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  1 / 138 MEDLINE  
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PMID:28953656
Autor:Sun J; Duan G; Li N; Guo S; Zhang Y; Ying Y; Zhang M; Wang Q; Liu JY; Zhang X
Endereço:aDepartment of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan bDepartment of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing cDepartment of Anesthesiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai dDepartment of Anesthesiology, Wuhan General Hospital of Guangzhou Military eKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Título:SCN11A variants may influence postoperative pain sensitivity after gynecological surgery in Chinese Han female patients.
Fonte:Medicine (Baltimore); 96(39):e8149, 2017 Sep.
ISSN:1536-5964
País de publicação:United States
Idioma:eng
Resumo:Nav1.9, encoded by sodium voltage-gated channel alpha subunit 11 (SCN11A), is one of the main sodium channels involved in pain transmission. Dysfunction of Nav1.9 alters pain sensitivity, resulting in insensitivity to pain or familial episodic pain. Our purpose was to explore the effects of SCN11A single-nucleotide polymorphisms (SNPs) on postoperative pain sensitivity in Chinese Han female patients after gynecological surgery.Here, we combined the methods of tag SNPs and candidate SNPs. The associations between eleven SCN11A SNPs and basic pain sensitivity in female healthy volunteers were analyzed using the Plink software. The SNPs associated with basic pain sensitivity were termed positive SCN11A SNPs. The effect of these positive SNPs on postoperative pain sensitivity was explored in patients undergoing elective gynecological laparoscopic surgery and receiving postoperative patient-controlled analgesia (PCA). We assessed pain intensity using the numeric pain rating scale (NRS) and recorded PCA consumption.Our results suggested that 5 SNPs (rs33985936, rs13080116, rs11720988, rs11709492, and rs11720013) in 11 tag and candidate SNPs were associated with basic pain sensitivity (P < .05). No evident association was found between the 5 positive SNPs and NRS (P > .05). However, among these positive SNPs, the minor alleles of rs33985936 and rs13080116 were significantly associated with increased PCA consumption (P < .01).To our knowledge, this is the first study to report that SCN11A SNPs affect postoperative pain sensitivity in Chinese Han women after gynecological surgery. The SNP rs33985936 and rs13080116 may serve as novel predictors for postoperative pain.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Genetic Markers); 0 (NAV1.9 Voltage-Gated Sodium Channel); 0 (SCN11A protein, human)


  2 / 138 MEDLINE  
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PMID:28530638
Autor:Huang J; Vanoye CG; Cutts A; Goldberg YP; Dib-Hajj SD; Cohen CJ; Waxman SG; George AL
Endereço:Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine; and Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut, USA.
Título:Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability.
Fonte:J Clin Invest; 127(7):2805-2814, 2017 Jun 30.
ISSN:1558-8238
País de publicação:United States
Idioma:eng
Resumo: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 NaV1.9 mutation (L1302F) that is associated with insensitivity to pain. We investigated the effects of L1302F and a previously reported mutation (L811P) on neuronal excitability. In transfected heterologous cells, the L1302F mutation caused a large hyperpolarizing shift in the voltage-dependence of activation, leading to substantially enhanced overlap between activation and steady-state inactivation relationships. In transfected small rat dorsal root ganglion neurons, expression of L1302F and L811P evoked large depolarizations of the resting membrane potential and impaired action potential generation. Therefore, our findings implicate a cellular loss of function as the basis for impaired pain sensation. We further demonstrated that a U-shaped relationship between the resting potential and the neuronal action potential threshold explains why NaV1.9 mutations that evoke small degrees of membrane depolarization cause hyperexcitability and familial episodic pain disorder or painful neuropathy, while mutations evoking larger membrane depolarizations cause hypoexcitability and insensitivity to pain.
Tipo de publicação: CASE REPORTS; JOURNAL ARTICLE
Nome de substância:0 (NAV1.9 Voltage-Gated Sodium Channel); 0 (SCN11A protein, human)


