Action potential conduction in the mouse and rat vagus nerve is dependent on multiple voltage-gated sodium channels (Na1s).

Action potential (AP) conduction depends on voltage-gated sodium channels, of which there are nine subtypes. The vagus nerve, comprising sensory afferent fibers and efferent parasympathetic fibers, provides autonomic regulation of visceral organs, but the voltage-gated sodium channels (Na1) subtypes involved in its AP conduction are poorly defined. We studied the A- and C-waves of electrically stimulated compound action potentials (CAPs) of the mouse and rat vagus nerves with and without Na1 inhibitor administration: tetrodotoxin (TTX), PF-05089771 (mouse Na1.

Role of Na 1.7 in action potential conduction along human bronchial vagal afferent C-fibres.

Background And Purpose: The purpose of this study was to determine the role of Na 1.7 in action potential conduction in C-fibres in the bronchial branches of the human vagus nerve.

Experimental Approach: Bronchial branches of the vagus nerve were dissected from human donor tissue.

Contribution of tetrodotoxin-sensitive, voltage-gated sodium channels (Na1) to action potential discharge from mouse esophageal tension mechanoreceptors.

Action potentials depend on voltage-gated sodium channels (Na1s), which have nine α subtypes. Na1 inhibition is a target for pathologies involving excitable cells such as pain. However, because Na1 subtypes are widely expressed, inhibitors may inhibit regulatory sensory systems.

Antitussive effects of Na 1.7 blockade in Guinea pigs.

Our previous studies implicated the voltage-gated sodium channel subtype Na 1.7 in the transmission of action potentials by the vagal afferent nerves regulating cough and thus identified this channel as a rational therapeutic target for antitussive therapy. But it is presently unclear whether a systemically administered small molecule inhibitor of Na 1.

Acute activation of bronchopulmonary vagal nociceptors by type I interferons.

Type I interferon receptors are expressed by the majority of vagal C-fibre neurons innervating the respiratory tract Interferon alpha and beta acutely and directly activate vagal C-fibers in the airways. The interferon-induced activation of C-fibers occurs secondary to stimulation of type 1 interferon receptors Type 1 interferons may contribute to the symptoms as well as the spread of respiratory viral infections by causing coughing and other defensive reflexes associated with vagal C-fibre activation ABSTRACT: We evaluated the ability of type I interferons to acutely activate airway vagal afferent nerve terminals in mouse lungs. Using single cell RT-PCR of lung-specific vagal neurons we found that IFNAR1 and IFNAR2 were expressed in 70% of the TRPV1-positive neurons (a marker for vagal C-fibre neurons) and 44% of TRPV1-negative neurons.

Stimulus intensity-dependent recruitment of Na1 subunits in action potential initiation in nerve terminals of vagal C-fibers innervating the esophagus.

We investigated voltage-gated sodium channel (Na1) subunits that regulate action potential initiation in the nerve terminals of vagal nodose C-fibers innervating the esophagus. Extracellular single fiber recordings were made from the nodose C-fibers, with mechanically sensitive nerve terminals in the isolated innervated guinea pig esophagus. Na1 inhibitors were selectively delivered to the tissue-containing nerve terminals.

Development of a Mouse Reporter Strain for the Purinergic P2X Receptor.

The ATP-sensitive P2X ionotropic receptor plays a critical role in a number of signal processes including taste and hearing, carotid body detection of hypoxia, the exercise pressor reflex and sensory transduction of mechanical stimuli in the airways and bladder. Elucidation of the role of P2X has been hindered by the lack of selective tools. In particular, detection of P2X using established pharmacological and biochemical techniques yields dramatically different expression patterns, particularly in the peripheral and central nervous systems.

Mapping of Sensory Nerve Subsets within the Vagal Ganglia and the Brainstem Using Reporter Mice for Pirt, TRPV1, 5-HT3, and Tac1 Expression.

Vagal afferent sensory nerves, originating in jugular and nodose ganglia, are composed of functionally distinct subsets whose activation evokes distinct thoracic and abdominal reflex responses. We used Cre-expressing mouse strains to identify specific vagal afferent populations and map their central projections within the brainstem. We show that Pirt is expressed in virtually all vagal afferents; whereas, 5-HT3 is expressed only in nodose neurons, with little expression in jugular neurons.

