Nav 1.8

Airway smooth muscle cells (ASM) from mouse bronchus express a fast sodium current mediated by NaV 1.7. We present evidence that this current is regulated by cAMP. ASM were isolated by enzymatic dispersal and studied using the whole-cell patch clamp technique at room temperature. A fast sodium current, INa , was observed on holding cells under voltage clamp at -100 mV and stepping to -20 mV. This current was reduced in a concentration-dependent manner by denopamine (10 and 30 mM), a b-adrenergic agonist. Forskolin (1 mM), an activator of adenylate cyclase, reduced the current by 35%, but 6-MB-cAMP (300 mM), an activator of protein kinase A (PKA), had no effect...

BACKGROUND: Follow-up assessment of visceral leishmaniasis (VL) treated cases is important to monitor the long term effectiveness of treatment regimens. The main objective of this study was to identify the gaps and challenges in the follow-up of treated VL cases, to monitor treatment outcome and to assess the impact of COVID-19 on VL elimination services and activities. METHODS: Clinicians treating VL patients, district focal persons for VL, and patients treated for VL in seven high endemic districts in Nepal during 2019-2022 were interviewed to collect data on challenges in the follow-up of VL treated patients as per national strategy...

The SCN1A gene encodes the alpha subunit of a voltage-gated sodium channel (Nav 1.1), which is essential for the function of inhibitory neurons in the brain. Mutations in this gene cause severe encephalopathies such as Dravet syndrome (DS). Upregulation of SCN1A expression by different approaches has demonstrated promising therapeutic effects in preclinical models of DS. Limiting the effect to inhibitory neurons may contribute to the restoration of brain homeostasis, increasing the safety and efficacy of the treatment...

OBJECTIVE: Identify trends of navigation and robotic-assisted elective spine surgeries. METHODS: Elective spine surgery patients between 2007 and 2015 in the Nationwide Inpatient Sample (NIS) were isolated by ICD-9 codes for Navigation [Nav] or Robotic [Rob]-Assisted surgery. Basic demographics and surgical variables were identified via chi-squared and t tests. Each system was analyzed from 2007 to 2015 for trends in usage. RESULTS: Included 3,759,751 patients: 100,488 Nav; 4724 Rob...

The present work continues our recent series of articles that aim to elucidate the ligand-receptor binding mechanism of short cationic peptides to the NaV 1.8 channel in the nociceptive neuron. The applied methodological approach has involved several methods: the patch-clamp experimental evaluation of the effective charge of the NaV 1.8 channel activation gating system, the organotypic tissue culture method, the formalin test, and theoretical conformational analysis. The lysine-containing short peptide Ac-KEKK-NH2 has been shown to effectively modulate the NaV 1...

OBJECTIVE: Osteoarthritis is a disease with sex-dependent prevalence and severity in both humans and animal models. We sought to elucidate sex differences in synovitis, mechanical sensitization, structural damage, bone remodeling, and the synovial transcriptome in the anterior cruciate ligament rupture (ACLR) mouse model of post-traumatic osteoarthritis (PTOA). DESIGN: Male and female 12-week-old C57/BL6J mice were randomized to Sham or noninvasive ACLR with harvests at 7d or 28d post-ACLR (n=9 per sex in each group - Sham, 7d ACLR, 28d ACLR)...

The voltage-gated sodium channel NaV 1.8 is prominently expressed in the soma and axons of small-caliber sensory neurons, and pathogenic variants of the corresponding gene SCN10A are associated with peripheral pain and autonomic dysfunction. While most disease-associated SCN10A variants confer gain-of-function properties to NaV 1.8, resulting in hyperexcitability of sensory neurons, a few affect afferent excitability through a loss-of-function mechanism. Using whole-exome sequencing, we here identify a rare heterozygous SCN10A missense variant resulting in alteration p...

Voltage-gated sodium (NaV ) channels are transmembrane proteins that play a critical role in electrical signaling in the nervous system and other excitable tissues. µ-Conotoxins are peptide toxins from the venoms of marine cone snails (genus Conus) that block NaV channels with nanomolar potency. Most species of the subgenera Textilia and Afonsoconus are difficult to acquire; therefore, their venoms have yet to be comprehensively interrogated for µ-conotoxins. The goal of this study was to find new µ-conotoxins from species of the subgenera Textilia and Afonsoconus and investigate their selectivity at human NaV channels...

Drive from peripheral neurons is essential in almost all pain states, but pharmacological silencing of these neurons to effect analgesia has proved problematic. Reversible gene therapy using long-lived chemogenetic approaches is an appealing option. We used the genetically-activated chloride channel PSAM4 -GlyR to examine pain pathways in mice. Using recombinant AAV9-based delivery to sensory neurons, we found a reversal of acute pain behavior and diminished neuronal activity using in vitro and in vivo GCaMP imaging upon activation of PSAM4 -GlyR with varenicline...

