Biomedical subjects

Bradley J Undem

Publications and source records attributed to Bradley J Undem.

At least 19 recordsLinked to original sources

PubMed2006

Design and synthesis of 3,5-disubstituted benzamide analogues of DNK333 as dual NK1/NK2 receptor probes.

N-[(R,R)-(E)-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (DNK333, 1b) has been reported to be a potent and balanced dual neurokinin (tachykinin) receptor antagonist. A recent clinical trial using DNK333 has shown that it blocks the NKA-induced bronchoconstriction in patients with asthma. A series of six analogues 3-8 derived from modification of 3,5-bis(trifluoromethyl)benzamide moiety of DNK333 has been synthesized to serve as the dual NK(1)/NK(2) receptor probes. The 3,5-dinitro substituted benzamide compound 3 was found to possess potent and balanced dual NK(1)/NK(2) receptor antagonist activities (pK(b)=8.4 for the NK(1) receptors, pK(b)=7.87 for the NK(2) receptors) in the functional assay using guinea pig trachea. Furthermore, SAR analysis suggests that steric, electronic, and lipophilic characteristics of substituents in the benzamide region of DNK333 have a crucial effect on both the NK(1) and NK(2) receptor antagonist activities.

Animals↗

PubMed2006

Evidence for both adenosine A1 and A2A receptors activating single vagal sensory C-fibres in guinea pig lungs.

We addressed the hypothesis that single vagal afferent C-fibres can be stimulated via either the adenosine A1 or A2A receptor subtypes. The effect of adenosine on the nerve terminals of vagal sensory nerve subtypes was evaluated in an ex vivo perfused guinea pig lung preparation using extracellular recording techniques. Adenosine (10 microm) consistently evoked action potential discharge in lung C-fibre terminals arising from the nodose ganglia, but failed to evoke action potential discharge in most jugular ganglion C-fibres. Adenosine also failed to activate stretch-sensitive nodose A-fibres in the lungs. The selective A1 antagonist DPCPX (0.1 microm) or the selective A2A antagonist SCH 58261 (0.1 microm) partially inhibited the nodose C-fibre activation by adenosine, and the combination of both antagonists almost completely inhibited the response. The adenosine-induced action potential discharge in nodose C-fibres was mimicked by either the selective A1 agonist CCPA (1 microm) or the selective A2A agonist CGS 21680 (1 microm). Single cell PCR techniques revealed that adenosine A1 and A2A receptor mRNA was expressed in individual nodose neurons retrogradely labelled from the lungs. The gramicidin-perforated patch clamp technique on neurons retrogradely labelled from the lungs was employed to study the functional consequence of adenosine receptor agonists directly on neuronal membrane properties. Both the selective A1 agonist CCPA (1 microm) and the selective A2A agonist CGS 21680 (1 microm) depolarized the airway-specific, capsaicin-sensitive, nodose neurons to action potential threshold. The data support the hypothesis that adenosine selectively depolarizes vagal nodose C-fibre terminals in the lungs to action potential threshold, by stimulation of both adenosine A1 and A2A receptor subtypes located in the neuronal membrane.

Action Potentials↗

PubMed2006

Transduction mechanisms in airway sensory nerves.

The induction of action potentials in airway sensory nerves relies on events leading to the opening of cation channels in the nerve terminal membrane and subsequent membrane depolarization. If the membrane depolarization is of sufficient rate and amplitude, action potential initiation will occur. The action potentials are then conducted to the central nervous system, leading to the initiation of various sensations and cardiorespiratory reflexes. Triggering events in airway sensory nerves include mechanical perturbation, inflammatory mediators, pH, temperature, and osmolarity acting through a variety of ionotropic and metabotropic receptors. Action potential initiation can be modulated (positively or negatively) through independent mechanisms caused mainly by autacoids and other metabotropic receptor ligands. Finally, gene expression of sensory nerves can be altered in adult mammals. This neuroplasticity can change the function of sensory nerves and likely involve both neurotrophin and use-dependent mechanisms. Here we provide a brief overview of some of the transduction mechanisms underlying these events.

