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https://www.readbyqxmd.com/read/28530638/sodium-channel-nav1-9-mutations-associated-with-insensitivity-to-pain-dampen-neuronal-excitability
#1
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
#2
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/28490900/complex-management-of-a-patient-with-refractory-primary-erythromelalgia-lacking-a-scn9a-mutation
#3
Sarah A Low, Wendye Robbins, Vivianne L Tawfik
A 41-year-old woman presented with burning and erythema in her extremities triggered by warmth and activity, which was relieved by applying ice. Extensive workup was consistent with adult-onset primary erythromelalgia (EM). Several pharmacological treatments were tried including local anesthetics, capsaicin, ziconotide, and dantrolene, all providing 24-48 hours of relief followed by symptom flare. Interventional therapies, including peripheral and sympathetic ganglion blocks, also failed. Thus far, clonidine and ketamine have been the only effective agents for our patient...
2017: Journal of Pain Research
https://www.readbyqxmd.com/read/28480765/targeting-dorsal-root-ganglia-and-primary-sensory-neurons-for-the-treatment-of-chronic-pain
#4
Temugin Berta, Yawar Qadri, Ping-Heng Tan, Ru-Rong Ji
Currently the treatment of chronic pain is inadequate and compromised by debilitating central nervous system side effects. Here we discuss new therapeutic strategies that target dorsal root ganglia (DRGs) in the peripheral nervous system for a better and safer treatment of chronic pain. Areas covered: The DRGs contain the cell bodies of primary sensory neurons including nociceptive neurons. After painful injuries, primary sensory neurons demonstrate maladaptive molecular changes in DRG cell bodies and in their axons...
May 8, 2017: Expert Opinion on Therapeutic Targets
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
#5
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 ganglia (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...
May 4, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28465103/benzoxazolinone-aryl-sulfonamides-as-potent-selective-nav1-7-inhibitors-with-in-vivo-efficacy-in-a-preclinical-pain-model
#6
Joseph E Pero, Michael A Rossi, Hannah D G F Lehman, Michael J Kelly, James J Mulhearn, Scott E Wolkenberg, Matthew J Cato, Michelle K Clements, Christopher J Daley, Tracey Filzen, Eleftheria N Finger, Yun Gregan, Darrell A Henze, Aneta Jovanovska, Rebecca Klein, Richard L Kraus, Yuxing Li, Annie Liang, John M Majercak, Jacqueline Panigel, Mark O Urban, Jixin Wang, Ying-Hong Wang, Andrea K Houghton, Mark E Layton
Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1...
April 22, 2017: Bioorganic & Medicinal Chemistry Letters
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
#7
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
#8
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/28428547/the-tarantula-toxin-%C3%AE-%C3%AE-trtx-pre1a-highlights-the-importance-of-the-s1-s2-voltage-sensor-region-for-sodium-channel-subtype-selectivity
#9
Joshua S Wingerd, Christine A Mozar, Christine A Ussing, Swetha S Murali, Yanni K-Y Chin, Ben Cristofori-Armstrong, Thomas Durek, John Gilchrist, Christopher W Vaughan, Frank Bosmans, David J Adams, Richard J Lewis, Paul F Alewood, Mehdi Mobli, Macdonald J Christie, Lachlan D Rash
Voltage-gated sodium (NaV) channels are essential for the transmission of pain signals in humans making them prime targets for the development of new analgesics. Spider venoms are a rich source of peptide modulators useful to study ion channel structure and function. Here we describe β/δ-TRTX-Pre1a, a 35-residue tarantula peptide that selectively interacts with neuronal NaV channels inhibiting peak current of hNaV1.1, rNaV1.2, hNaV1.6, and hNaV1.7 while concurrently inhibiting fast inactivation of hNaV1.1 and rNaV1...
April 20, 2017: Scientific 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
#10
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/28420967/organization-and-plasticity-of-sodium-channel-expression-in-the-mouse-olfactory-and-vomeronasal-epithelia
#11
Florian Bolz, Stephanie Kasper, Bernd Bufe, Frank Zufall, Martina Pyrski
To understand the molecular basis of neuronal excitation in the mammalian olfactory system, we conducted a systematic analysis of the organization of voltage-gated sodium (Nav) channel subunits in the main olfactory epithelium (MOE) and vomeronasal organ (VNO) of adult mice. We also analyzed changes in Nav channel expression during development in these two systems and during regeneration of the MOE. Quantitative PCR shows that Nav1.7 is the predominant isoform in both adult MOE and VNO. We detected pronounced immunoreactivity for Nav1...