OBJECTIVE: This study aimed to evaluate the effectiveness of motivational interviewing (MI) - a counselling approach offered by caseworkers at the Norwegian Labor and Welfare Administration (NAV) - on return to work (RTW) for individuals sick-listed for ≥8 weeks due to any diagnoses. MI was compared to usual case management and an active control during 12 months of follow-up. METHODS: In a randomized clinical trial with three parallel arms, participants were randomized to MI (N=257), usual case management (N=266), or an active control group (N=252)...

Inspiration is the inexorable active phase of breathing. The brainstem pre-Bötzinger complex (preBötC) gives rise to inspiratory neural rhythm, but its underlying cellular and ionic bases remain unclear. The long-standing "pacemaker hypothesis" posits that the persistent Na+ current (INaP ) that gives rise to bursting-pacemaker properties in preBötC interneurons is essential for rhythmogenesis. We tested the pacemaker hypothesis by conditionally knocking out and knocking down the Scn8a (Nav 1...

Action potential (AP) conduction depends on voltage-gated sodium channels, of which there are nine subtypes. The vagus nerve, comprised of sensory afferent fibers and efferent parasympathetic fibers, provides autonomic regulation of visceral organs, but the NaV 1 subtypes involved in its AP conduction are poorly defined. We studied the A- and C-waves of electrically-stimulated compound action potentials (CAP) of the mouse and rat vagus nerves with and without NaV 1 inhibitor administration: tetrodotoxin (TTX), PF-05089771 (mouse NaV 1...

BACKGROUND: There are comparatively few international studies investigating suicide in military veterans and no recent UK-wide studies. This is important because the wider context of being a UK Armed Forces (UKAF) veteran has changed in recent years following a period of intensive operations. We aimed to investigate the rate, timing, and risk factors for suicide in personnel who left the UKAF over a 23-year period. METHODS AND FINDINGS: We carried out a retrospective cohort study of suicide in personnel who left the regular UKAF between 1996 and 2018 linking national databases of discharged personnel and suicide deaths, using survival analysis to examine the risk of suicide in veterans compared to the general population and conditional logistic regression to investigate factors most strongly associated with suicide after discharge...

BACKGROUND: The NaV 1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral, highly selective inhibitor of NaV 1.8, on control of acute pain is being studied. METHODS: After establishing the selectivity of VX-548 for NaV 1.8 inhibition in vitro, we conducted two phase 2 trials involving participants with acute pain after abdominoplasty or bunionectomy. In the abdominoplasty trial, participants were randomly assigned in a 1:1:1:1 ratio to receive one of the following over a 48-hour period: a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours (the high-dose group); a 60-mg loading dose of VX-548, followed by a 30-mg maintenance dose every 12 hours (the middle-dose group); hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours...

The signaling or non-pumping Na,K-ATPase function was first observed by us in the nociceptive neuron; Na,K-ATPase transduced the signals from the opioid-like receptors to NaV 1.8 channels. This study elucidates the role of the rhamnosyl residue of ouabain in the activation of the Na,K-ATPase signaling function. The effects resulting from activation of Na,K-ATPase signaling by the Ca2+ chelate complex of ouabain (EO) are not manifested upon removal of the rhamnosyl residue, as demonstrated in viable cells by the highly sensitive patch-clamp and organotypic cell culture methods...

Provided herein are novel nitrogen-containing 2,3-dihydroquinazolinone compounds as Nav 1.8 inhibitors, pharmaceutical compositions, use of such compounds in treating pain and cardiovascular diseases, and processes for preparing such compounds.

Clinical studies suggest low testosterone levels are associated with cardiac arrhythmias, especially in later life. We investigated whether chronic exposure to low circulating testosterone promoted maladaptive electrical remodeling in ventricular myocytes from aging male mice and determined the role of late inward sodium current (INa-L ) in this remodeling. C57BL/6 mice had a gonadectomy (GDX) or sham surgery (1-month) and were aged to 22-28-months. Ventricular myocytes were isolated; transmembrane voltage and currents were recorded (37°C)...

In heart failure and atrial fibrillation, a persistent Na+ current (INaL ) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that NaV 1.8 contributes to arrhythmogenesis by inducing a INaL . Genome-wide association studies indicate that mutations in the SCN10A gene (NaV 1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these NaV 1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion...

BACKGROUND: Self-harm and eating disorders share multiple risk factors, with onset typically during adolescence or early adulthood. We aimed to examine the incidence rates of these psychopathologies among young people in the UK in the 2 years following onset of the COVID-19 pandemic. METHODS: We conducted a population-based study using the primary care electronic health records of patients aged 10-24 years in the UK Clinical Practice Research Datalink (CPRD). The observation period was from Jan 1, 2010, to March 31, 2022...

Our results from quantitative RT-PCR, Western blotting, immunohistochemistry, and the tissue microarray of medullary thyroid cancer (MTC) cell lines and patient specimens confirm that VGSC subtype NaV 1.7 is uniquely expressed in aggressive MTC and not expressed in normal thyroid cells and tissues. We establish the druggability of NaV 1.7 in MTC by identifying a novel inhibitor ( SV188 ) and investigate its mode of binding and ability to inhibit I Na current in NaV 1.7. The whole-cell patch-clamp studies of the SV188 in the NaV 1...