Action Potentials↗

PubMed2006

Sensory transduction in cough-associated nerves.

Before a tussive stimulus in the airways can evoke a cough reflex it must first cause action potential discharge in cough-associated vagal sensory nerves. This is initiated by the stimulus first interacting with the receptors and ion channels in the terminal membrane of the sensory fiber in a manner that leads to membrane depolarization. If the stimulus-induced membrane depolarization, referred to as a generator potential, is of sufficient magnitude, action potentials are elicited that are then conducted to the central nervous system. If the action potentials are of sufficient number and frequency, a cough is evoked. The most common tussive stimuli include mechanical perturbations, anosmotic solutions, acidic solutions, and various chemical agents. The mechanisms underlying the transduction of most of these tussive stimuli into a generator potential are only partially understood. In general terms, chemical stimuli interact directly with receptors that are classified as either ligand gated ion channels or metabotropic receptors (e.g. G-protein coupled receptors). Ligand gated receptors are those in which the receptor protein also serves as the ion channel. The metabotropic receptors indirectly modulate the ion channels activity via various signal transduction schemes. Mechanical stimuli are thought to interact with mechanically gated ion channels, and acid can interact with acid sensing ion channels in addition to the capsaicin receptor TRPV1. In this overview some of the specific receptors and ion channels involved in the tussive stimulus-induced generator potentials in vagal afferent nerve terminals are discussed.

Animals↗

PubMed2005

Nasal sensory nerve populations responding to histamine and capsaicin.

BACKGROUND: Inflammation of the nasal mucosa leads to sneezing, nasal itch, rhinorrhea, and nasal blockage. Many of these symptoms are likely the result of nasal trigeminal sensory nerve stimulation by inflammatory mediators. Nasal challenge with the C-fiber stimulant capsaicin causes a different set of symptoms than those evoked by histamine, suggesting that these 2 stimuli may activate separate subpopulations of nasal sensory nerves. OBJECTIVE: To investigate the trigeminal sensory nerves innervating the guinea pig nasal mucosa and to address specifically the hypothesis that histamine and capsaicin activate distinct subgroups of these nerves. METHODS: Guinea pig trigeminal neurons (retrogradely labeled from the nasal mucosa) were assessed for their responses to histamine and capsaicin by studying changes in the intracellular free calcium concentration, and assessed for substance P immunoreactivity. RESULTS: Only 60% of the nasal-specific trigeminal sensory neurons were found to be capsaicin-sensitive. Histamine stimulated only a subset (<40%) of these capsaicin-sensitive neurons. No nasal-specific capsaicin-insensitive neurons responded to histamine, although about 10% of trigeminal ganglion neurons per se responded to histamine but not capsaicin. Immunohistochemical analysis revealed that most (about 60%) of the sensory neurons innervating the nasal mucosa did not express the neuropeptide substance P, including nearly all large-diameter neurons, but also a significant number of small-diameter neurons (presumably C-fiber neurons). CONCLUSION: Nasal neurons are not homogenous with respect to chemosensitivity or substance P content. It is likely that this heterogeneity in nasal afferent nerves underlies the differences in nasal responses to specific inflammatory mediators associated with the allergic reaction.

Animals↗

PubMed2005

Effect of nociceptin in acid-evoked cough and airway sensory nerve activation in guinea pigs.

