scholarly journals Selective inhibition of vagal afferent nerve pathways regulating cough using Nav 1.7 shRNA silencing in guinea pig nodose ganglia

2013 ◽  
Vol 304 (11) ◽  
pp. R1017-R1023 ◽  
Author(s):  
Yukiko Muroi ◽  
Fei Ru ◽  
Yang-Ling Chou ◽  
Michael J. Carr ◽  
Bradley J. Undem ◽  
...  
Keyword(s):  
Action Potential ◽  
Guinea Pigs ◽  
Fluorescent Protein ◽  
Nerve Fibers ◽  
Vagal Nerve ◽  
Afferent Nerve ◽  
Tracheal Mucosa ◽  
C Fibers ◽  
Nodose Ganglia ◽  
Vagal Afferent

Adeno-associated virus delivery systems and short hairpin RNA (shRNA) were used to selectively silence the voltage-gated sodium channel NaV 1.7 in the nodose ganglia of guinea pigs. The cough reflex in these animals was subsequently assessed. NaV 1.7 shRNA was delivered to the majority of nodose ganglia neurons [50–60% transfection rate determined by green fluorescent protein (GFP) gene cotransfection] and action potential conduction in the nodose vagal nerve fibers, as evaluated using an extracellular recording technique, was markedly and significantly reduced. By contrast, <5% of neurons in the jugular vagal ganglia neurons were transfected, and action potential conduction in the jugular vagal nerve fibers was unchanged. The control virus (with GFP expression) was without effect on action potential discharge and conduction in either ganglia. In vivo, NaV 1.7 silencing in the nodose ganglia nearly abolished cough evoked by mechanically probing the tracheal mucosa in anesthetized guinea pigs. Stimuli such as capsaicin and bradykinin that are known to stimulate both nodose and jugular C-fibers evoked coughing in conscious animals was unaffected by NaV 1.7 silencing in the nodose ganglia. Nodose C-fiber selective stimuli including adenosine, 2-methyl-5-HT, and ATP all failed to evoke coughing upon aerosol challenge. These results indicate that cough is independently regulated by two vagal afferent nerve subtypes in guinea pigs, with nodose Aδ fibers regulating cough evoked mechanically from the trachea and bradykinin- and capsaicin-evoked cough regulated by C-fibers arising from the jugular ganglia.

scholarly journals Opposing effects of bronchopulmonary C-fiber subtypes on cough in guinea pigs

2018 ◽  
Vol 314 (3) ◽  
pp. R489-R498 ◽  
Author(s):  
Yang-Ling Chou ◽  
Nanako Mori ◽  
Brendan J. Canning
Keyword(s):  
Citric Acid ◽  
Guinea Pigs ◽  
Respiratory Pattern ◽  
Tracheal Mucosa ◽  
Cough Reflex ◽  
C Fibers ◽  
Selective Agonist ◽  
Nodose Ganglia ◽  
C Fiber ◽  
Opposing Effects

We have addressed the hypothesis that the opposing effects of bronchopulmonary C-fiber activation on cough are attributable to the activation of C-fiber subtypes. Coughing was evoked in anesthetized guinea pigs by citric acid (0.001–2 M) applied topically in 100-µl aliquots to the tracheal mucosa. In control preparations, citric acid evoked 10 ± 1 coughs cumulatively. Selective activation of the pulmonary C fibers arising from the nodose ganglia with either aerosols or continuous intravenous infusion of adenosine or the 5-HT3 receptor-selective agonist 2-methyl-5-HT nearly abolished coughing evoked subsequently by topical citric acid challenge. Delivering adenosine or 2-methyl-5-HT directly to the tracheal mucosa (where few if any nodose C fibers terminate) was without effect on citric acid-evoked cough. These actions of pulmonary administration of adenosine and 2-methyl-5-HT were accompanied by an increase in respiratory rate, but it is unlikely that the change in respiratory pattern caused the decrease in coughing, as the rapidly adapting receptor stimulant histamine also produced a marked tachypnea but was without effect on cough. In awake guinea pigs, adenosine failed to evoke coughing but reduced coughing induced by the nonselective C-fiber stimulant capsaicin. We conclude that bronchopulmonary C-fiber subtypes in guinea pigs have opposing effects on cough, with airway C fibers arising from the jugular ganglia initiating and/or sensitizing the cough reflex and the intrapulmonary C fibers arising from the nodose ganglia actively inhibiting cough upon activation.

Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs

2006 ◽  
Vol 291 (2) ◽  
pp. R454-R463 ◽  
Author(s):  
Brendan J. Canning ◽  
David G. Farmer ◽  
Nanako Mori
Keyword(s):  
Citric Acid ◽  
Guinea Pigs ◽  
Transient Receptor Potential ◽  
Superior Laryngeal Nerve ◽  
Transient Receptor Potential Vanilloid ◽  
Receptor Antagonists ◽  
Tracheal Mucosa ◽  
C Fibers ◽  
Afferent Nerves ◽  
Vagal Afferent

Experiments carried out in conscious guinea pigs suggest that citric acid-evoked coughing is partly mediated by transient receptor potential vanilloid type 1 (TRPV1) receptor-dependent activation of tachykinin-containing, capsaicin-sensitive C fibers. In vitro electrophysiological analyses indicate, however, that acid also activates capsaicin-sensitive and -insensitive vagal afferent nerves by a TRPV1-independent mechanism, and studies in anesthetized guinea pigs show that coughing evoked by acid is mediated by activation of capsaicin-insensitive vagal afferent nerves. In the present study, we have characterized the mechanisms of citric acid-evoked coughing in anesthetized guinea pigs. Drugs were administered directly to the Krebs buffer perfusing the extrathoracic trachea. Citric acid was applied topically to the tracheal mucosa, directly into the tracheal perfusate in increasing concentrations and at 1-min intervals. Citric acid dose dependently evoked coughing in anesthetized guinea pigs. This was mimicked by hydrochloric acid but not by sodium citrate. The coughing evoked by acid was nearly or completely abolished by TTX or by cutting the recurrent laryngeal nerves. Perfusing the trachea with a low Cl− buffer potentiated the acid-induced cough reflex. In contrast, prior capsaicin desensitization, 10 μM capsazepine, Ca2+-free perfusate, 0.1 μM iberiotoxin, 1 μM atropine, 10 μM isoproterenol, 10 μM albuterol, 3 μM indomethacin, 0.1 μM HOE-140, a combination of neurokinin1 (NK1; CP-99994), NK2 (SR-48968), and NK3 (SB-223412) receptor antagonists (0.1 μM each), a combination of histamine H1 (3 μM pyrilamine) and cysLT1 (1 μM ICI-198615) receptor antagonists, superior laryngeal nerve transection, or epithelium removal did not inhibit citric acid-evoked coughing. These and other data indicate that citric acid-evoked coughing in anesthetized guinea pigs is mediated by direct activation of capsaicin-insensitive vagal afferent nerves, perhaps through sequential activation of acid-sensing ion channels and chloride channels.

scholarly journals Differential effects of airway afferent nerve subtypes on cough and respiration in anesthetized guinea pigs

2008 ◽  
Vol 295 (5) ◽  
pp. R1572-R1584 ◽  
Author(s):  
Yang-Ling Chou ◽  
Mark D. Scarupa ◽  
Nanako Mori ◽  
Brendan J. Canning
Keyword(s):  
Citric Acid ◽  
Hypertonic Saline ◽  
Guinea Pigs ◽  
Afferent Nerve ◽  
Vagal Afferents ◽  
C Fibers ◽  
Afferent Nerves ◽  
Nodose Ganglia ◽  
Opposing Effects ◽  
Respiratory Reflexes

The hypothesis that respiratory reflexes, such as cough, reflect the net and often opposing effects of activation of multiple afferent nerve subpopulations throughout the airways was evaluated. Laryngeal and tracheal mucosal challenge with either citric acid or mechanical probing reliably evoked coughing in anesthetized guinea pigs. No other stimulus reliably evoked coughing in these animals, regardless of route of administration and despite some profound effects on respiration. Selectively activating vagal C-fibers arising from the nodose ganglia with either adenosine or 2-methyl-5-HT evoked only tachypnea. Selectively activating vagal afferents arising from the jugular ganglia induced respiratory slowing and apnea. Nasal afferent nerve activation by capsaicin, citric acid, hypertonic saline, or histamine evoked only respiratory slowing. Histamine, which activates intrapulmonary rapidly adapting receptors but not airway or lung C-fibers or tracheal bronchial cough receptors induced bronchospasm and tachypnea, but no coughing. The results indicate that the reflexes initiated by stimuli thought to be selective for some afferent nerve subtypes will likely depend on the net and potentially opposing effects of multiple afferent nerve subpopulations throughout the airways. The data also provide further evidence that the afferent nerves regulating cough in anesthetized guinea pigs are distinct from either C-fibers or intrapulmonary rapidly adapting receptors.

scholarly journals Effect of Extracellular Calcium on Excitability of Guinea Pig Airway Vagal Afferent Nerves

2003 ◽  
Vol 89 (3) ◽  
pp. 1196-1204 ◽  
Author(s):  
Bradley J. Undem ◽  
Eun Joo Oh ◽  
Eric Lancaster ◽  
Daniel Weinreich
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Extracellular Calcium ◽  
C Fibers ◽  
Afferent Nerves ◽  
Nodose Ganglia ◽  
Cation Conductance ◽  
Afferent Fibers ◽  
Low Threshold ◽  
Vagal Afferent

