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https://www.readbyqxmd.com/read/28611388/aberrant-plasticity-of-peripheral-sensory-axons-in-a-painful-neuropathy
#1
Takashi Hirai, Yatendra Mulpuri, Yanbing Cheng, Zheng Xia, Wei Li, Supanigar Ruangsri, Igor Spigelman, Ichiro Nishimura
Neuronal cells express considerable plasticity responding to environmental cues, in part, through subcellular mRNA regulation. Here we report on the extensive changes in distribution of mRNAs in the cell body and axon compartments of peripheral sensory neurons and the 3' untranslated region (3'UTR) landscapes after unilateral sciatic nerve entrapment (SNE) injury in rats. Neuronal cells dissociated from SNE-injured and contralateral L4 and L5 dorsal root ganglia were cultured in a compartmentalized system. Axonal and cell body RNA samples were separately subjected to high throughput RNA sequencing (RNA-Seq)...
June 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28558976/chronic-exposure-to-tumor-necrosis-factor-in-vivo-induces-hyperalgesia-upregulates-sodium-channel-gene-expression-and-alters-the-cellular-electrophysiology-of-dorsal-root-ganglion-neurons
#2
Bradford D Fischer, Cojen Ho, Igor Kuzin, Andrea Bottaro, Michael E O'Leary
The goal of these studies was to investigate the links between chronic exposure to the pro-inflammatory cytokine tumor necrosis factor (TNF), hyperalgesia and the excitability of dorsal root ganglion (DRG) sensory neurons. We employed transgenic mice that constitutively express TNF (TNFtg mice), a well-established model of chronic systemic inflammation. At 6 months of age, TNFtg mice demonstrated increased sensitivity to both mechanical and thermal heat stimulation relative to aged-matched wild-type controls...
May 27, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28554967/basal-late-sodium-current-is-a-significant-contributor-to-the-duration-of-action-potential-of-guinea-pig-ventricular-myocytes
#3
Yejia Song, Luiz Belardinelli
In cardiac myocytes, an enhancement of late sodium current (INaL) under pathological conditions is known to cause prolongation of action potential duration (APD). This study investigated the contribution of INaL under basal, physiological conditions to the APD Whole-cell INaL and the APD of ventricular myocytes isolated from healthy adult guinea pigs were measured at 36°C. The INaL inhibitor GS967 or TTX was applied to block INaL The amplitude of basal INaL and the APD at 50% repolarization in myocytes stimulated at a frequency of 0...
May 2017: Physiological Reports
https://www.readbyqxmd.com/read/28530638/sodium-channel-nav1-9-mutations-associated-with-insensitivity-to-pain-dampen-neuronal-excitability
#4
Jianying Huang, Carlos G Vanoye, Alison Cutts, Y Paul Goldberg, Sulayman D Dib-Hajj, Charles J Cohen, Stephen G Waxman, Alfred L George
Voltage-gated sodium channel (NaV) mutations cause genetic pain disorders that range from severe paroxysmal pain to a congenital inability to sense pain. Previous studies on NaV1.7 and NaV1.8 established clear relationships between perturbations in channel function and divergent clinical phenotypes. By contrast, studies of NaV1.9 mutations have not revealed a clear relationship of channel dysfunction with the associated and contrasting clinical phenotypes. Here, we have elucidated the functional consequences of a NaV1...
May 22, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28522215/blocking-voltage-gated-sodium-channels-as-a-strategy-to-suppress-pathological-cough
#5
REVIEW
Hui Sun, Marian Kollarik, Bradley J Undem
Pathological cough is thought to be secondary to inappropriate activation of vagal sensory nerves. Sensory nerves can be activated by a large number of disparate stimuli. The most relevant stimuli to block for effective anti-tussive therapy likely depend on the specific underlying pathology that is leading to the coughing. Blocking voltage-gated sodium channels (NaV) will prevent action potential initiation and conduction and therefore prevent sensory communication between the airways and brainstem. In so doing, they would be expected to inhibit evoked cough independently of the nature of the stimulus and underlying pathology...
May 15, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28515230/crosstalk-from-camp-to-erk1-2-emerges-during-postnatal-maturation-of-nociceptive-neurons-and-is-maintained-during-aging
#6
Joerg Isensee, Cosimo Schild, Frank Schwede, Tim Hucho
Maturation of nociceptive neurons depends on changes of transcription factors, ion channels, and neuropeptides. Mature nociceptors initiate pain in part by drastically reducing the activation threshold via intracellular sensitization signaling. If sensitization signaling also changes during development and aging remains so far unknown.Using a novel automated microscopy approach, we quantified changes of intracellular signaling protein expression, of their signaling dynamics, as well as of intracellular signaling cascade wiring in sensory neurons from newborn to senescent rats...