  3 / 138 MEDLINE  
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PMID:28326938
Autor:Nencini S; Ringuet M; Kim DH; Chen YJ; Greenhill C; Ivanusic JJ
Endereço:Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Australia.
Título:Mechanisms of nerve growth factor signaling in bone nociceptors and in an animal model of inflammatory bone pain.
Fonte:Mol Pain; 13:1744806917697011, 2017 Jan.
ISSN:1744-8069
País de publicação:United States
Idioma:eng
Resumo: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. We demonstrate that nerve growth factor injected directly into rat tibia rapidly activates and sensitizes bone nociceptors and produces acute behavioral responses with a similar time course. The nerve growth factor-induced changes in the activity and sensitivity of bone nociceptors we report are dependent on signaling through the TrkA receptor, but are not affected by mast cell stabilization. We failed to show evidence for longer term changes in expression of TrkA, TRPV1, Nav1.8 or Nav1.9 in the soma of bone nociceptors in a rat model of inflammatory bone pain. Thus, retrograde transport of NGF/TrkA and increased expression of some of the common nerve growth factor signaling molecules do not appear to be important for the maintenance of inflammatory bone pain. The findings are relevant to understand the basis of nerve growth factor sequestration and other therapies directed at nerve growth factor signaling, in managing pain in bone disease.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Antibodies); 0 (NAV1.8 Voltage-Gated Sodium Channel); 0 (NAV1.9 Voltage-Gated Sodium Channel); 0 (Scn10a protein, rat); 0 (Scn11a protein, rat); 0 (TRPV Cation Channels); 0 (Trpv1 protein, rat); 33507-63-0 (Substance P); 83652-28-2 (Calcitonin Gene-Related Peptide); 9007-81-2 (Freund's Adjuvant); 9061-61-4 (Nerve Growth Factor); EC 3.4.19.12 (UCHL1 protein, rat); EC 3.4.19.12 (Ubiquitin Thiolesterase)


  4 / 138 MEDLINE  
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PMID:27780178
Autor:Hoffmann T; Kistner K; Carr RW; Nassar MA; Reeh PW; Weidner C
Endereço:aInstitute for Physiology and Pathophysiology, University of Erlangen-Nuremberg, Erlangen, Germany bDepartment of Anesthesiology and Operative Intensive Care, Heidelberg University, Mannheim, Germany cDepartment of Biomedical Science, University of Sheffield, Sheffield, United Kingdom.
Título:Reduced excitability and impaired nociception in peripheral unmyelinated fibers from Nav1.9-null mice.
Fonte:Pain; 158(1):58-67, 2017 Jan.
ISSN:1872-6623
País de publicação:United States
Idioma:eng
Resumo:The upregulation of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 has previously been associated with inflammatory hyperalgesia. Na1.9 knockout (KO) mice, however, did not seem insensitive in conventional tests of acute nociception. Using electrophysiological, neurochemical, and behavioral techniques, we now show NaV1.9-null mice exhibit impaired mechanical and thermal sensory capacities and reduced electrical excitability of nociceptors. In single-fiber recordings from isolated skin, the electrical threshold of NaV1.9 KO C fibers was elevated by 55% and the median von Frey threshold was 32 mN in contrast to 8 mN in wild types (WTs). The prevalence of C mechano-heat-sensitive (CMH) fibers was only 25.6% in NaV1.9 KO animals compared to 75.8% in the WT group, and the heat threshold of these CMH fibers was 40.4°C in the control vs 44°C in the KO group. Compound action potential recordings from isolated sciatic nerve segments of NaV1.9 KO mice revealed lower activity-induced slowing of conduction velocity upon noxious heat stimulation: 8% vs 30% in WTs. Heat-induced calcitonin gene-related peptide release from the skin was less in the KO than in the WT group. The reduced noxious heat sensitivity was finally confirmed with the Hargreaves test using 2 rates of radiant heating of the plantar hind paws. In conclusion, NaV1.9 presumably contributes to acute thermal and mechanical nociception in mice, most likely through increasing the excitability but probably also by amplifying receptor potentials irrespective of the stimulus modality.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (NAV1.9 Voltage-Gated Sodium Channel); 0 (Scn11a protein, mouse); 83652-28-2 (Calcitonin Gene-Related Peptide)


