Biomedical subjects

Michael J Carr

Publications and source records attributed to Michael J Carr.

27 records · Page 2Linked to original sources

PubMed2004

Plasticity of vagal afferent fibres mediating cough.

Increased sensitivity of cough pathways has been demonstrated in numerous studies. The underlying mechanisms of this sensitization are largely unknown; however, a burgeoning body of evidence suggests that vagal primary afferent neurones that innervate the airways are likely to be involved. This plasticity includes changes in anatomy, neurochemistry and function. PGE2 is an example of an inflammatory mediator that increases responsiveness to tussive stimuli. Electrophysiological studies of neurone cell bodies isolated from afferent ganglia have revealed that prostanoids modulate the function of a variety of distinct ion channels including those that carry TTX-insensitive voltage-gated sodium currents, slow post-spike hyperpolarizations and a hyperpolarization-activated cation current. Mediator-induced modulation of the function of various voltage-gated currents operating at the peripheral terminals of airway afferent neurons would probably influence input from the airways into the central nervous system and contribute to the urge to cough and increased responsiveness to tussive stimuli.

Cough↗

PubMed2003

Effect of olvanil on the afferent and efferent function of capsaicin-sensitive C-fibers in guinea pig airways.

The aim of the present study was to examine the ability of the nonpungent vanilloid VR1 receptor agonist, olvanil, to activate the afferent and efferent function of capsaicin-sensitive C-fibers in guinea pig airways. We found that while capsaicin (10 nM-10 microM) and resiniferatoxin (0.1 nM-1.0 microM) evoked a robust contraction of the guinea pig trachea in vitro, olvanil (10 nM-10 microM) was a weak spasmogen. In addition, pretreatment with olvanil caused only a minor reduction of subsequent responses to capsaicin or resiniferatoxin. Using single fiber recording from guinea pig airway C-fibers, we found that olvanil (10 microM) did not evoke action potential discharge although these fibers responded vigorously to capsaicin after prolonged treatment with olvanil (10 microM). These findings are indicative of significant differences in the relative sensitivity of vanilloid VR1 receptor-transfected cells and the peripheral terminals of airway C-fibers to pungent and nonpungent vanilloid VR1 receptor agonists.

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↗

PubMed2003

Bronchopulmonary afferent nerves.

Vagal afferent nerves are the primary communication pathways between the bronchopulmonary system and the central nervous system. Input from airway afferent nerves to the CNS is integrated in the brainstem and ultimately leads to sensations and various reflex outputs. Afferent nerves innervating the airways can be classified into various distinct phenotypes. However, there is no single classification scheme that takes all features, including conduction velocity, cell body diameter, ganglionic origin, and stimuli to which they respond (modality) into account. At present, bronchopulmonary afferent nerves are typically considered to belong to one of three general categories, namely C-fibres, rapidly adapting stretch receptors (RARs), and slowly adapting stretch receptors (SARs). As our understanding of bronchopulmonary afferent nerves continues to deepen, we are likely to see more sophisticated classification schemes emerge. It is clear that the function of afferent fibres can be substantively influenced by airway inflammation and remodelling. The perturbations and perversions of afferent nerve function that occur during these states almost certainly contributes to many of the signs and symptoms of inflammatory airway disease. A more lucid characterization of bronchopulmonary afferent nerves, and a better understanding of the mechanisms by which these nerves influence pulmonary physiology during health and disease anticipates future research.

Afferent Pathways↗

PubMed2003

A role for TRPV1 in bradykinin-induced excitation of vagal airway afferent nerve terminals.

Using single-unit extracellular recording techniques, we have examined the role of the vanilloid receptor-1 (VR1 aka TRPV1) in bradykinin-induced activation of vagal afferent C-fiber receptive fields in guinea pig isolated airways. Of 17 airway C-fibers tested, 14 responded to bradykinin and capsaicin, 2 fibers responded to neither capsaicin nor bradykinin, and 1 fiber responded to capsaicin but not bradykinin. Thus, every bradykinin-responsive C-fiber was also responsive to capsaicin. Bradykinin (200 microl of 0.3 microM solution) evoked a burst of approximately 130 action potentials in C-fibers. In the presence of the TRPV1 antagonist capsazepine (10 microM), bradykinin evoked 83 +/- 9% (n = 6; P < 0.01) fewer action potentials. Similarly, the TRPV1 blocker, ruthenium red (10 microM), inhibited the number of bradykinin-evoked action potentials by 75 +/- 10% (n = 4; P < 0.05). In the presence of 5,8,11,14-eicosatetraynoic acid (10 microM), an inhibitor of lipoxygenase and cyclooxygenase enzymes, the number of bradykinin-induced action potentials was reduced by 76 +/- 10% (n = 6; P < 0.05). Similarly, a combination of the 12-lipoxygenase inhibitor, baicalein (10 microM) and the 5-lipoxygenase inhibitor ZD2138 [6-[3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone] (10 microM) caused significant inhibition of bradykinin-induced responses. Our data suggest a role for lipoxygenase products in bradykinin B(2) receptor-induced activation of TRPV1 in the peripheral terminals of afferent C-fibers within guinea pig trachea.