2017: Frontiers in Neuroanatomy
https://www.readbyqxmd.com/read/28412697/sema3a-signalling-requires-crmp1-and-nav1-7
#12
(no author information available yet)
No abstract text is available yet for this article.
April 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28410768/-small-fiber-neuropathy
#13
V Langlois, A-L Bedat Millet, M Lebesnerais, S Miranda, F Marguet, Y Benhamou, P Marcorelles, H Lévesque
Small fiber neuropathy (SFN) is still unknown. Characterised by neuropathic pain, it typically begins by burning feet, but could take many other expression. SFN affects the thinly myelinated Aδ and unmyelinated C-fibers, by an inherited or acquired mechanism, which could lead to paresthesia, thermoalgic disorder or autonomic dysfunction. Recent studies suggest the preponderant role of ion channels such as Nav1.7. Furthermore, erythromelalgia or burning mouth syndrome are now recognized as real SFN. Various aetiologies of SFN are described...
April 11, 2017: La Revue de Médecine Interne
https://www.readbyqxmd.com/read/28389149/discovery-of-selective-orally-bioavailable-n-linked-arylsulfonamide-nav1-7-inhibitors-with-pain-efficacy-in-mice
#14
Anthony J Roecker, Melissa Egbertson, Kristen L G Jones, Robert Gomez, Richard L Kraus, Yuxing Li, Amy Jo Koser, Mark O Urban, Rebecca Klein, Michelle Clements, Jacqueline Panigel, Christopher Daley, Jixin Wang, Eleftheria N Finger, John Majercak, Vincent Santarelli, Irene Gregan, Matthew Cato, Tracey Filzen, Aneta Jovanovska, Ying-Hong Wang, Deping Wang, Leo A Joyce, Edward C Sherer, Xuanjia Peng, Xiu Wang, Haiyan Sun, Paul J Coleman, Andrea K Houghton, Mark E Layton
The voltage-gated sodium channel Nav1.7 is a genetically validated target for the treatment of pain with gain-of-function mutations in man eliciting a variety of painful disorders and loss-of-function mutations affording insensitivity to pain. Unfortunately, drugs thought to garner efficacy via Nav1 inhibition have undesirable side effect profiles due to their lack of selectivity over channel isoforms. Herein we report the discovery of a novel series of orally bioavailable arylsulfonamide Nav1.7 inhibitors with high levels of selectivity over Nav1...
March 30, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28381558/gain-of-function-mutation-of-a-voltage-gated-sodium-channel-nav1-7-associated-with-peripheral-pain-and-impaired-limb-development
#15
Brian S Tanaka, Phuong T Nguyen, Eray Yihui Zhou, Yong Yang, Vladimir Yarov-Yarovoy, Sulayman D Dib-Hajj, Stephen G Waxman
Dominant mutations in voltage-gated sodium channel NaV1.7 cause inherited erythromelalgia (IEM), a debilitating pain disorder characterized by severe burning pain and redness of the distal extremities. NaV1.7 is preferentially expressed within peripheral sensory and sympathetic neurons. Here, we describe a novel NaV1.7 mutation in an 11-year old male with under-development of the limbs, recurrent attacks of burning pain with erythema and swelling in his feet and hands. Frequency and duration of the episodes gradually increased with age and relief by cooling became less effective...
April 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28375911/trigeminal-neuralgia
#16
Giorgio Cruccu
PURPOSE OF REVIEW: Although trigeminal neuralgia is well known to neurologists, recent developments in classification and clinical diagnosis, new MRI methods, and a debate about surgical options necessitate an update on the topic. RECENT FINDINGS: Currently, a worldwide controversy exists regarding the classification, diagnostic process, and surgical treatment of trigeminal neuralgia. This controversy has been caused on one side by the recognition that some 50% of patients with trigeminal neuralgia, apart from characteristic paroxysmal attacks, also have continuous pain in the same territory, which results in greater diagnostic difficulties and is associated with a lower response to medical and surgical treatments...
