Modulation of Sensory Nerve Function and the Cough Reflex
Author(s)
Nasra , Julie
Type
Thesis or dissertation
Abstract
Cough is an important protective reflex. Sensory nerve activity mediating cough may
be enhanced during disease. Current antitussives possess little clinical efficacy,
therefore research is needed to investigate the modulation of airway sensory nerves in
order to understand the mechanisms driving chronic cough.
A conscious guinea-pig cough model using different tussive stimuli, known to elicit
cough in man, was established. Corresponding in vitro effects of these tussive agents
on sensory nerve activation were characterised. These agents were also characterised
into sub-types as they produced distinct patterns of response.
Cigarette smoke (CS) exposure elicited distinct effects on the cough reflex in
conscious guinea-pigs and on sensory nerve activity measured in vitro; CS enhanced
responses to citric acid (CA), capsaicin (CAPS) and bradykinin, inhibited a
prostaglandin E2 (PGE2)-induced response and had no effect on the response to
hypertonic saline. The CS model demonstrated neutrophilia and increased mucus in
the airways. Focussing on mechanisms driving enhanced cough, revealed that nerve
growth factor (NGF) and brain derived neurotrophic factor (BDNF), may play a role
in cough reflex sensitisation. An in vitro bioassay confirmed that NGF and BDNF
exhibited bioactivity and the anticipated species cross-reactivity.
CS exposure augmented the expression of transient receptor potential vanilloid 1
(TRPV1) in vagal sensory nerve ganglion. Pharmacological modulation of guinea-pig
and human vagus nerve activation showed that TRPV1 antagonists, capsazepine and
SB366791, abolished CAPS-induced depolarisation, partially inhibited low pH,
bradykinin and PGE2-induced responses and had no effect on hypertonic saline.
Despite positive in vitro and pharmacokinetic analyses, TRPV1 antagonists did not
inhibit CAPS-induced cough in vivo. Further work is required to expand upon these
findings.
This thesis contains an assessment of the effects of sensory nerve modulation in
guinea-pig models of cough. Understanding the neural mechanisms associated with
this research may help to guide the development of novel antitussive therapies.
be enhanced during disease. Current antitussives possess little clinical efficacy,
therefore research is needed to investigate the modulation of airway sensory nerves in
order to understand the mechanisms driving chronic cough.
A conscious guinea-pig cough model using different tussive stimuli, known to elicit
cough in man, was established. Corresponding in vitro effects of these tussive agents
on sensory nerve activation were characterised. These agents were also characterised
into sub-types as they produced distinct patterns of response.
Cigarette smoke (CS) exposure elicited distinct effects on the cough reflex in
conscious guinea-pigs and on sensory nerve activity measured in vitro; CS enhanced
responses to citric acid (CA), capsaicin (CAPS) and bradykinin, inhibited a
prostaglandin E2 (PGE2)-induced response and had no effect on the response to
hypertonic saline. The CS model demonstrated neutrophilia and increased mucus in
the airways. Focussing on mechanisms driving enhanced cough, revealed that nerve
growth factor (NGF) and brain derived neurotrophic factor (BDNF), may play a role
in cough reflex sensitisation. An in vitro bioassay confirmed that NGF and BDNF
exhibited bioactivity and the anticipated species cross-reactivity.
CS exposure augmented the expression of transient receptor potential vanilloid 1
(TRPV1) in vagal sensory nerve ganglion. Pharmacological modulation of guinea-pig
and human vagus nerve activation showed that TRPV1 antagonists, capsazepine and
SB366791, abolished CAPS-induced depolarisation, partially inhibited low pH,
bradykinin and PGE2-induced responses and had no effect on hypertonic saline.
Despite positive in vitro and pharmacokinetic analyses, TRPV1 antagonists did not
inhibit CAPS-induced cough in vivo. Further work is required to expand upon these
findings.
This thesis contains an assessment of the effects of sensory nerve modulation in
guinea-pig models of cough. Understanding the neural mechanisms associated with
this research may help to guide the development of novel antitussive therapies.
Date Issued
2008
Online Publication Date
2009-08-20T11:18:33Z
Date Awarded
2008-11
Advisor
Belvisi, Maria
Birrell, Mark
Creator
Nasra , Julie
Publisher Department
National Heart and Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)