Animals↗

PubMed2002

Expression of tachykinins in nonnociceptive vagal afferent neurons during respiratory viral infection in guinea pigs.

Immunohistochemistry was combined with retrograde labeling to characterize the effect of respiratory infection with Sendai virus on the number of Substance P/Neurokinin A-containing vagal afferent neurons whose cell bodies resided in the nodose ganglia and whose receptive fields were located in guinea pig trachea. Of the neurons labeled from the trachea of vehicle-inoculated guinea pigs, few stained positively for Substance P/Neurokinin A (approximately 3% of total labeled neurons). These neurons had small diameter cell bodies (mode = 16-20 microm), a feature of nociceptive-like C-fibers. Viral infection (Day 4 after inoculation) was associated with a significantly greater number of labeled neurons containing Substance P/Neurokinin A (approximately 20% of total labeled neurons). The majority of these had a relatively large cell body diameter (mode = 36- 40 microm), a feature of nonnociceptive afferent neurons. This induction appeared to be reversible as there were significantly fewer Substance P/Neurokinin A positive neurons in nodose ganglia from virus-inoculated guinea pigs at Day 28 after inoculation, a time point when virus-induced airway inflammation had all but resolved. These findings support the hypothesis that viral infection leads to a qualitative change in the vagal afferent innervation of guinea pig airways such that both small diameter nociceptive-like neurons and large diameter nonnociceptive neurons express tachykinins.

Action Potentials↗

PubMed2002

Physiology and plasticity of putative cough fibres in the Guinea pig.

Cough is initiated by activation of afferent nerve fibers with rapidly adapting receptors (RAR) that conduct action potentials in the Adelta range. In addition, various stimuli that activate airway unmylenated C-fibres evoke cough reflexes. We have used a vagally innervated, larynx-trachea-bronchus preparation, isolated from guinea pigs, to study the pharmacology of RARs and C-fibres in vitro. In this preparation afferent fibres with the RAR phenotype are exquisitely sensitive to mechanical perturbation of their receptive fields, but are unaffected by a variety of mediators (e.g. prostaglandins, histamine, bradykinin, serotonin) and by capsaicin. By contrast, C-fibres are much less sensitive to mechanical stimulation, but can be activated by capsaicin and bradykinin. Preliminary evidence supports the hypothesis that bradykinin activate C-fibre by stimulating the capsaicin (vanilloid) receptor VR1. Acids activate both C-fibres and RARs. Acids stimulate RAR fibres by a mechanism that is rapidly inactivated. C-fibres are stimulated by both a rapidly inactivating mechanism, as well as a slowly inactivating mechanism. Drugs that block VR1 inhibit the latter mechanism. Airway inflammation substantially increases the mechanical sensitivity of RAR fibres without affecting their adaptive properties. Airway inflammation also causes a phenotypic switch in neuropeptide innervation of the airways that RAR neurons begin to synthesis neurokinins and calcitonin gene related peptide. In non-inflamed animals these peptides are expressed only in C-fibre neurons. Thus, airway inflammation may not only increase the sensitivity of cough fibres, but may also qualitatively change the role played by sensory neuropeptides in cough reflexes.

Animals↗

PubMed2002

The role of nerves in asthma.

Asthma is a syndrome characterized by reversible episodes of wheezing, cough, and sensations of chest tightness and breathlessness. These symptoms are secondary to changes in the activity of the nervous system. The mechanisms by which the nervous system is altered such that the symptoms of asthma occur have not yet been elucidated. Airway inflammation associated with asthma may affect neuronal activity at several points along the neural reflex pathway, including the function of the primary afferent (sensory) nerves, integration within the central nervous system, synaptic transmission within autonomic ganglia, and transmission at the level of the postganglionic neuroeffector junction. We provide a brief overview of these interactions and the relevance they may have to asthma.

Animals↗

PubMed2002

The study of airway primary afferent neuron excitability.

The activation of airway afferent neurons initiates a variety of reflexes including cough and bronchoconstriction. Like somatic afferent neurons involved in inflammation-induced hyperalgesia, the excitability of airway afferent neurons is not fixed but, rather, can be increased by the action of a variety of mediators produced during inflammation. A variety of techniques have been applied to study the pharmacological modulation of the excitability of afferent neurons. Although airway afferent neurons have not been studied to the same extent as fibers involved in hyperalgesia, similar pathways may control their excitability. The ability to study the pharmacological modulation of airway afferent neuron excitability is crucial to our understanding of airway afferent neurophysiology and may also provide insight into novel therapeutic targets for various inflammatory lung diseases.

Animals↗