Comprehensive analysis of acidic pharyngeal reflux before and after proton pump inhibitor treatment in patients with suspected laryngopharyngeal reflux.

Objectives: The usefulness of pharyngeal pH monitoring in patients with symptoms attributed to laryngopharyngeal reflux (LPR) has been questioned. One problem is the uncertainty whether the pharyngeal pH monitoring captures the aspects of LPR which are responsible for symptoms. We aimed to gain more insight into this problem by performing a comprehensive analysis of acidic pharyngeal reflux before and after the treatment with proton pump inhibitors (PPIs) in patients with suspected LPR.

The infusion of menthol into the esophagus evokes cold sensations in healthy subjects but induces heartburn in patients with gastroesophageal reflux disease (GERD).

Recent studies in animal models have reported that some afferent fibers innervating the esophagus express the cold receptor TRPM8. In the somatosensory system the stimulation of TRPM8 leads to cold sensations and in certain circumstances alleviates pain. It is therefore hypothesized in this paper that the esophageal infusion of the TRPM8 activator menthol evokes cold sensations from the esophagus and alleviates heartburn in humans.

Phenotypic distinctions between the nodose and jugular TRPV1-positive vagal sensory neurons in the cynomolgus monkey.

Vagal capsaicin-sensitive afferent C-fibers play an important role in the maintenance of visceral homeostasis and contribute to symptoms in visceral diseases. Based on their developmental origin two functionally distinct types of vagal C-fibers are recognized: those with neurons in the vagal nodose ganglia (derived from epibranchial placodes) and in the vagal jugular ganglia (from neural crest). Studies in nonprimate species demonstrated that the vagal nodose and jugular C-fibers differ in activation profile, neurotrophic regulation, and expression of neurotransmitters.

Acidic Pharyngeal Reflux Does Not Correlate with Symptoms and Laryngeal Injury Attributed to Laryngopharyngeal Reflux.

Background: Laryngopharyngeal reflux (LPR) is suspected when the symptoms are attributed to the penetration of acidic gastroesophageal reflux (GER) into the larynx. However, the relationships between the intensity of LPR and symptoms and laryngeal injury have not been elucidated. Several factors confound the study of LPR, namely pH is monitored in the pharynx (pharyngeal reflux) but the pharyngeal acidity (pH) required to induce laryngeal injury is unknown, the GER origin of pharyngeal acid is not always established, and a recent treatment with proton pump inhibitors (PPI) confounds the analysis.

Ras homolog family member A/Rho-associated protein kinase 1 signaling modulates lineage commitment of mesenchymal stem cells in asthmatic patients through lymphoid enhancer-binding factor 1.

Background: Numbers of mesenchymal stem cells (MSCs) are increased in the airways after allergen challenge. Ras homolog family member A (RhoA)/Rho-associated protein kinase 1 (ROCK) signaling is critical in determining the lineage fate of MSCs in tissue repair/remodeling.

Objectives: We sought to investigate the role of RhoA/ROCK signaling in lineage commitment of MSCs during allergen-induced airway remodeling and delineate the underlying mechanisms.

Voltage-Gated Sodium Channels Regulating Action Potential Generation in Itch-, Nociceptive-, and Low-Threshold Mechanosensitive Cutaneous C-Fibers.

We evaluated the effect of voltage-gated sodium channel 1 (Na1) blockers in three nonoverlapping C-fiber subtypes in the mouse skin: chloroquine (CQ)-sensitive C-fibers with high mechanical thresholds- second, CQ-insensitive, capsaicin-sensitive C-fibers with high mechanical thresholds- and CQ and capsaicin-insensitive C-fibers with a very low mechanical threshold-C-LTMs. Na1-blocking drugs were applied to the nerve terminal receptive fields using an innervated isolated dorsal mouse skin-nerve preparation where the drugs are delivered into the skin intra-arterially. We combined these studies with an analysis of the mRNA expression of the -subunits of Na1 in individual dorsal root ganglia neurons labeled from the same region of the skin.

Novel computer algorithm for cough monitoring based on octonions.