  5 / 138 MEDLINE  
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PMID:27503742
Autor:Han C; Yang Y; Te Morsche RH; Drenth JP; Politei JM; Waxman SG; Dib-Hajj SD
Endereço:Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA.
Título:Familial gain-of-function Na 1.9 mutation in a painful channelopathy.
Fonte:J Neurol Neurosurg Psychiatry; 88(3):233-240, 2017 Mar.
ISSN:1468-330X
País de publicação:England
Idioma:eng
Resumo:OBJECTIVE: Gain-of-function mutations in Na 1.9 have been identified in three families with rare heritable pain disorders, and in patients with painful small-fibre neuropathy. Identification and functional assessment of new Na 1.9 mutations will help to elucidate the phenotypic spectrum of Na 1.9 channelopathies. METHODS: Patients from a large family with early-onset pain symptoms were evaluated by clinical examination and genomic screening for mutations in and . Electrophysiological recordings and multistate modelling analysis were implemented for functional analyses. RESULTS: A novel Na 1.9 mutation, p.Arg222His, was identified in patients with early-onset pain in distal extremities including joints and gastrointestinal disturbances, but was absent from an asymptomatic blood relative. This mutation alters channel structure by substituting the highly conserved first arginine residue in transmembrane segment 4 (domain 1), the voltage sensor, with histidine. Voltage-clamp recordings demonstrate a hyperpolarising shift and acceleration of activation of the p.Arg222His mutant channel, which make it easier to open the channel. When expressed in dorsal root ganglion neurons, mutant p.Arg222His channels increase excitability via a depolarisation of resting potential and increased evoked firing. CONCLUSIONS: This study expands the spectrum of heritable pain disorders linked to gain-of-function mutations in Na 1.9, strengthening human validation of this channel as a potential therapeutic target for pain.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (NAV1.7 Voltage-Gated Sodium Channel); 0 (NAV1.9 Voltage-Gated Sodium Channel); 0 (SCN11A protein, human); 0 (SCN9A protein, human)


  6 / 138 MEDLINE  
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PMID:27781142
Autor:Kleggetveit IP; Schmidt R; Namer B; Salter H; Helås T; Schmelz M; Jørum E
Endereço:Section of Clinical Neurophysiology Department of Neurology Oslo University Hospital-Rikshospitalet Oslo Norway.
Título:Pathological nociceptors in two patients with erythromelalgia-like symptoms and rare genetic Nav 1.9 variants.
Fonte:Brain Behav; 6(10):e00528, 2016 Oct.
ISSN:2162-3279
País de publicação:United States
Idioma:eng
Resumo:INTRODUCTION: The sodium channel Nav 1.9 is expressed in peripheral nociceptors and has recently been linked to human pain conditions, but the exact role of Nav 1.9 for human nociceptor excitability is still unclear. METHODS: C-nociceptors from two patients with late onset of erythromelalgia-like pain, signs of small fiber neuropathy, and rare genetic variants of Nav 1.9 (N1169S, I1293V) were assessed by microneurography. RESULTS: Compared with patients with comparable pain phenotypes (erythromelalgia-like pain without Nav-mutations and painful polyneuropathy), there was a tendency toward more activity-dependent slowing of conduction velocity in mechanoinsensitive C-nociceptors. Hyperexcitability to heating and electrical stimulation were seen in some nociceptors, and other unspecific signs of increased excitability, including spontaneous activity and mechanical sensitization, were also observed. CONCLUSIONS: Although the functional roles of these genetic variants are still unknown, the microneurography findings may be compatible with increased C-nociceptor excitability based on increased Nav 1.9 function.
Tipo de publicação: CASE REPORTS; JOURNAL ARTICLE
Nome de substância:0 (NAV1.9 Voltage-Gated Sodium Channel); 0 (SCN11A protein, human)


