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https://www.readbyqxmd.com/read/28905186/antidepressants-inhibit-nav1-3-nav1-7-and-nav1-8-neuronal-voltage-gated-sodium-channels-more-potently-than-nav1-2-and-nav1-6-channels-expressed-in-xenopus-oocytes
#1
Takafumi Horishita, Nobuyuki Yanagihara, Susumu Ueno, Dan Okura, Reiko Horishita, Tomoko Minami, Yuichi Ogata, Yuka Sudo, Yasuhito Uezono, Takeyoshi Sata, Takashi Kawasaki
Tricyclic antidepressants (TCAs) and duloxetine are used to treat neuropathic pain. However, the mechanisms underlying their analgesic effects remain unclear. Although many investigators have shown inhibitory effects of antidepressants on voltage-gated sodium channels (Nav) as a possible mechanism of analgesia, to our knowledge, no one has compared effects on the diverse variety of sodium channel α subunits. We investigated the effects of antidepressants on sodium currents in Xenopus oocytes expressing Nav1...
September 14, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28880874/discovery-and-mode-of-action-of-a-novel-analgesic-%C3%AE-toxin-from-the-african-spider-ceratogyrus-darlingi
#2
Silmara R Sousa, Joshua S Wingerd, Andreas Brust, Christopher Bladen, Lotten Ragnarsson, Volker Herzig, Jennifer R Deuis, Sebastien Dutertre, Irina Vetter, Gerald W Zamponi, Glenn F King, Paul F Alewood, Richard J Lewis
Spider venoms are rich sources of peptidic ion channel modulators with important therapeutical potential. We screened a panel of 60 spider venoms to find modulators of ion channels involved in pain transmission. We isolated, synthesized and pharmacologically characterized Cd1a, a novel peptide from the venom of the spider Ceratogyrus darlingi. Cd1a reversibly paralysed sheep blowflies (PD50 of 1318 pmol/g) and inhibited human Cav2.2 (IC50 2.6 μM) but not Cav1.3 or Cav3.1 (IC50 > 30 μM) in fluorimetric assays...
2017: PloS One
https://www.readbyqxmd.com/read/28871199/morphine-induced-hyperalgesia-involves-mu-opioid-receptors-and-the-metabolite-morphine-3-glucuronide
#3
Laurie-Anne Roeckel, Valérie Utard, David Reiss, Jinane Mouheiche, Hervé Maurin, Anne Robé, Emilie Audouard, John N Wood, Yannick Goumon, Frédéric Simonin, Claire Gaveriaux-Ruff
Opiates are potent analgesics but their clinical use is limited by side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). The Opiates produce analgesia and other adverse effects through activation of the mu opioid receptor (MOR) encoded by the Oprm1 gene. However, MOR and morphine metabolism involvement in OIH have been little explored. Hence, we examined MOR contribution to OIH by comparing morphine-induced hyperalgesia in wild type (WT) and MOR knockout (KO) mice. We found that repeated morphine administration led to analgesic tolerance and hyperalgesia in WT mice but not in MOR KO mice...
September 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28867800/ciguatoxins-evoke-potent-cgrp-release-by-activation-of-voltage-gated-sodium-channel-subtypes-nav1-9-nav1-7-and-nav1-1
#4
Filip Touska, Simon Sattler, Philipp Malsch, Richard J Lewis, Peter W Reeh, Katharina Zimmermann
Ciguatoxins (CTXs) are marine toxins that cause ciguatera fish poisoning, a debilitating disease dominated by sensory and neurological disturbances that include cold allodynia and various painful symptoms as well as long-lasting pruritus. Although CTXs are known as the most potent mammalian sodium channel activator toxins, the etiology of many of its neurosensory symptoms remains unresolved. We recently described that local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1) into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP) from nerve terminals...
August 30, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28790377/the-analgesic-activities-of-stauntonia-brachyanthera-and-ym11-through-regulating-inflammatory-mediators-and-directly-controlling-the-sodium-channel-prompt
#5
Dali Meng, Lei Wang, Jingnan Du, Jianchao Chen, Chao Chen, Wei Xu, Chunli Li
The analgesic studies on Stauntonia brachyanthera, a traditional Chinese folk medicine used to treat headache, pains and inflammatory diseases in local areas, showed that the EtOH extracts (EESB) and the characteristic ingredient YM11 could significantly inhibit the acetic acid-induced writhing responses by 43.1% and 78.95%, and decrease the xylene-induced ear edemas by 48.9% and 21.4%, respectively. EESB could significantly increase pain threshold of mice in hot-plate test, but the effect of YM11 was not obviously...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28769585/%C3%AE-lipoic-acid-suppresses-neuronal-excitability-and-attenuates-colonic-hypersensitivity-to-colorectal-distention-in-diabetic-rats
#6
Yan Sun, Pan-Pan Yang, Zhen-Yuan Song, Yu Feng, Duan-Min Hu, Ji Hu, Guang-Yin Xu, Hong-Hong Zhang
AIM: Patients with long-standing diabetes often demonstrate intestinal dysfunction, characterized as constipation or colonic hypersensitivity. Our previous studies have demonstrated the roles of voltage-gated sodium channels NaV1.7 and NaV1.8 in dorsal root ganglion (DRG) in colonic hypersensitivity of rats with diabetes. This study was designed to determine roles of antioxidant α-lipoic acid (ALA) on sodium channel activities and colonic hypersensitivity of rats with diabetes. METHODS: Streptozotocin was used to induce diabetes in adult female rats...
