Modulation of sensory nerve function and the cough reflex: Understanding disease pathogenesis

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Abstract

To cough is a protective defence mechanism that is vital to remove foreign material and secretions from the airways and which in the normal state serves its function appropriately. Modulation of the cough reflex pathway in disease can lead to inappropriate chronic coughing and an augmented cough response. Chronic cough is a symptom that can present in conjunction with a number of diseases including chronic obstructive pulmonary disease (COPD) and asthma, although often the cause of chronic cough may be unknown. As current treatments for cough have proved to exhibit little efficacy and are largely ineffective, there is a need to develop novel, efficacious and safe antitussive therapies. The underlying mechanisms of the cough reflex are complex and involve a network of events, which are not fully understood. It is accepted that the cough reflex is initiated following activation of airway sensory nerves. Therefore, in the hope of identifying novel antitussives, much research has focused on understanding the neural mechanisms of cough provocation. Experimentally this has been undertaken using chemical or mechanical tussive stimuli in conjunction with animal models of cough and clinical cough assessments. This review will discuss the neural mechanisms involved in the cough, changes that occur under pathophysiological conditions and and how current research may lead to novel therapeutic opportunities for the treatment of cough.

Introduction

Cough is a protective reflex that is vital to remove foreign material and secretions from the airways. In the normal state this reflex serves its function appropriately. However, modulation of the cough reflex pathway can lead to inappropriate coughing and an augmented cough response. Clinically, the aetiology and treatment of cough can be broadly classified into acute and chronic. Chronic cough is a symptom that can present in conjunction with a number of respiratory and extrapulmonary diseases including chronic obstructive pulmonary disease (COPD), asthma, post-nasal drip syndrome and gastro-oesophageal reflux disease (GORD) (Morice et al., 2004). Patients suffering from chronic cough can be affected for months or years from this debilitating symptom, which if left untreated can impact quality of life (French et al., 1998). Although the cause of chronic cough can be delineated as a symptom of specific diseases, often the cause may be unknown and the incidence of ‘idiopathic cough’ may be as high as 18% or more of patients seeking treatment at specialist cough clinics (McGarvey et al., 1998). The prevalence of cough is reflected in antitussives being one of the most widely used therapies in the world. Furthermore, cough is the most common condition for which patients seek consultation from a doctor (Schappert & Burt, 2006). Current antitussives, such as the opioids, exhibit little efficacy (Smith et al., 2006) and are limited by their unwanted side-effects. Therefore, the treatment of cough remains an unmet medical need and novel therapies will be of immense value to those who suffer from chronic cough. Despite cough being a symptom of a number of distinct diseases, it is accepted that reflex cough is always produced via activation of airway sensory nerves. Therefore, clinical and laboratory based experimental approaches are being employed to understand the neural components of the cough reflex. The utilisation of animal models exhibiting an enhanced cough reflex response and an underlying pathology will be vital to gain insight into the mechanisms underlying chronic cough and may prove important in the identification and validation of novel, efficacious and safe antitussive therapies. This review will discuss the physiology and pathophysiology of the cough reflex and how current research may lead to novel antitussive therapies.

Section snippets

Overview of the cough reflex

The cough reflex response can be divided into three components: the first initiates the reflex through a sensory nerve input, the second is a complex central nervous network which processes the information and the third part is the stimulation of the efferent limb and the motor output to produce a cough. Cough can be initiated in humans and animals by a variety of stimuli including citric acid (CA) (Bickerman and Barach, 1954, Lalloo et al., 1995, Usmani et al., 2005, Morice et al., 2007),

Physiology of cough

Physiologically, cough is a reflex, forced expiratory event, which clears irritant material up and out of the airways. The first stage of a cough is a rapid deep inspiration through a widely open glottis. This inspiration results in a large lung volume and the airways are now open for the subsequent expiratory phase. There is a reflex increase in expiratory effort and contraction of muscles producing an expiratory effort against a closed glottis. During this compressive phase of cough there is

Prevalence of cough

Cough is the most common condition for which patients seek consultation from a doctor (Schappert & Burt, 2006). Many antitussives are available without medical prescriptions and are among the most widely used over-the-counter (OTC) remedies. A US survey of over 8000 subjects reported that more than half of pre-school children were given OTC treatments and that cough medicines composed 67% of the OTC medications used (Kogan et al., 1994). However, a recent review of trials involving over 2100