May 17, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28473457/pharmacologic-characterization-of-amg8379-a-potent-and-selective-small-molecule-sulfonamide-antagonist-of-the-voltage-gated-sodium-channel-nav1-7
#7
Thomas J Kornecook, Ruoyuan Yin, Stephen Altmann, Xuhai Be, Virginia Berry, Christopher P Ilch, Michael Jarosh, Danielle Johnson, Josie H Lee, Sonya G Lehto, Joseph Ligutti, Dong Liu, Jason Luther, David Matson, Danny Ortuno, John Roberts, Kristin Taborn, Jinti Wang, Matthew M Weiss, Violeta Yu, Dawn X D Zhu, Robert T Fremeau, Bryan D Moyer
Potent and selective antagonists of the voltage-gated sodium channel NaV1.7 represent a promising avenue for the development of new chronic pain therapies. We generated a small molecule atropisomer quinolone sulfonamide antagonist AMG8379 and a less active enantiomer AMG8380. Here we show that AMG8379 potently blocks human NaV1.7 channels with an IC50 of 8.5 nM and endogenous tetrodotoxin (TTX)-sensitive sodium channels in dorsal root ganglion (DRG) neurons with an IC50 of 3.1 nM in whole-cell patch clamp electrophysiology assays using a voltage protocol that interrogates channels in a partially inactivated state...
July 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28450535/sodium-channel-nav1-8-underlies-ttx-resistant-axonal-action-potential-conduction-in-somatosensory-c-fibers-of-distal-cutaneous-nerves
#8
Amanda H Klein, Alina Vyshnevska, Timothy V Hartke, Roberto De Col, Joseph L Mankowski, Brian Turnquist, Frank Bosmans, Peter W Reeh, Martin Schmelz, Richard W Carr, Matthias Ringkamp
Voltage-gated sodium (NaV) channels are responsible for the initiation and conduction of action potentials within primary afferents. The nine NaV channel isoforms recognized in mammals are often functionally divided into tetrodotoxin (TTX)-sensitive (TTX-s) channels (NaV1.1-NaV1.4, NaV1.6-NaV1.7) that are blocked by nanomolar concentrations and TTX-resistant (TTX-r) channels (NaV1.8 and NaV1.9) inhibited by millimolar concentrations, with NaV1.5 having an intermediate toxin sensitivity. For small-diameter primary afferent neurons, it is unclear to what extent different NaV channel isoforms are distributed along the peripheral and central branches of their bifurcated axons...
May 17, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28440280/targeting-asic3-for-relieving-mice-fibromyalgia-pain-roles-of-electroacupuncture-opioid-and-adenosine
#9
Liang-Ta Yen, Ching-Liang Hsieh, Hsin-Cheng Hsu, Yi-Wen Lin
Many scientists are seeking better therapies for treating fibromyalgia (FM) pain. We used a mouse model of FM to determine if ASIC3 and its relevant signaling pathway participated in FM pain. We demonstrated that FM-induced mechanical hyperalgesia was attenuated by electroacupuncture (EA). The decrease in fatigue-induced lower motor function in FM mice was also reversed by EA. These EA-based effects were abolished by the opioid receptor antagonist naloxone and the adenosine A1 receptor antagonist rolofylline...
April 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28438981/acute-inflammation-reveals-gabaa-receptor-mediated-nociception-in-mouse-dorsal-root-ganglion-neurons-via-pge2-receptor-4-signaling
#10
In Jeong Jang, Alexander J Davies, Nozomi Akimoto, Seung Keun Back, Pa Reum Lee, Heung Sik Na, Hidemasa Furue, Sung Jun Jung, Yong Ho Kim, Seog Bae Oh
Gamma-aminobutyric acid (GABA) depolarizes dorsal root ganglia (DRG) primary afferent neurons through activation of Cl(-) permeable GABAA receptors but the physiologic role of GABAA receptors in the peripheral terminals of DRG neurons remains unclear. In this study, we investigated the role of peripheral GABAA receptors in nociception using a mouse model of acute inflammation. In vivo, peripheral administration of the selective GABAA receptor agonist muscimol evoked spontaneous licking behavior, as well as spinal wide dynamic range (WDR) neuron firing, after pre-conditioning with formalin but had no effect in saline-treated mice...