The effect of reducing extracellular calcium concentration ([Ca2+]o) on vagal afferent excitability was analyzed in a guinea pig isolated vagally innervated trachea-bronchus preparation. Afferent fibers were characterized as either having low-threshold, rapidly adapting mechanosensors (Aδ fibers) or nociceptive-like phenotypes (Aδ and C fibers). The nociceptors were derived from neurons within the jugular ganglia, whereas the low-threshold mechanosensors were derived from neurons within the nodose ganglia. Reducing [Ca2+]o did not affect the excitability of the low-threshold mechanosensors in the airway. By contrast, reducing [Ca2+]o selectively increased the excitability of airway nociceptors as manifested by a substantive increase in action potential discharge in response to mechanical stimulation, and in a subset of fibers, by overtly evoking action potential discharge. This increase in the excitability of nociceptors was not mimicked by a combination of ω-conotoxin and nifedipine or tetraethylammonium. Whole cell patch recordings from airway-labeled and unlabeled neurons in the vagal jugular ganglia support the hypothesis that [Ca2+]o inhibits a nonselective cation conductance in vagal nociceptors that may serve to regulate excitability of the nerve terminals within the airways.

scholarly journals Kv1.3 channels regulate synaptic transmission in the nucleus of solitary tract

2011 ◽  
Vol 105 (6) ◽  
pp. 2772-2780 ◽  
Author(s):  
Angelina Ramirez-Navarro ◽  
Patricia A. Glazebrook ◽  
Michelle Kane-Sutton ◽  
Caroline Padro ◽  
David D. Kline ◽  
...  
Keyword(s):  
Action Potential ◽  
Transmitter Release ◽  
Brain Slices ◽  
Presynaptic Terminal ◽  
Solitary Tract ◽  
Sensory Afferents ◽  
Peripheral Neurons ◽  
C Fibers ◽  
Nodose Ganglia ◽  
Nucleus Of Solitary Tract

The voltage-gated K+ channel Kv1.3 has been reported to regulate transmitter release in select central and peripheral neurons. In this study, we evaluated its role at the synapse between visceral sensory afferents and secondary neurons in the nucleus of the solitary tract (NTS). We identified mRNA and protein for Kv1.3 in rat nodose ganglia using RT-PCR and Western blot analysis. In immunohistochemical experiments, anti-Kv1.3 immunoreactivity was very strong in internal organelles in the soma of nodose neurons with a weaker distribution near the plasma membrane. Anti-Kv1.3 was also identified in the axonal branches that project centrally, including their presynaptic terminals in the medial and commissural NTS. In current-clamp experiments, margatoxin (MgTx), a high-affinity blocker of Kv1.3, produced an increase in action potential duration in C-type but not A- or Ah-type neurons. To evaluate the role of Kv1.3 at the presynaptic terminal, we examined the effect of MgTx on tract evoked monosynaptic excitatory postsynaptic currents (EPSCs) in brain slices of the NTS. MgTx increased the amplitude of evoked EPSCs in a subset of neurons, with the major increase occurring during the first stimuli in a 20-Hz train. These data, together with the results from somal recordings, support the hypothesis that Kv1.3 regulates the duration of the action potential in the presynaptic terminal of C fibers, limiting transmitter release to the postsynaptic cell.

Role of NaV1.7 in Action Potential Conduction along Human Bronchial Vagal Afferent C‐fibers

2021 ◽  
Author(s):  
Marian Kollarik ◽  
Fei Ru ◽  
Nikoleta Pavelkova ◽  
John Mulcahy ◽  
John Hunter ◽  
...  
Keyword(s):  
Action Potential ◽  
C Fibers ◽  
Vagal Afferent

scholarly journals THE POSTSPIKE POSITIVITY OF UNMEDULLATED FIBERS OF DORSAL ROOT ORIGIN

1958 ◽  
Vol 41 (4) ◽  
pp. 613-632 ◽  
Author(s):  
Herbert S. Gasser
Keyword(s):  
Action Potential ◽  
Dorsal Root ◽  
Nerve Fibers ◽  
Positive Potential ◽  
Apparent Increase ◽  
C Fibers ◽  
Large Size ◽  
New Findings ◽  
Supernormal Period ◽  
The Difference

