a premature stop codon. To model the disease and dissect the physiological role of PRRT2, we studied the phenotype of neurons differentiated from induced pluripotent stem cells from previously described heterozygous and homozygous siblings carrying the c...
March 15, 2018: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29545351/endothelin-type-a-receptors-mediate-pain-in-a-mouse-model-of-sickle-cell-disease
#7
Brianna Marie Lutz, Shaogen Wu, Xiyao Gu, Fidelis E Atianjoh, Zhen Li, Brandon M Fox, David M Pollock, Yuan-Xiang Tao
Sickle cell disease is associated with acute painful episodes and chronic intractable pain. Endothelin-1, a known pain inducer, is elevated in the blood plasma of both sickle cell patients and mouse models of sickle cell disease. We show here that the levels of endothelin-1 and its endothelin type A receptor are increased in the dorsal root ganglia of a mouse model of sickle cell disease. Pharmacologic inhibition or neuron-specific knockdown of endothelin type A receptors in primary sensory neurons of dorsal root ganglion alleviated basal and post-hypoxia evoked pain hypersensitivities in sickle cell mice...
March 15, 2018: Haematologica
https://www.readbyqxmd.com/read/29533926/reducing-cxcr4-mediated-nociceptor-hyperexcitability-reverses-painful-diabetic-neuropathy
#8
Nirupa D Jayaraj, Bula J Bhattacharyya, Abdelhak A Belmadani, Dongjun Ren, Craig A Rathwell, Sandra Hackelberg, Brittany E Hopkins, Herschel R Gupta, Richard J Miller, Daniela M Menichella
Painful diabetic neuropathy (PDN) is an intractable complication of diabetes that affects 25% of patients. PDN is characterized by neuropathic pain and small-fiber degeneration, accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability and loss of their axons within the skin. The molecular mechanisms underlying DRG nociceptor hyperexcitability and small-fiber degeneration in PDN are unknown. We hypothesize that chemokine CXCL12/CXCR4 signaling is central to this mechanism, as we have shown that CXCL12/CXCR4 signaling is necessary for the development of mechanical allodynia, a pain hypersensitivity behavior common in PDN...
April 23, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29495239/-homocysteine-induces-calcium-overload-in-neonatal-rat-atrial-cells-through-activation-of-sodium-current-and-camk%C3%A2-%C3%AE
#9
L Han, Q B Dong, Y C Wei, A C Zheng, J X Li, K Hong, Y Q Wu, X S Cheng
Objective: To investigate the effect and related mechanism of homocysteine (Hcy) on calcium overload in neonatal rat atrial cells (NRICs). Methods: NRICs were assigned to 9 groups after culture for 3 days: (1) control group; (2) Hcy group (0, 50, 100, 200, 500 μmol/L for 48 hours); (3) antioxidant group (NAC, 10 μmol/L for 24 hours); (4) Hcy+NAC group (500 μmol/L Hcy for 48 hours, then treated with 10 μmol/L NAC for 24 hours); (5) calcium/calmodulin dependent protein kinase Ⅱδ (CaMKⅡδ) inhibitor group (KN-93, 3 μmol/L KN-93 for 5 hours); (6) specific sodium current inhibitor group (ELE, 1 μmol/L ELE for 5 hours); (7) Hcy+KN-93 group (500 μmol/L Hcy for 48 hours, then treated with 3 μmol/L KN-93 for 5 hours); (8) Hcy+ELE group (500 μmol/L Hcy for 48 hours, then treated with 1 μmol/L ELE for 5 hours; (9) Hcy+KN-93+ELE group (500 μmol/L Hcy for 48 hours, then treated with 3 μmol/L KN-93 and 1 μmol/L ELE for 5 hours)...
February 24, 2018: Zhonghua Xin Xue Guan Bing za Zhi
https://www.readbyqxmd.com/read/29474860/pharmacological-targeting-of-the-mammalian-clock-reveals-a-novel-analgesic-for-osteoarthritis-induced-pain
#10
Vaskar Das, Ranjan Kc, Xin Li, Disha Varma, Sujun Qiu, Jeffrey S Kroin, Christopher B Forsyth, Ali Keshavarzian, Andre J van Wijnen, Thomas J Park, Gary S Stein, Insug O-Sullivan, Thomas P Burris, Hee-Jeong Im
Environmental disruption of the circadian rhythm is linked with increased pain due to osteoarthritis (OA). We aimed to characterize the role of the clock gene in OA-induced pain more systemically using both genetic and pharmacological approaches. Genetically modified mice, (bmal1f/fNav1.8CreERT mice), generated by deleting the critical clock gene, bmal1, from Nav1.8 sensory neurons, were resistant to the development of mechanical hyperalgesia associated with OA induced by partial medial meniscectomy (PMM) of the knee...
May 20, 2018: Gene
https://www.readbyqxmd.com/read/29470418/tetrodotoxin-a-candidate-drug-for-nav1-1-induced-mechanical-pain
#11
César Mattei
Tetrodotoxin (TTX), the mode of action of which has been known since the 1960s, is widely used in pharmacology as a specific inhibitor of voltage-gated sodium channels (Nav channels). This toxin has contributed to the characterization of the allosteric model of the Nav channel, and to discriminating TTX-sensitive and TTX-resistant subtypes. In addition to its role as a pharmacological tool, TTX is now considered a therapeutic molecule, and its development should lead to its use in certain pathologies involving Nav channels, particularly in the field of pain...