April 2017: Physiological Reports
https://www.readbyqxmd.com/read/28424991/expression-and-role-of-voltage-gated-sodium-channels-in-human-dorsal-root-ganglion-neurons-with-special-focus-on-nav1-7-species-differences-and-regulation-by-paclitaxel
#11
Wonseok Chang, Temugin Berta, Yong Ho Kim, Sanghoon Lee, Seok-Yong Lee, Ru-Rong Ji
Voltage-gated sodium channels (Navs) play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained human dorsal root ganglion (hDRG) tissues from healthy donors. PCR analysis of seven DRG-expressed Nav subtypes revealed that the hDRG has higher expression of Nav1.7 (~50% of total Nav expression) and lower expression of Nav1.8 (~12%), whereas the mouse DRG has higher expression of Nav1.8 (~45%) and lower expression of Nav1...
April 19, 2017: Neuroscience Bulletin
https://www.readbyqxmd.com/read/28388364/piezo2-expression-in-mechanosensitive-dental-primary-afferent-neurons
#12
J Won, H Vang, P R Lee, Y H Kim, H W Kim, Y Kang, S B Oh
Mechanosensitive ion channels have been suggested to be expressed in dental primary afferent (DPA) neurons to transduce the movement of dentinal fluid since the proposal of hydrodynamic theory. Piezo2, a mechanosensitive, rapidly inactivating (RI) ion channel, has been recently identified in dorsal root ganglion (DRG) neurons to mediate tactile transduction. Here, we examined the expression of Piezo2 in DPA neurons by in situ hybridization, single-cell reverse transcriptase polymerase chain reaction, and whole-cell patch-clamp recordings...
April 1, 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/28373696/blocking-the-nav1-8-channel-in-the-left-stellate-ganglion-suppresses-ventricular-arrhythmia-induced-by-acute-ischemia-in-a-canine-model
#13
Lilei Yu, Menglong Wang, Dan Hu, Bing Huang, Liping Zhou, Xiaoya Zhou, Zhuo Wang, Songyun Wang, Hong Jiang
Left stellate ganglion (LSG) hyperactivity promotes ischemia induced ventricular arrhythmia (VA). Blocking the Nav1.8 channel decreases neuron activity. Therefore, the present study aimed to investigate whether blocking the Nav1.8 channel with its specific blocker A-803467 in the LSG reduces sympathetic activity and exerts anti-arrhythmic effects. Forty canines were divided into dimethylsulfoxide (DMSO) group and 10 mM, 15 mM, and 20 mM A-803467 groups. A volume of 0.1 ml of A-803467 or DMSO was injected into the LSG...
April 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28373680/activity-and-connectivity-changes-of-central-projection-areas-revealed-by-functional-magnetic-resonance-imaging-in-nav1-8-deficient-mice-upon-cold-signaling
#14
C Heindl-Erdmann, K Zimmermann, P Reeh, K Brune, A Hess
The voltage-gated sodium channel subtype NaV1.8 is expressed in the peripheral nervous system in primary afferent nociceptive C-fibers and is essential for noxious cold signaling. We utilized functional magnetic resonance imaging on NaV1.8-deficient (NaV1.8(-/-)) compared with wildtype (WT) mice to identify brain structures decoding noxious cold and/or heat signals. In NaV1.8(-/-) mice functional activity patterns, activated volumes and BOLD signal amplitudes are significantly reduced upon noxious cold stimulation whereas differences of noxious heat processing are less pronounced...
April 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28345287/contribution-of-platelet-p2y12-receptors-to-chronic-complete-freund-s-adjuvant-induced-inflammatory-pain
#15
K Bekő, B Koványi, F Gölöncsér, G Horváth, Á Dénes, Z Környei, B Botz, Z Helyes, C E Müller, B Sperlágh
Essentials The role of platelet P2Y12 receptors in the regulation of chronic inflammatory pain is unknown. Complete Freund's Adjuvant (CFA)-induced chronic inflammatory pain model was used in mice. Gene deficiency and antagonists of P2Y12 receptors attenuate hyperalgesia and local inflammation. Platelet P2Y12 receptors contribute to these effects in the chronic phase of inflammation. SUMMARY: Background P2Y12 receptor antagonists are widely used in clinical practice to inhibit platelet aggregation...