The positivity following the spike in the action potential of unmedullated nerve fibers of dorsal root origin (d.r.C) has been shown to be homologous with the first positive potential (P1) of other varieties of nerve fibers. Thus it is only through the large size of the positivity that this group of nerve fibers is set apart from other groups. New findings accentuate and make more explicit the difference of d.r.C fiber behavior from that of the sympathetic unmedullated fibers. Support of the conclusion is derived from re-examination of the A fibers as well as from observations on the d.r.C fibers. Increase in size of the P1's in a tetanus of the d.r.C fibers can occur if the frequency is high enough; and it does not occur in an A fiber tetanus if the frequency is low enough. Frequency is also critical in the obtainment of increasing P1's in a tetanus of sympathetic C fibers. Decrease in the size of the P1's in the course of a tetanus is attributable to development of the negative after-potential (N a-p). In rested d.r.C fibers the N a-p is latent. But it appears during a tetanus, develops in size, and after the tetanus leads to a long lasting and clearly defined second positive potential. Absence of a supernormal period during the N a-p of the d.r.C fibers is accounted for. An analysis is made of the apparent increase in size of the spike elevations during a tetanus, for the two subgroups of the C fibers. The difference between the after-potentials of A fibers and of sympathetic C fibers is correlated with the shapes of the curves of cathodal electrotonus of these fibers.

Synergistic interactions between airway afferent nerve subtypes mediating reflex bronchospasm in guinea pigs

2002 ◽  
Vol 283 (1) ◽  
pp. R86-R98 ◽  
Author(s):  
Stuart B. Mazzone ◽  
Brendan J. Canning
Keyword(s):  
Guinea Pigs ◽  
Afferent Nerve ◽  
Solitary Tract ◽  
Synergistic Interactions ◽  
C Fibers ◽  
Neurokinin Receptor ◽  
Cholinergic Tone ◽  
Airway Tone ◽  
Afferent Innervation

The hypothesis that airway afferent nerve subtypes act synergistically to initiate reflex bronchospasm in guinea pigs was addressed. Laryngeal mucosal application of capsaicin or bradykinin or the epithelial lipoxygenase metabolite 15( S)-hydroxyeicosatetraenoic acid evoked slowly developing but pronounced and sustained increases in tracheal cholinergic tone in situ. These reflexes were reversed by atropine and prevented by vagotomy, trimethaphan, or laryngeal denervation. Central nervous system-acting neurokinin receptor antagonists also abolished the reflexes without altering baseline cholinergic tone. Baseline tone was, however, reversed by disrupting pulmonary afferent innervation while preserving the innervation of the trachea and larynx. Surprisingly, selective pulmonary denervation also prevented the laryngeal capsaicin-induced tracheal reflexes, suggesting that laryngeal C-fibers act synergistically with continuously active intrapulmonary mechanoreceptors to initiate reflex bronchospasm. Indeed, reflex bronchospasm evoked by histamine was markedly potentiated by bradykinin, an effect mimicked by intracerebroventricular, but not intravenous, substance P. These data, as well as anatomic evidence for afferent nerve subtype convergence in the commissural nucleus of the solitary tract, suggest that airway nociceptors and mechanoreceptors may act synergistically to regulate airway tone.

Enhancement of Ectopic Discharge in Regenerating A- and C-Fibers by Inflammatory Mediators

2009 ◽  
Vol 101 (6) ◽  
pp. 2762-2774 ◽  
Author(s):  
Lydia Grossmann ◽  
Natalia Gorodetskaya ◽  
Ralf Baron ◽  
Wilfrid Jänig
Keyword(s):  
Inflammatory Mediators ◽  
Inflammatory Cells ◽  
Nerve Fibers ◽  
Afferent Nerve ◽  
Cold Sensitivity ◽  
Nerve Crush ◽  
C Fibers ◽  
Afferent Nerve Fibers ◽  
Evoked Activity

Afferent A- and C-fibers regenerating into a nerve following peripheral nerve injury are exposed to inflammatory mediators released by Schwann cells, resident and invading macrophages, and other inflammatory cells. Here we tested the hypothesis that ongoing and evoked activity in these afferent fibers are enhanced by a mixture of inflammatory mediators [inflammatory soup (IS)] applied to the injured nerve. Using in vivo electrophysiology, regenerating afferent nerve fibers were studied 7–14 days after sural nerve crush lesion. The ectopic activity was studied before and ≤1.5 h after topical application of IS to the nerve in 73 C-fibers and 22 A-fibers that were either ectopically active before application of IS (61 C-fibers, 17 A-fibers) or recruited by IS (12 C-fibers, 5 A-fibers). More than one half of the C-fibers were activated by IS for ≤90 min after its removal. The majority of mechano- (23/38) and heat-sensitive (29/35) C-fibers as well as mechano-sensitive A-fibers (12/17) decreased their activation thresholds and/or increased the response magnitude to mechanical and/or heat stimulation of the nerve. Noxious cold sensitivity, but not nonnoxious cold sensitivity, was weakly influenced by IS. Some initially nonresponsive C- and A-fibers developed new ectopic properties, i.e., were recruited, and exhibited ongoing activity and/or could be activated by physiological stimuli after application of IS. The results suggest that inflammatory mediators may be critical to enhance ectopic excitability of regenerating afferent nerve fibers. These peripheral mechanisms may be important triggering and maintaining neuropathic pain.

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