The objective assessment of cough frequency is essential for evaluation of cough and antitussive therapies. Nonetheless, available algorithms for automatic detection of cough sound have limited sensitivity and the analysis of cough sound often requires input from human observers. Therefore, an algorithm for the cough sound detection with high sensitivity would be very useful for development of automatic cough monitors.

Mrgprs on vagal sensory neurons contribute to bronchoconstriction and airway hyper-responsiveness.

Asthma, accompanied by lung inflammation, bronchoconstriction and airway hyper-responsiveness, is a significant public health burden. Here we report that Mas-related G protein-coupled receptors (Mrgprs) are expressed in a subset of vagal sensory neurons innervating the airway and mediates cholinergic bronchoconstriction and airway hyper-responsiveness. These findings provide insights into the neural mechanisms underlying the pathogenesis of asthma.

Structure of vagal afferent nerve terminal fibers in the mouse trachea.

The structure of primary afferent nerve terminals profoundly influences their function. While the complex vagal airway nerve terminals (stretch receptors, cough receptors and neuroepithelial bodies) were thoroughly characterized, much less is known about the structure of airway nerves that do not form distinct complex terminals (often termed free nerve fibers). We selectively induced expression of GFP in vagal afferent nerves in the mouse by transfection with AAV-GFP virus vector and visualized nerve terminals in the trachea by whole organ confocal imaging.

Distinct Expression of Phenotypic Markers in Placodes- and Neural Crest-Derived Afferent Neurons Innervating the Rat Stomach.

Background: Visceral pain is initiated by activation of primary afferent neurons among which the capsaicin-sensitive (TRPV1-positive) neurons play an important role. The stomach is a common source of visceral pain. Similar to other organs, the stomach receives dual spinal and vagal afferent innervation.

Distinct and common expression of receptors for inflammatory mediators in vagal nodose versus jugular capsaicin-sensitive/TRPV1-positive neurons detected by low input RNA sequencing.

Capsaicin-sensitive sensory C-fibers derived from vagal ganglia innervate the visceral organs, and respond to inflammatory mediators and noxious stimuli. These neurons play an important role in maintenance of visceral homeostasis, and contribute to the symptoms of visceral inflammatory diseases. Vagal sensory neurons are located in two ganglia, the jugular ganglia (derived from the neural crest), and the nodose ganglia (from the epibranchial placodes).

Blocking voltage-gated sodium channels as a strategy to suppress pathological cough.

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.

Control of Neurotransmission by NaV1.7 in Human, Guinea Pig, and Mouse Airway Parasympathetic Nerves.

Little is known about the neuronal voltage-gated sodium channels (NaVs) that control neurotransmission in the parasympathetic nervous system. We evaluated the expression of the subunits of each of the nine NaVs in human, guinea pig, and mouse airway parasympathetic ganglia. We combined this information with a pharmacological analysis of selective NaV blockers on parasympathetic contractions of isolated airway smooth muscle.

Cough reflex sensitization from esophagus and nose.

The diseases of the esophagus and nose are among the major factors contributing to chronic cough although their role in different patient populations is debated. Studies in animal models and in humans show that afferent C-fiber activators applied on esophageal or nasal mucosa do not initiate cough, but enhance cough induced by inhaled irritants. These results are consistent with the hypothesis that activation of esophageal and nasal C-fibers contribute to cough reflex hypersensitivity observed in chronic cough patients with gastroesophageal reflux disease (GERD) and chronic rhinitis, respectively.

Vagotomy reverses established allergen-induced airway hyperreactivity to methacholine in the mouse.

We evaluated the role of vagal reflexes in a mouse model of allergen-induced airway hyperreactivity. Mice were actively sensitized to ovalbumin then exposed to the allergen via inhalation. Prior to ovalbumin inhalation, mice also received intratracheally-instilled particulate matter in order to boost the allergic response.

TRPM8 function and expression in vagal sensory neurons and afferent nerves innervating guinea pig esophagus.

Sensory transduction in esophageal afferents requires specific ion channels and receptors. TRPM8 is a new member of the transient receptor potential (TRP) channel family and participates in cold- and menthol-induced sensory transduction, but its role in visceral sensory transduction is still less clear. This study aims to determine TRPM8 function and expression in esophageal vagal afferent subtypes.