June 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28337946/up-regulation-of-cxcr4-expression-contributes-to-persistent-abdominal-pain-in-rats-with-chronic-pancreatitis
#16
Hong-Yan Zhu, Xuelian Liu, Xiuhua Miao, Di Li, Shusheng Wang, Guang-Yin Xu
Background Pain in patients with chronic pancreatitis is critical hallmark that accompanied inflammation, fibrosis, and destruction of glandular pancreas. Many researchers have demonstrated that stromal cell-derived factor 1 (also named as CXCL12) and its cognate receptor C-X-C chemokine receptor type 4 (CXCR4) involved in mediating neuropathic and bone cancer pain. However, their roles in chronic pancreatic pain remain largely unclear. Methods Chronic pancreatitis was induced by intraductal injection of trinitrobenzene sulfonic acid to the pancreas...
January 2017: Molecular Pain
https://www.readbyqxmd.com/read/28326938/mechanisms-of-nerve-growth-factor-signaling-in-bone-nociceptors-and-in-an-animal-model-of-inflammatory-bone-pain
#17
Sara Nencini, Mitchell Ringuet, Dong-Hyun Kim, Yu-Jen Chen, Claire Greenhill, Jason J Ivanusic
Sequestration of nerve growth factor has been used successfully in the management of pain in animal models of bone disease and in human osteoarthritis. However, the mechanisms of nerve growth factor-induced bone pain and its role in modulating inflammatory bone pain remain to be determined. In this study, we show that nerve growth factor receptors (TrkA and p75) and some other nerve growth factor-signaling molecules (TRPV1 and Nav1.8, but not Nav1.9) are expressed in substantial proportions of rat bone nociceptors...
January 2017: Molecular Pain
https://www.readbyqxmd.com/read/28298301/in-vivo-optogenetic-activation-of-nav1-8-cutaneous-nociceptors-and-their-responses-to-natural-stimuli
#18
Megan L Uhelski, Daniel J Bruce, Philippe Séguéla, George L Wilcox, Donald A Simone
Optogenetic methods that utilize expression of the light-sensitive protein channelrhodopsin-2 (ChR2) in neurons have enabled selective activation of specific subtypes or groups of neurons to determine their functions. Using a transgenic mouse model in which neurons natively expressing Nav1.8 (a tetrodotoxin-resistant voltage-gated sodium channel) also express the light-gated channel ChR2, we have been able to determine the functional properties of Nav1.8-expressing cutaneous nociceptors of the glabrous skin in vivo...
June 1, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28225079/multiple-sodium-channel-isoforms-mediate-the-pathological-effects-of-pacific-ciguatoxin-1
#19
Marco C Inserra, Mathilde R Israel, Ashlee Caldwell, Joel Castro, Jennifer R Deuis, Andrea M Harrington, Angelo Keramidas, Sonia Garcia-Caraballo, Jessica Maddern, Andelain Erickson, Luke Grundy, Grigori Y Rychkov, Katharina Zimmermann, Richard J Lewis, Stuart M Brierley, Irina Vetter
Human intoxication with the seafood poison ciguatoxin, a dinoflagellate polyether that activates voltage-gated sodium channels (NaV), causes ciguatera, a disease characterised by gastrointestinal and neurological disturbances. We assessed the activity of the most potent congener, Pacific ciguatoxin-1 (P-CTX-1), on NaV1.1-1.9 using imaging and electrophysiological approaches. Although P-CTX-1 is essentially a non-selective NaV toxin and shifted the voltage-dependence of activation to more hyperpolarising potentials at all NaV subtypes, an increase in the inactivation time constant was observed only at NaV1...
February 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28216001/loperamide-inhibits-sodium-channels-to-alleviate-inflammatory-hyperalgesia
#20
Ying Wu, Beiyan Zou, Lingli Liang, Min Li, Yuan-Xiang Tao, Haibo Yu, Xiaoliang Wang, Min Li
Previous studies demonstrated that Loperamide, originally known as an anti-diarrheal drug, is a promising analgesic agent primarily targeting mu-opioid receptors. However some evidences suggested that non-opioid mechanisms may be contributing to its analgesic effect. In the present study, Loperamide was identified as a Nav1.7 blocker in a pilot screen. In HEK293 cells expressing Nav1.7 sodium channels, Loperamide blocked the resting state of Nav1.7 channels (IC50 = 1.86 ± 0.11 μM) dose-dependently and reversibly...
February 16, 2017: Neuropharmacology
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