RATIONALE: Nociceptin/orphanin FQ has been reported to inhibit capsaicin- and mechanically provoked cough in animal models, but the mechanism of this effect has not been elucidated. OBJECTIVES: The objectives of this study were to determine whether nociceptin inhibits acid-evoked cough in conscious animals and to evaluate the mechanism of this effect. METHODS: We tested the effect of nociceptin on acid-induced cough in conscious guinea pigs and acid-induced nerve activation in airway-specific vagal sensory neurons using calcium imaging techniques and the gramicidin-perforated patch clamp technique. MEASUREMENTS AND MAIN RESULTS: Nociceptin (3 mg/kg, intraperitoneal) effectively inhibited acid-evoked cough in guinea pigs by nearly 70%. Acid (pH 5) increased intracellular free calcium in acutely dissociated vagal jugular ganglionic neurons. The acid-induced increase in intracellular calcium was inhibited by a selective transient receptor potential vanilloid-1 antagonist, 5-iodo-resiniferatoxin (1 microM, approximately 80% reduction). The inhibitory effect of 5-iodo-resiniferatoxin on acid-induced increases in calcium was mimicked by nociceptin (0.1 microM). In gramicidin-perforated patch clamp recordings on airway-specific capsaicin-sensitive jugular ganglion neurons, acid (pH 5) induced two distinct inward currents. A transient current was evoked that was inhibited by amiloride and a sustained current was evoked that was inhibited by 5-iodo-resiniferatoxin. Nociceptin selectively inhibited only the sustained component of acid-induced inward current. CONCLUSION: These results indicate that the inhibitory effect of nociceptin on acid-induced cough may result from a direct inhibitory effect on peripheral C-fiber activity caused by the selective inhibition of acid-induced transient receptor potential vanilloid-1 activation.

Animals↗

PubMed2005

Role of chloride channels in bradykinin-induced guinea pig airway vagal C-fibre activation.

We tested the hypothesis that an ionic current carried by chloride ions contributes to bradykinin (BK)-induced membrane depolarization and activation of vagal afferent C-fibres. In an ex vivo innervated trachea/bronchus preparation, BK (1 microM) consistently produced action potential discharge in vagal afferent C-fibres with receptive fields in the trachea or main stem bronchus. The Ca2+-activated Cl- channel (CLCA) inhibitor, niflumic acid (NFA, 100 microM), significantly reduced BK-induced action potential discharge to 21 +/- 7% of the control BK response. NFA did not inhibit capsaicin-induced or citric-acid-induced action potential discharge in tracheal C-fibres. The inhibitory effect of NFA was mimicked by another CLCA inhibitor, 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB, 100 microM). NFA also inhibited the BK-induced inward current in gramicidin-perforated whole-cell patch-clamp recordings of capsaicin-sensitive jugular ganglion neurones retrogradely labelled from the airways. NFA did not inhibit the BK-induced increase in intracellular free Ca2+. The TRPV1 inhibitor, iodo-resiniferatoxin (1 microM), also partially inhibited BK-induced action potential discharge, and the combination of iodo-resiniferatoxin and NFA virtually abolished the BK-induced action potential discharge. We concluded that in vagal afferent C-fibres, BK evokes membrane depolarization and action potential discharge through the additive effects of TRPV1 and Cl- channel activation.

Afferent Pathways↗

PubMed2005

Vagal afferent nerves with nociceptive properties in guinea-pig oesophagus.