Acute and chronic cough

Clinically, the aetiology and treatment of cough can be broadly classified into acute and chronic as deduced from the length of time the cough persists. Acute cough is classified as lasting less than three weeks (Irwin et al., 1998) and although transient, acute cough can be very troublesome to normal daily life. The most common causes of acute cough are viral or bacterial upper respiratory tract infections such as the common cold, acute bacterial sinusitis, rhinitis and exacerbations of COPD (

Current antitussive therapies

The site of action of antitussive therapies can be broadly classified into two groups: those that act centrally and those that act peripherally to suppress cough. Centrally acting cough suppressants are often associated with neurological side-effects such as sedation and physical dependence, which can limit their effective use. Peripherally acting antitussives exert their effects by acting outside of the central nervous system by targeting peripheral vagal sensory nerve afferents, which could

Experimental approaches in the study of cough

Exposure to irritant substances to induce cough can provide a measure of the sensitivity of the cough reflex, both in the laboratory and in the clinic. Clinical cough studies and animal models of cough are vital in order to elucidate disease pathophysiology, understand the mechanisms occurring in the healthy and disease state and help in the identification of effective new drug therapies.

Classification of airway sensory nerves

In order to identify novel therapies for the treatment of cough, a greater understanding of the mechanisms by which cough is generated is essential. Despite cough being a symptom of a number of different diseases, it is accepted that irrespective of the cause, reflex cough is always produced via activation of airway sensory nerves. Therefore, in the hope of identifying new targets to suppress cough, research has focussed on understanding the neural mechanisms of cough provocation. The following

Pharmacological activation of airway sensory nerves

Numerous chemical or mechanical tussive stimuli have been employed experimentally in animals and humans to increase our understanding of the cough reflex and in the pursuit of new therapies. However, there is still a great deal to learn about the mechanisms by which exogenous and endogenous tussive stimuli can activate sensory nerves to mediate cough. Irrespective of the subtype of stimulus, a tussive agent can only activate sensory nerve terminals following interactions at the nerve membrane

Which airway sensory nerves mediate the cough reflex?

Research to determine precisely which airway afferent nerve subtypes mediate cough has not been conclusive and there has been a debate in the literature regarding the primary sensory nerve(s) responsible for this reflex. Establishing which airway sensory nerves mediate the cough reflex may prove vital in the search for novel cough therapies. The use of different species, distinctive experimental set-ups and the state of consciousness or anaesthesia during investigation contributes to the

Central nervous regulation of the cough reflex

There is still a great deal to learn about the central nervous mechanisms underlying the cough reflex. Interestingly, cough is a respiratory event that can be initiated via a reflex pathway or accurately initiated voluntarily. It is believed that the conscious cough reflex involves complex integrations mediated in the brainstem, which is under the control of regulatory mechanisms and also voluntarily cortical control (Shannon et al., 2004). The activation of airway sensory nerves results in

Experimental models and mechanisms of cough reflex sensitisation

It is hypothesised that the activity of sensory nerves may be enhanced during airway disease, resulting in exacerbation of the protective cough reflex and manifestation of chronic cough. The majority of cough research in the laboratory has focussed on the direct tussive stimuli-induced activation of airway afferent nerves to initiate cough. In comparison, there is less research on the mechanisms of sensitisation resulting in an enhanced cough response upon stimulation with tussive agents. Focus

Overview of novel therapeutic opportunities for cough

Generally the site of action of potential antitussive agents can be classified into two groups: those that act peripherally and those that act centrally to suppress the cough. Enhanced cough in disease situations may well be due to peripheral or central sensitisation and this may dictate to which compartment the therapeutic would need to be targeted to have a selective effect without just generally suppressing the reflex. However, in reality targeting either compartment would lead to a reduced

Conclusion

Chronic cough is an unmet medical need and the development of novel, effective and safe antitussive therapies is needed. Knowledge of the neural mechanisms of cough is expanding, particularly through evidence gained from experimental animal studies. A greater understanding of the modulation of sensory nerve function in disease will be important in developing new antitussive treatments. Further research aimed at understanding the neural mechanisms of peripheral sensitisation of airway sensory

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