Review
Central mechanisms of airway sensation and cough hypersensitivity

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Abstract

The airway sensory nervous system is composed of two anatomically distinct processing pathways that allow for the production of respiratory reflexes and voluntary evoked respiratory behaviours in response to sensing an airway irritation. Disordered sensory processing is a hallmark feature of many pulmonary disorders and results in the development of cough hypersensitivity syndrome, characterised by chronic cough and a persistent urge-to-cough in affected individuals. However, the mechanism underpinning how the airway sensory circuits become disordered, especially at the level of the central nervous system, is not well understood. In this mini-review we present well-defined mechanisms that lead to the development of chronic pain as a framework to explore the evidence that cough disorders may manifest due to neuroplasticity and sensitisation of important components of the airway sensory circuitry in the brain. We highlight recent discoveries of how airway sensory processing occurs in the brain in health and disease and additionally suggest areas where gaps exist in our current knowledge on the topic, with the goal of providing a better understanding of how airway circuits become dysfunctional in disease. This may in turn help identify novel therapeutic targets for restoring normal airway sensory processing and alleviating excessive cough.

Introduction

The airways are innervated by heterogeneous populations of jugular and nodose vagal ganglia sensory neurons that respond to a wide range of chemical and mechanical stimuli. Activation of these sensory neurons results in the transmission of information about the airway environment, firstly to the brainstem and then to higher order brain regions, allowing for the production of both respiratory and autonomic reflexes, as well as more complex behavioural respiratory responses. Collectively, these reflexes and respiratory behaviours serve to protect the airways from endogenous or exogenous stimuli that are potentially damaging and by doing so they contribute to the maintenance of adequate physiological respiratory function. The characterisation and physiology of airway vagal afferent neurons has been reviewed in detail, as has the neuroanatomical organisation of airway vagal afferent pathways in the brain [81], [9], [8], [15], [55], and as such the present review will only briefly cover these topics. Rather, we will focus on plasticity in the central neural circuitry involved in airway sensory processing and the current understanding of how this may provide insight into the airway sensory dysfunctions that underpin two prominent and related clinical presentations in pulmonary disease; excessive coughing and the urge-to-cough. In doing so, we will present some original data and draw from the advanced work that has been conducted in a comparable area of research (chronic pain), with the aim of highlighting important gaps in our current understanding of central cough neurophysiology.

Section snippets

Neuroanatomy of airway sensation

The central representation of jugular and nodose airway afferents has been investigated using a variety of physiological and neuroanatomical techniques [56], [57], [14], [58], [59]. Such studies have described in detail a primary termination site for airway vagal afferents in the brainstem nucleus of the solitary tract (nTS) and not surprisingly this nucleus has underpinned a substantial body of work on airway sensory neurotransmission [36], [41], [61], [66], [51], [1], [85]. However, our own

Can airway afferent circuits in the brain be altered in disease?

Neuronal sensitisation. Disordered airway sensory neural circuit activity, precipitated (for example) by the inflammatory processes induced by acute viral or allergen exposure or that associated with chronic illness in asthma or other respiratory diseases, contribute to excessive coughing and the increased perception of airway irritation common to many pulmonary disorders [12], [2], [31], [3], [82]. As such, it has become increasingly important to understand how airway sensory circuits are

Concluding remarks

Cough and the urge-to-cough contribute significantly to morbidity in pulmonary diseases and as such understanding the neuronal processes that underpin the development and maintenance of cough hypersensitivity is essential. We now have a reasonably advanced knowledge of the central processing circuits involved in airway sensation that will allow for hypothesis driven investigations of how the brain may contribute to chronic coughing in disease. Although this area of research is still in its

Funding

NHMRC of Australia. #1078943.

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