Some vagal afferent nerves are thought to mediate autonomic responses evoked by noxious oesophageal stimuli and participate in the perception of pain originating in the oesophagus. However, the vagal nociceptive nerve phenotypes implicated in this function have yet to be identified. In this study, nociceptive fibres were defined by the capacity to discriminate noxious mechanical stimuli (wide range of oesophageal distension with pressure up to 100 mmHg) and detect noxious chemical stimuli (the activators of capsaicin receptor TRPV1). Using immunohistochemical techniques with retrogradely labelled oesophagus-specific neurones and performing extracellular recordings from the isolated vagally innervated oesophagus, we show that in the guinea-pig, the vagus nerves supply the oesophagus with a large population of nociceptive-like afferent nerve fibres. Vagal nociceptive-like fibres in the guinea-pig oesophagus are derived from two embryonically distinct sources: neurones situated in the nodose vagal ganglia and neurones situated in the jugular vagal ganglia. Nodose (placode-derived) nociceptive-like fibres are exclusively C-fibres sensitive to a P2X receptors agonist and rarely express the neuropeptide substance P. In contrast, jugular (neural crest-derived) nociceptive-like fibres include both A-fibres and C-fibres, are insensitive to P2X receptors agonist and mostly express substance P. The non-nociceptive vagal tension mechanoreceptors are distinguished from nociceptors by their saturable response to oesophageal distension and by the lack of TRPV1. These tension mechanoreceptors are exclusively A-fibres arising from the nodose ganglion. We conclude that the vagus nerves supply the guinea-pig oesophagus with nociceptors in addition to tension mechanoreceptors. The vagal nociceptive-like fibres in the oesophagus comprise two distinct subtypes dictated by the ganglionic location of their cell bodies.

Action Potentials↗

PubMed2005

Allergen-induced substance P synthesis in large-diameter sensory neurons innervating the lungs.

BACKGROUND: Tachykinins such as substance P are localized in unmyelinated slow-conducting C fibers that can be activated by noxious stimuli and tissue inflammation. Substance P is seldom expressed in fast-conducting large-diameter (A-fiber) vagal sensory neurons. We have previously found that allergic inflammation causes a phenotypic change in tachykinergic innervation of the trachea such that the production of substance P is induced in large-diameter sensory neurons projecting mechanosensitive A fibers to the trachea. OBJECTIVE: To evaluate whether allergic inflammation also induces substance P synthesis in large-diameter sensory stretch-receptor neurons innervating guinea pig lungs, and to investigate potential mechanisms by which this may occur. METHODS: Sensitized guinea pigs were exposed to allergen (ovalbumin) aerosol. One day later, immunohistochemical analysis was performed on vagal sensory neurons that had been retrogradely labeled from the lungs. RESULTS: Ovalbumin inhalation caused a significant increase in substance P expression in large-diameter neurofilament-positive nodose ganglion neurons that innervate the lungs (P < .05). This effect was decreased by ipsilateral vagotomy. Exposing isolated nodose ganglia to the sensitizing antigen, ovalbumin, also significantly increased substance P expression compared with control. CONCLUSION: Allergic inflammation induces substance P synthesis in large-diameter (A-fiber) nodose ganglion neurons innervating guinea pig lungs. This could contribute to the hyperreflexia seen in allergic airway disease. The full expression of this phenotypic switch in vagus nodose ganglion neurons requires intact vagus nerve, but if allergen reached the systemic circulation in sufficient quantities, it could also affect substance P synthesis by local activation of vagal ganglionic mast cells.

Allergens↗

PubMed2005

Effect of 5-hydroxytryptamine on vagal C-fiber subtypes in guinea pig lungs.

5-Hydroxytryptamine (5-HT, serotonin) evokes pulmonary reflexes partially by activating vagal bronchopulmonary C-fibers. In the guinea pig, vagal bronchopulmonary C-fibers arise from cell bodies situated in the nodose and the jugular ganglia. The nodose and the jugular C-fibers differ both pharmacologically and neurochemically, and may subserve different functions. In this study, we compared the effect of 5-HT on the nodose and jugular C-fibers with receptive fields within the guinea pig lungs. The nerve terminals of the vagal bronchopulmonary C-fibers were studied in an ex vivo isolated perfused lung nerve preparation using the extracellular recordings. All nodose C-fibers responded to transient administration of 5-HT (10 microM) and to the selective 5-HT3 receptor agonist, 2-methyl-5-HT (10 microM), with the action potential discharge. The selective 5-HT3 receptor antagonist ondansetron (10 microM) inhibited (by approximately 90%) the activation of the nodose C-fibers evoked by 5-HT (10 microM). In contrast to the nodose C-fibers, the jugular C-fibers were unresponsive or poorly responsive to 5-HT (n=9) and unresponsive to 2-methyl-5-HT (n=11). A direct action of 5-HT on the C-fiber neurons was supported using the whole cell patch clamp recordings from the isolated vagal sensory neurons retrogradely labeled from the lungs. Consistently with the studies on the nerve terminals, 5-HT (10 microM) induced inward current in nodose lung-specific capsaicin-sensitive neurons. Conversely, 5-HT was inefficient to stimulate the lung-specific jugular neurons. We conclude that in the guinea pig lungs, 5-HT selectively stimulates vagal nodose, but not jugular C-fibers via the 5-HT3 receptors in the neuronal membrane.