April 2017: Continuum: Lifelong Learning in Neurology
https://www.readbyqxmd.com/read/28349234/prostaglandin-e2-upregulated-trigeminal-ganglionic-sodium-channel-1-7-involving-temporomandibular-joint-inflammatory-pain-in-rats
#17
Peng Zhang, Ye-Hua Gan
Prostaglandin E2 (PGE2) is a key proinflammatory mediator that contributes to inflammatory hyperalgesia. Voltage-gated sodium channel 1.7 (Nav1.7) plays an important role in inflammatory pain. However, the modulation of Nav1.7 in inflammatory pain remains poorly understood. We hypothesized that PGE2 might regulate Nav1.7 expression in inflammatory pain. We here showed that treatment of rat trigeminal ganglion (TG) explants with PGE2 significantly upregulated the mRNA and protein expressions of Nav1.7 through PGE2 receptor EP2...
March 27, 2017: Inflammation
https://www.readbyqxmd.com/read/28337335/correction-to-sulfonamides-as-selective-nav1-7-inhibitors-optimizing-potency-and-pharmacokinetics-to-enable-in-vivo-target-engagement
#18
Isaac E Marx, Thomas A Dineen, Jessica Able, Christiane Bode, Howard Bregman, Margaret Chu-Moyer, Erin F DiMauro, Bingfan Du, Robert S Foti, Robert T Fremeau, Hua Gao, Hakan Gunaydin, Brian E Hall, Liyue Huang, Thomas Kornecook, Charles R Kreiman, Daniel S La, Joseph Ligutti, Min-Hwa Jasmine Lin, Dong Liu, Jeff S McDermott, Bryan D Moyer, Hanh N Nguyen, Emily A Peterson, Jonathan T Roberts, Paul Rose, Jean Wang, Beth D Youngblood, Violeta Yu, Matthew M Weiss
[This corrects the article DOI: 10.1021/acsmedchemlett.6b00243.].
March 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28324649/sulfonamides-as-selective-nav1-7-inhibitors-optimizing-potency-pharmacokinetics-and-metabolic-properties-to-obtain-atropisomeric-quinolinone-am-0466-that-affords-robust-in-vivo-activity
#19
Russell F Graceffa, Alessandro A Boezio, Jessica Able, Steven Altmann, Loren M Berry, Christiane Boezio, John R Butler, Margaret Chu-Moyer, Melanie Cooke, Erin F DiMauro, Thomas A Dineen, Elma Feric Bojic, Robert S Foti, Robert T Fremeau, Angel Guzman-Perez, Hua Gao, Hakan Gunaydin, Hongbing Huang, Liyue Huang, Christopher Ilch, Michael Jarosh, Thomas Kornecook, Charles R Kreiman, Daniel S La, Joseph Ligutti, Benjamin C Milgram, Min-Hwa Jasmine Lin, Isaac E Marx, Hanh N Nguyen, Emily A Peterson, Gwen Rescourio, John Roberts, Laurie Schenkel, Roman Shimanovich, Brian A Sparling, John Stellwagen, Kristin Taborn, Karina R Vaida, Jean Wang, John Yeoman, Violeta Yu, Dawn Zhu, Bryan D Moyer, Matthew M Weiss
Because of its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [ Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation . WO 2014201206, 2014 ] of NaV1...
April 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28301520/the-structure-dynamics-and-selectivity-profile-of-a-nav1-7-potency-optimised-huwentoxin-iv-variant
#20
Sassan Rahnama, Jennifer R Deuis, Fernanda C Cardoso, Venkatraman Ramanujam, Richard J Lewis, Lachlan D Rash, Glenn F King, Irina Vetter, Mehdi Mobli
Venom-derived peptides have attracted much attention as potential lead molecules for pharmaceutical development. A well-known example is Huwentoxin-IV (HwTx-IV), a peptide toxin isolated from the venom of the Chinese bird-eating spider Haplopelma schmitdi. HwTx-IV was identified as a potent blocker of a human voltage-gated sodium channel (hNaV1.7), which is a genetically validated analgesic target. The peptide was promising as it showed high potency at NaV1.7 (IC50 ~26 nM) and selectivity over the cardiac NaV subtype (NaV1...
2017: PloS One
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