2017: Journal of Pain Research
https://www.readbyqxmd.com/read/28727712/intervertebral-foramen-injection-of-ozone-relieves-mechanical-allodynia-and-enhances-analgesic-effect-of-gabapentin-in-animal-model-of-neuropathic-pain
#7
Wen-Jun Luo, Fan Yang, Fei Yang, Wei Sun, Wei Zheng, Xiao-Liang Wang, Fang-Fang Wu, Jiang-Lin Wang, Jia-Shuang Wang, Su-Min Guan, Jun Chen
BACKGROUND: In a 5-year follow-up study in a hospital in southern China, it was shown that intervertebral foramen (IVF) injection of ozone at the involved segmental levels could significantly alleviate paroxysmal spontaneous pain and mechanical allodynia in patients with chronic, intractable postherpetic neuralgia (PHN) and improve the quality of life. However, so far no proof-of-concept studies in animals have been available. OBJECTIVE: This study was designed to investigate whether IVF ozone has an analgesic effect on animal models of neuropathic and inflammatory pain...
July 2017: Pain Physician
https://www.readbyqxmd.com/read/28710467/human-ipsc-derived-cardiomyocytes-cultured-in-3d-engineered-heart-tissue-show-physiological-upstroke-velocity-and-sodium-current-density
#8
Marc D Lemoine, Ingra Mannhardt, Kaja Breckwoldt, Maksymilian Prondzynski, Frederik Flenner, Bärbel Ulmer, Marc N Hirt, Christiane Neuber, András Horváth, Benjamin Kloth, Hermann Reichenspurner, Stephan Willems, Arne Hansen, Thomas Eschenhagen, Torsten Christ
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising tool for drug testing and modelling genetic disorders. Abnormally low upstroke velocity is a current limitation. Here we investigated the use of 3D engineered heart tissue (EHT) as a culture method with greater resemblance to human heart tissue in comparison to standard technique of 2D monolayer (ML) format. INa was measured in ML or EHT using the standard patch-clamp technique. INa density was ~1.8 fold larger in EHT (-18...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28701920/tlx3-function-in-the-dorsal-root-ganglion-is-pivotal-to-itch-and-pain-sensations
#9
Chengcheng Huang, Fumin Lu, Ping Li, Cheng Cao, Zijing Liu
Itch, a sensation eliciting a desire to scratch, is distinct from but not completely independent of pain. Inspiring achievements have been made in the characterization of itch-related receptors and neurotransmitters, but the molecular mechanisms controlling the development of pruriceptors remain poorly understood. Here, our RNAseq and in situ hybridization data show that the transcription factor Tlx3 is required for the expression of a majority of itch-related molecules in the dorsal root ganglion (DRG). As a result, Tlx3(F/F);Nav1...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28658621/nociceptors-boost-the-resolution-of-fungal-osteoinflammation-via-the-trp-channel-cgrp-jdp2-axis
#10
Kenta Maruyama, Yasunori Takayama, Takeshi Kondo, Ken-Ichi Ishibashi, Bikash Ranjan Sahoo, Hisashi Kanemaru, Yutaro Kumagai, Mikaël M Martino, Hiroki Tanaka, Naohito Ohno, Yoichiro Iwakura, Naoki Takemura, Makoto Tominaga, Shizuo Akira
Candida albicans can enter skeletal tissue through a skin wound in an immunocompromised host or by contamination during orthopedic surgery. Such Candida osteomyelitis is accompanied by severe pain and bone destruction. It is established that nociceptor innervation occurs in skin and bone, but the mechanisms of nociceptive modulation in fungal inflammation remain unclear. In this study, we show that C. albicans stimulates Nav1.8-positive nociceptors via the β-glucan receptor Dectin-1 to induce calcitonin gene-related peptide (CGRP)...
June 27, 2017: Cell Reports
https://www.readbyqxmd.com/read/28611388/aberrant-plasticity-of-peripheral-sensory-axons-in-a-painful-neuropathy
#11
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
#12
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...
July 13, 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
#13
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
#14
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...
June 30, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28522215/blocking-voltage-gated-sodium-channels-as-a-strategy-to-suppress-pathological-cough
#15
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
#16
Joerg Isensee, Cosimo Schild, Frank Schwede, Tim Hucho
Maturation of nociceptive neurons depends on changes in transcription factors, ion channels and neuropeptides. Mature nociceptors initiate pain in part by drastically reducing the activation threshold via intracellular sensitization signaling. Whether sensitization signaling also changes during development and aging remains so far unknown. Using a novel automated microscopy approach, we quantified changes in intracellular signaling protein expression and in their signaling dynamics, as well as changes in intracellular signaling cascade wiring, in sensory neurons from newborn to senescent (24 months of age) rats...
July 1, 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
#17
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
#18
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
#19
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
#20
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
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