Animals↗

PubMed2005

Effect of olvanil and anandamide on vagal C-fiber subtypes in guinea pig lung.

Certain fatty acid amides such as anandamide (AEA) and olvanil are agonists for the transient receptor potential, vanilloid-1 (TRPV1) receptor, but have been found to activate TRPV1-containing C-fibers in some tissues but not others. We used extracellular recording and whole-cell patch clamp techniques to investigate the effect of olvanil and AEA on different types of vagal C-fibers innervating the same tissue, namely jugular and nodose vagal C-fibers in guinea pig lungs. A 30 s exposure to AEA and olvanil caused action potential discharge in all nodose C-fiber innervating lung but failed to activate jugular C-fibers innervating lung and airways. The activation of nodose C-fibers was blocked by the TRPV1 antagonist iodo-resiniferatoxin. In whole-cell patch clamp recordings of dissociated nodose and jugular capsaicin-sensitive neurons labeled from lungs and airways, olvanil induced large TRPV1-dependent inward currents in cell bodies of both nodose and jugular ganglion neurons. Prolonged exposure (up to 5 min) to olvanil caused action potential discharge in jugular C-fiber innervating lung but the onset latency was four times longer in jugular than in nodose C-fibers. The onsets of capsaicin response in nodose and jugular C-fibers were not different. Decreasing the tissue temperature to 25 degrees C increased the onset latency of olvanil-induced activation of nodose C-fibers 2-3-fold, but did not effect the latency of the capsaicin response. Capsaicin, olvanil, and AEA stimulate jugular C-fibers leading to tachykinergic contractions of isolated bronchi. The time to reach half-maximum is more than four times longer for olvanil and AEA, as compared to capsaicin in evoking contractions. We conclude that brief exposure to certain fatty acid amides, such as AEA and olvanil activate nodose but not jugular C-fiber terminals in the lungs. We hypothesize that this is because the nodose C-fiber terminals are equipped with a temperature-dependent mechanism for effectively and rapidly transporting the TRPV1 agonists so that they gain access to the intracellular binding sites on TRPV1. This transport mechanism may be differently expressed in two distinct subtypes of pulmonary C-fiber terminals innervating the same tissue.

Action Potentials↗

PubMed2005

The role of vagal afferent nerves in chronic obstructive pulmonary disease.

Circumstantial evidence supports the hypothesis that the vagal nervous system is dysregulated in chronic obstructive pulmonary disease. This dysregulation can lead to an increased sensitivity of the cough reflex such that the coughing becomes, at times, "nonproductive" or inappropriate. Vagal dysregulation can also lead to an increase in the activity of the parasympathetic reflex control of the airways, which contributes to greater mucus secretion and bronchial smooth muscle contraction. Indirect evidence indicates that lung disease is accompanied by substantive changes to the entire reflex pathways, including enhanced activity of the primary afferent nerves, increases in synaptic efficacy at secondary nerves in the central nervous system, and changes in the autonomic nerve pathways. Drugs aimed at normalizing neuronal activity may, therefore, be beneficial in chronic obstructive pulmonary disease.

Animals↗

PubMed2004

Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs.