February 22, 2018: Marine Drugs
https://www.readbyqxmd.com/read/29435993/different-role-of-ttx-sensitive-voltage-gated-sodium-channel-na-v-1-subtypes-in-action-potential-initiation-and-conduction-in-vagal-airway-nociceptors
#12
M Kollarik, H Sun, R A Herbstsomer, F Ru, M Kocmalova, S N Meeker, B J Undem
KEY POINTS: The action potential initiation in the nerve terminals and its subsequent conduction along the axons of afferent nerves are not necessarily dependent on the same voltage-gated sodium channel (NaV 1) subunits. The action potential initiation in jugular C-fibres within airway tissues is not blocked by TTX; nonetheless, conduction of action potentials along the vagal axons of these nerves is often dependent on TTX-sensitive channels. This is not the case for nodose airway Aδ-fibres and C-fibres, where both action potential initiation and conduction is abolished by TTX or selective NaV 1...
April 15, 2018: Journal of Physiology
https://www.readbyqxmd.com/read/29433959/the-effect-of-ethanol-extract-of-glycyrrhiza-uralensis-on-the-voltage-gated-sodium-channel-subtype-1-4
#13
Guangwei Zhu, Shengjun Ma, Xiwen Li, Peng Zhang, Lin Tang, Lijuan Cao, Aoxue Liu, Toru Sugita, Takehisa Tomoda
To investigate the inhibitory effect of Glycyrrhiza uralensis (G. uralensis) and its monomeric compounds on Nav1.4 voltage-gated sodium channels (VGSCs) and analyze the relationship between the content of its marker compounds and the inhibitory rate. Based on this study, we found that 4 mg/ml ethanol extract of G. uralensis at 30%, 50%, 70% and 90% (v/v) exhibited 77.00 ± 0.03%, 34.75 ± 0.09%, 100.00 ± 0.01% and 2.00 ± 0.01% inhibitory rates on INav 1.4 respectively, and 8 mg/ml ethanol extract of G...
February 2018: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/29369966/orally-active-epac-inhibitor-reverses-mechanical-allodynia-and-loss-of-intraepidermal-nerve-fibers-in-a-mouse-model-of-chemotherapy-induced-peripheral-neuropathy
#14
Pooja Singhmar, XiaoJiao Huo, Yan Li, Patrick M Dougherty, Fang Mei, Xiaodong Cheng, Cobi J Heijnen, Annemieke Kavelaars
Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of cancer treatment that significantly compromises quality of life of cancer patients and survivors. Identification of targets for pharmacological intervention to prevent or reverse CIPN is needed. We investigated exchange protein regulated by cAMP (Epac) as a potential target. Epacs are cAMP-binding proteins known to play a pivotal role in mechanical allodynia induced by nerve injury and inflammation. We demonstrate that global Epac1-knockout (Epac1-/-) male and female mice are protected against paclitaxel-induced mechanical allodynia...
May 2018: Pain
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
#15
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...
April 2018: Acupuncture in Medicine: Journal of the British Medical Acupuncture Society
https://www.readbyqxmd.com/read/29299961/erythromelalgia
#16
REVIEW
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...
February 2018: VASA. Zeitschrift Für Gefässkrankheiten
https://www.readbyqxmd.com/read/29229553/human-vs-mouse-nociceptors-similarities-and-differences
#17
Charlotte Rostock, Katrin Schrenk-Siemens, Jörg Pohle, Jan Siemens
The somatosensory system allows us to detect a diverse range of physical and chemical stimuli including noxious ones, which can initiate protective reflexes to prevent tissue damage. However, the sensation of pain can - under pathological circumstances - outlive its usefulness and perpetrate ongoing suffering. Rodent model systems have been tremendously useful to help understand basic mechanisms of pain perception. Unfortunately, the translation of this knowledge into novel therapies has been challenging. We have investigated similarities and differences of human and mouse peptidergic (TRKA expressing) nociceptors using dual-color fluorescence in situ hybridization of dorsal root ganglia...
December 8, 2017: Neuroscience
https://www.readbyqxmd.com/read/29194125/nav1-7-and-pain-contribution-of-peripheral-nerves
#18
Tal Hoffmann, Ohad Sharon, Jürgen Wittmann, Richard W Carr, Alina Vyshnevska, Roberto De Col, Mohammed A Nassar, Peter W Reeh, Christian Weidner
The sodium channel NaV1.7 contributes to action potential (AP) 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 central nervous system 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 normally mechanosensitive C-fibers, although (2) the rare heat responses seemed quite vigorous, and (3) heat-induced calcitonin gene-related peptide release was normal...
March 2018: Pain
https://www.readbyqxmd.com/read/29161016/selective-voltage-gated-sodium-channel-peptide-toxins-from-animal-venom-pharmacological-probes-and-analgesic-drug-development
#19
Ying Wu, Hui Ma, Fan Zhang, Chunlei 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 represent valuable probes to elucidate the structures, gating properties, and cellular functions of ion channels...
February 21, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29138838/effects-of-scn9a-gene-modification-on-na-channel-and-the-expression-of-nerve-growth-factor-in-a-rat-model-of-diarrhea%C3%A2-predominant-irritable-bowel-syndrome
#20
Yong-Yan Cai, Chen Li, Zhi-Xin Yan, Na Ma, Fang-Fang Li
The aim of the present study was to identify whether the sodium voltage-gated channel alpha subunit 9 (SCN9A) gene modification is a potential treatment for diarrhea‑predominant irritable bowel syndrome (D‑IBS), via regulating the Na+ channel and the expression of nerve growth factor (NGF). The recombinant adenovirus vector of the SCN9A gene was established, and rat colon cells were isolated for SCN9A gene modification. All subjects were divided into four groups: i) The SCN9A‑modified (D‑IBS rat model implanted with SCN9A‑modified colon cells), ii) negative control (NC; D‑IBS rat model implanted with colon cells without SCN9A gene modification), iii) blank (D‑IBS rat model without any treatment) and iv) normal (normal rats without any treatment)...
January 2018: Molecular Medicine Reports
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