  7 / 138 MEDLINE  
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PMID:27556810
Autor:Lin Z; Santos S; Padilla K; Printzenhoff D; Castle NA
Endereço:Neuroscience and Pain Research Unit, Pfizer Inc., Durham, North Carolina, United States of America.
Título:Biophysical and Pharmacological Characterization of Nav1.9 Voltage Dependent Sodium Channels Stably Expressed in HEK-293 Cells.
Fonte:PLoS One; 11(8):e0161450, 2016.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:The voltage dependent sodium channel Nav1.9, is expressed preferentially in peripheral sensory neurons and has been linked to human genetic pain disorders, which makes it target of interest for the development of new pain therapeutics. However, characterization of Nav1.9 pharmacology has been limited due in part to the historical difficulty of functionally expressing recombinant channels. Here we report the successful generation and characterization of human, mouse and rat Nav1.9 stably expressed in human HEK-293 cells. These cells exhibit slowly activating and inactivating inward sodium channel currents that have characteristics of native Nav1.9. Optimal functional expression was achieved by coexpression of Nav1.9 with ß1/ß2 subunits. While recombinantly expressed Nav1.9 was found to be sensitive to sodium channel inhibitors TC-N 1752 and tetracaine, potency was up to 100-fold less than reported for other Nav channel subtypes despite evidence to support an interaction with the canonical local anesthetic (LA) binding region on Domain 4 S6. Nav1.9 Domain 2 S6 pore domain contains a unique lysine residue (K799) which is predicted to be spatially near the local anesthetic interaction site. Mutation of this residue to the consensus asparagine (K799N) resulted in an increase in potency for tetracaine, but a decrease for TC-N 1752, suggesting that this residue can influence interaction of inhibitors with the Nav1.9 pore. In summary, we have shown that stable functional expression of Nav1.9 in the widely used HEK-293 cells is possible, which opens up opportunities to better understand channel properties and may potentially aid identification of novel Nav1.9 based pharmacotherapies.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Anesthetics, Local); 0 (NAV1.9 Voltage-Gated Sodium Channel); 0 (Sodium Channel Agonists); 0 (Sodium Channel Blockers); K3Z4F929H6 (Lysine)


  8 / 138 MEDLINE  
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PMID:27297039
Autor:O'Donnell AM; Coyle D; Puri P
Endereço:National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.
Título:Decreased Nav1.9 channel expression in Hirschsprung's disease.
Fonte:J Pediatr Surg; 51(9):1458-61, 2016 Sep.
ISSN:1531-5037
País de publicação:United States
Idioma:eng
Resumo:AIM: Voltage-gated sodium channel subtype 9 (Nav1.9) are expressed in dorsal root ganglion neurons and are known to be involved in pain during inflammation. Animal studies have reported Nav1.9 channel expression in myenteric intrinsic primary afferent neurons (IPANs). More recently, a study involving Nav1.9 knockout mice showed clear evidence of colonic dysmotility. However, there are no data regarding the expression of these channels in the human intestine, thus, the aim of our study was to determine Nav1.9 channel expression within the human colon and to elucidate if Nav1.9 channel expression is altered in Hirschsprung's disease (HD). METHODS: HD tissue specimens (n=10) were collected at the time of pull-through surgery, while normal controls were obtained at the time of colostomy closure in patients with imperforate anus (n=10). Nav1.9 immunofluorescence was visualized using confocal microscopy to assess the distribution of the protein. Western blot analysis was undertaken to determine Nav1.9 protein quantification. RESULTS: Confocal microscopy revealed Nav1.9-immunoreactive neurons within the submucosal and myenteric plexus in normal controls, with a reduction in the HD specimens. Calbindin double-labeling showed that Nav1.9-immunoreactive neurons were IPANs. Nav1.9 channels were also seen to be co-localized on smooth muscle cells in all tissues. Western blotting revealed high levels of Nav1.9 protein expression in normal controls, while there was a marked decrease in Nav1.9 protein expression in the HD tissue. CONCLUSION: Our results show the expression of Nav1.9 channels within the human colon for the first time. Furthermore, Nav1.9 channel expression is decreased in HD versus normal controls.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Biomarkers); 0 (NAV1.9 Voltage-Gated Sodium Channel); 0 (SCN11A protein, human)