We have identified the tracheal and laryngeal afferent nerves regulating cough in anaesthetized guinea-pigs. Cough was evoked by electrical or mechanical stimulation of the tracheal or laryngeal mucosa, or by citric acid applied topically to the trachea or larynx. By contrast, neither capsaicin nor bradykinin challenges to the trachea or larynx evoked cough. Bradykinin and histamine administered intravenously also failed to evoke cough. Electrophysiological studies revealed that the majority of capsaicin-sensitive afferent neurones (both Adelta- and C-fibres) innervating the rostral trachea and larynx have their cell bodies in the jugular ganglia and project to the airways via the superior laryngeal nerves. Capsaicin-insensitive afferent neurones with cell bodies in the nodose ganglia projected to the rostral trachea and larynx via the recurrent laryngeal nerves. Severing the recurrent nerves abolished coughing evoked from the trachea and larynx whereas severing the superior laryngeal nerves was without effect on coughing. The data indicate that the tracheal and laryngeal afferent neurones regulating cough are polymodal Adelta-fibres that arise from the nodose ganglia. These afferent neurones are activated by punctate mechanical stimulation and acid but are unresponsive to capsaicin, bradykinin, smooth muscle contraction, longitudinal or transverse stretching of the airways, or distension. Comparing these physiological properties with those of intrapulmonary mechanoreceptors indicates that the afferent neurones mediating cough are quite distinct from the well-defined rapidly and slowly adapting stretch receptors innervating the airways and lungs. We propose that these airway afferent neurones represent a distinct subtype and that their primary function is regulation of the cough reflex.

Anesthesia↗

PubMed2004

Mechanisms of chronic cough.

Chronic and uncontrollable cough is one of the most common and debilitating symptoms found in patients with chronic airway diseases. The physical trauma and stresses of chronic cough on the airway mucosa and respiratory muscles can further worsen the deteriorating process of the airway diseases. The articles presented in this section focus primarily on the effect of chronic cough on the cell structure and protective function of the airway mucosa, the mechanisms underlying the hypersensitivity of chronic cough, and new target areas for antitussive drug development. A major emphasis has been placed on the neuronal plasticity found at the peripheral and central sites of the neural pathway mediating the cough reflex, and its potential role in the development of chronic cough is discussed. A number of new and important questions concerning the physiological and pharmacological mechanisms underlying chronic cough have emerged in these presentations. Further studies are required to answer these questions, which should bring a better understanding of the pathogenic mechanisms of chronic cough and lead to the development of new therapeutic strategies.

Antitussive Agents↗

PubMed2004

Ionotropic and metabotropic receptor mediated airway sensory nerve activation.

There are several receptors capable of inducing activating generator potentials in cough-associated afferent terminals in the airways. The chemical receptors leading to generator potentials can be subclassified into ionotropic and metabotropic types. An ionotropic receptor has an agonist-binding domain, and also serves directly as an ion channel that is opened upon binding of the agonist. Examples of ionotropic receptors found in airway sensory nerve terminals include receptors for serotonin (5-HT3 receptors), ATP (P2X receptors), acetylcholine (nicotinic receptors), receptors for capsaicin and related vanilloids (TRPV1 receptors), and acid receptors (acid sensing ion channels). Afferent nerve terminals can also be depolarized via activation of metabotropic or G-protein coupled receptors (GPCRs). Among the GPCRs that can lead to activation of airway afferent fibers include bradykinin B2 and adenosine A1 receptors. The signaling events leading to GPCR-mediated membrane depolarization are more complex than that seen with ionotropic receptors. The GPCR-mediated effects are thought to occur through classical second messenger systems such as activation of phospholipase C. This may lead to membrane depolarization through interaction with specific ionotropic receptors (such as TRPV1) and/or various types of calcium activated channels.

Action Potentials↗

PubMed2003

Capsaicin-sensitive and -insensitive vagal bronchopulmonary C-fibres in the mouse.