  9 / 138 MEDLINE  
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PMID:27233519
Autor:Tibbs GR; Posson DJ; Goldstein PA
Endereço:Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA.
Título:Voltage-Gated Ion Channels in the PNS: Novel Therapies for Neuropathic Pain?
Fonte:Trends Pharmacol Sci; 37(7):522-42, 2016 Jul.
ISSN:1873-3735
País de publicação:England
Idioma:eng
Resumo:Neuropathic pain arises from injury to the nervous system. Conditions associated with neuropathic pain are diverse, and lesions and/or pathological changes in the central nervous system (CNS) or peripheral nervous system (PNS) can frequently, but not always, be identified. It is difficult to treat, with patients often on multiple, different classes of medications, all with appreciable adverse side effect profiles. Consequently, there is a pressing need for the development of new medications. The development of such therapeutics is predicated on a clear understanding of the relevant molecular and cellular processes that contribute to the development, and maintenance, of the neuropathic pain state. One proposed mechanism thought to contribute to the ontogeny of neuropathic pain is altered expression, trafficking, and functioning of ion channels expressed by primary sensory neurons. Here, we will focus on three voltage-gated ion channel families, CaV, HCN, and NaV, first reviewing the preclinical data and then the human data where it exists.
Tipo de publicação: JOURNAL ARTICLE; REVIEW
Nome de substância:0 (4-chloro-2-fluoro-N-(2-fluorophenyl)-5-(hexahydropyrrolo(1,2-a)pyrazin-2(1H)-ylcarbonyl)benzenesulfonamide); 0 (CACNA1B protein, human); 0 (CACNA1H protein, human); 0 (Calcium Channels, N-Type); 0 (Calcium Channels, T-Type); 0 (Heterocyclic Compounds, 2-Ring); 0 (Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels); 0 (Ion Channels); 0 (NAV1.8 Voltage-Gated Sodium Channel); 0 (NAV1.9 Voltage-Gated Sodium Channel); 0 (SCN10A protein, human); 0 (SCN11A protein, human); 0 (Sulfonamides)


  10 / 138 MEDLINE  
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PMID:27224030
Autor:Okuda H; Noguchi A; Kobayashi H; Kondo D; Harada KH; Youssefian S; Shioi H; Kabata R; Domon Y; Kubota K; Kitano Y; Takayama Y; Hitomi T; Ohno K; Saito Y; Asano T; Tominaga M; Takahashi T; Koizumi A
Endereço:Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Título:Infantile Pain Episodes Associated with Novel Nav1.9 Mutations in Familial Episodic Pain Syndrome in Japanese Families.
Fonte:PLoS One; 11(5):e0154827, 2016.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. In this study, we performed a genetic study in six unrelated multigenerational Japanese families with episodic pain syndrome. Affected participants (n = 23) were characterized by infantile recurrent pain episodes with spontaneous mitigation around adolescence. This unique phenotype was inherited in an autosomal-dominant mode. Linkage analysis was performed for two families with 12 affected and nine unaffected members, and a single locus was identified on 3p22 (LOD score 4.32). Exome analysis (n = 14) was performed for affected and unaffected members in these two families and an additional family. Two missense variants were identified: R222H and R222S in SCN11A. Next, we generated a knock-in mouse model harboring one of the mutations (R222S). Behavioral tests (Hargreaves test and cold plate test) using R222S and wild-type C57BL/6 (WT) mice, young (8-9 weeks old; n = 10-12 for each group) and mature (36-38 weeks old; n = 5-6 for each group), showed that R222S mice were significantly (p < 0.05) more hypersensitive to hot and cold stimuli than WT mice. Electrophysiological studies using dorsal root ganglion neurons from 8-9-week-old mice showed no significant difference in resting membrane potential, but input impedance and firing frequency of evoked action potentials were significantly increased in R222S mice compared with WT mice. However, there was no significant difference among Nav1.9 (WT, R222S, and R222H)-overexpressing ND7/23 cell lines. These results suggest that our novel mutation is a gain-of-function mutation that causes infantile familial episodic pain. The mouse model developed here will be useful for drug screening for familial episodic pain syndrome associated with SCN11A mutations.
Tipo de publicação: CLINICAL TRIAL; JOURNAL ARTICLE; MULTICENTER STUDY
Nome de substância:0 (NAV1.9 Voltage-Gated Sodium Channel); 0 (SCN11A protein, human); 0 (Scn11a protein, mouse)



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