We developed an isolated tracheally perfused (35-37 degrees C) nerve-lung preparation for the study of bronchopulmonary afferent nerve activity in the mouse. Extracellular recordings were made from the vagal sensory neurons located in the jugular-nodose ganglia complex (JNC) with identified receptive fields in the lungs. Analysis of the vagal compound action potential revealed that the mouse vagal C-fibre conduction velocities range from 0.3 to 1.5 m s(-1). A total of 83 bronchopulmonary C-fibres were studied. The sensitivity of the bronchopulmonary C-fibres to the vanilloid receptor 1 (VR1) agonist capsaicin was dependent on conduction velocity. Thus C-fibres with conduction velocities between 0.3 and 0.7 m s(-1) responded to capsaicin (1 microM) while C-fibres with conduction velocities between 0.7 and 1.5 m s(-1) were capsaicin insensitive. Similarly, bradykinin (1 microM) excited only those C-fibres with conduction velocities < 0.7 m s(-1). The response to bradykinin was not mimicked by the B1 receptor agonist [des-Arg9]bradykinin (1 microM) and was abolished by the bradykinin B2 receptor antagonist HOE 140 (1 microM). Adenosine 5'-triphosphate (ATP, 30 microM) activated the C-fibres irrespective of the conduction velocities. This response was mimicked by the selective P2X agonist alpha,beta-methylene-adenosine 5'-triphosphate (30 microM). Consistent with the electrophysiology, morphological analysis revealed that only approximately 40% of the lung-specific small diameter (< 20 microm) JNC neurons consistent with the C-fibre cell bodies display VR1 immunoreactivity. This study describes a convenient in vitro method for the study of mouse bronchopulmonary C-fibres. The results indicate that C-fibres in the mouse lungs are not homogeneous, but can be subclassified into capsaicin-sensitive and capsaicin-insensitive phenotypes.

Action Potentials↗

PubMed2003

Role of cyclooxygenase activation and prostaglandins in antigen-induced excitability changes of bronchial parasympathetic ganglia neurons.

In vitro antigen challenge has multiple effects on the excitability of guinea pig bronchial parasympathetic ganglion neurons, including depolarization, causing phasic neurons to fire with a repetitive action potential pattern and potentiating synaptic transmission. In the present study, guinea pigs were passively sensitized to the antigen ovalbumin. After sensitization, the bronchi were prepared for in vitro electrophysiological intracellular recording of parasympathetic ganglia neurons to investigate the contribution of cyclooxygenase activation and prostanoids on parasympathetic nerve activity. Cyclooxygenase inhibition with either indomethacin or piroxicam before in vitro antigen challenge blocked the change in accommodation. These cyclooxygenase inhibitors also blocked the release of prostaglandin D(2) (PGD(2)) from bronchial tissue during antigen challenge. We also determined that PGE(2) and PGD(2) decreased the duration of the action potential after hyperpolarization, whereas PGF(2alpha) potentiated synaptic transmission. Thus prostaglandins released during antigen challenge have multiple effects on the excitability of guinea pig bronchial parasympathetic ganglia neurons, which may consequently affect the output from these neurons and thereby alter parasympathetic tone in the lower airways.

Action Potentials↗

PubMed2003

Pharmacology of vagal afferent nerve activity in guinea pig airways.

The excitability and activity of vagal afferent nerves innervating the airways can be pharmacologically increased and decreased. Autacoids released as a result of airway inflammation can lead to substantial increases in afferent nerve activity, consequently altering pulmonary reflex physiology. In a manner analogous to hyperalgesia associated with inflammation in the somato-sensory system, increases in vagal afferent nerve activity in inflamed airways may lead to a heightened cough reflex, and increases in autonomic activity in the airways. These effects may contribute to many of the symptoms of inflammatory airway disease. Here we provide a brief overview of some of the mechanisms by which the afferent activity in airway nerves can be pharmacologically modified.

Animals↗