180 research outputs found
Chronic cough: nomenclature and classification
No full textCC imposes a significant burden on patients and remains a frequent challenge in routine practice. Current evidence indicates that CC is not merely a symptom, but represents a distinct disease entity characterised by dysregulation of the cough reflex. Nevertheless, current classification remains restricted to symptom duration (e.g. >8 weeks), lacking terminology that reflects underlying mechanisms or informs clinical decision-making. Accurate disease naming and classification are essential for effective communication between clinicians and patients, appropriate diagnostic coding and reimbursement, policy development and epidemiological tracking. In ICD-10, cough is listed solely as a symptom code. The advent of ICD-11 enables a more accurate and mechanism-based representation of diseases, as seen in the reclassification of chronic pain and allergic conditions. Many patients with CC demonstrate intrinsic pathophysiological features such as cough reflex hypersensitivity, which are not adequately captured by existing terms such as RCC or UCC. These labels may also carry unintended connotations of therapeutic failure or diagnostic ambiguity. This chapter outlines a rationale for redefining CC as a disease entity, grounded in recent advances in pathophysiology and clinical phenotyping. It proposes updated diagnostic terminology and a roadmap for future integration into classification systems such as ICD-11, aiming to improve patient care, resource allocation and research frameworks
Targeting tachykinins for the treatment of obstructive airways disease
No full textThe tachykinin family of peptides are distributed throughout the nervous system and are thought to play a critical role in inflammation and immunomodulation. Tachykinins have been implicated in the pathogenesis of many diseases and disease processes including inflammatory pain, emesis, depression, Parkinson’s disease and inflammatory bowel syndrome. In the airways of animals, substance P and neurokinin A are released from a subset of airway sensory nerves, and evoke vasodilatation, bronchoconstriction, mucus secretion, leukocyte recruitment, airways hyperreactivity and cough. These observations have led to suggestions that tachykinins may also be viable targets for the treatment of obstructive airways disease. Clinical trials in humans assessing the utility of tachykinin receptor antagonists such as nepadutant and saredutant for the treatment of asthma are limited, and the results for the most part have been inconclusive. Several new tachykinin receptor antagonists have been recently designed to target multiple tachykinin receptor subtypes and to readily penetrate into the central nervous system. Future clinical trials with these compounds should help to shed some light on the role of tachykinins in obstructive airways disease. Copyright 2004 Adis Data Information B
An overview of the sensory receptors regulating cough
No full textThe cough reflex represents a primary defensive mechanism for airway protection in a variety of mammalian species. However, excessive and inappropriate coughing can emerge as a primary presenting symptom of many airway diseases. Cough disorders are characterized by a reduction in the threshold for reflex initiation and, as a consequence, the occurrence of cough in response to stimuli that are normally innocuous in nature. The current therapeutic strategies for the treatment of cough disorders are only moderately effective. This undoubtedly relates in part to limitations in our understanding of the neural components comprising the cough reflex pathway. The aim of this review is to provide an overview of current concepts relating to the sensory innervation to the mammalian airways, focusing particularly on the sensory receptors that regulate cough. In addition, the review will highlight particular areas and issues relating to cough neurobiology that are creating controversy in the field
Splanchnic and Pelvic Spinal Afferent Pathways Relay Sensory Information From the Mouse Colorectum Into Distinct Brainstem Circuits
No full textThe distal colon and rectum (colorectum) are innervated by two distinct spinal (splanchnic and pelvic) afferent nerve pathways. This study aimed to identify where the sensory information relayed by splanchnic and pelvic afferents integrates within the brainstem. Microinjection of transneuronal viral tracer (herpes simplex virus-1 H129 strain expressing EGFP, H129-EGFP) into the distal colon was used to assess the brainstem structures receiving ascending input from the colorectum. H129-EGFP+ cells were distributed in structures involved in ascending sensory relay, descending pain modulation, and autonomic regulation in the medulla from 96 h and in the pontine and caudal midbrain at 120 h after inoculation. In a separate cohort of mice, in vivo noxious colorectal distension (CRD) followed by brainstem immunolabeling for phosphorylated MAP kinase ERK 1/2 (pERK) determined neurons activated by CRD. Many of the structures containing H129-EGFP+ labeling also contained pERK-labeled neurons, indicating H129-EGFP+ labeling in colorectal signaling pathways. Surgical removal of dorsal root ganglia (DRG) containing the cell bodies of splanchnic colorectal afferent neurons significantly reduced CRD-evoked pERK neuronal activation within the caudal ventrolateral medulla, rostral ventromedial medulla, and the lateral parabrachial nuclei. Surgical removal of the DRG containing the cell bodies of pelvic colorectal afferent neurons significantly reduced CRD-evoked pERK neuronal activation within the rostral ventromedial medulla, lateral parabrachial nuclei, the locus coeruleus, Barrington's nucleus, and periaqueductal gray. Collectively, this study showed that the two spinal afferent pathways innervating the colorectum relay information into different brainstem structures and provide new insight into their unique roles in relaying information into the gut-brain axis controlling colorectal sensory-motor function.QingQing Wang, Alice E. McGovern, Melinda Kyloh, Grigori Rychkov, Nick J. Spencer, Stuart B. Mazzone, Stuart M. Brierley, Andrea M. Harringto
Comparative localization of colorectal sensory afferent central projections in the mouse spinal cord dorsal horn and caudal medulla dorsal vagal complex
No full textFirst published: 14 October 2023The distal colon and rectum (colorectum) are innervated by spinal and vagal afferent pathways. The central circuits into which vagal and spinal afferents relay colorectal nociceptive information remain to be comparatively assessed. To address this, regional colorectal retrograde tracing and colorectal distension (CRD)-evoked neuronal activation were used to compare the circuits within the dorsal vagal complex (DVC) and dorsal horn (thoracolumbar [TL] and lumbosacral [LS] spinal levels) into which vagal and spinal colorectal afferents project. Vagal afferent projections were observed in the nucleus tractus solitarius (NTS), area postrema (AP), and dorsal motor nucleus of the vagus (DMV), labeled from the rostral colorectum. In the NTS, projections were opposed to catecholamine and pontine parabrachial nuclei (PbN)-projecting neurons. Spinal afferent projections were labeled from rostral through to caudal aspects of the colorectum. In the dorsal horn, the number of neurons activated by CRD was linked to pressure intensity, unlike in the DVC. In the NTS, 13% ± 0.6% of CRD-activated neurons projected to the PbN. In the dorsal horn, at the TL spinal level, afferent input was associated with PbN-projecting neurons in lamina I (LI), with 63% ± 3.15% of CRD-activated neurons in LI projecting to the PbN. On the other hand, at the LS spinal level, only 18% ± 0.6% of CRD-activated neurons in LI projected to the PbN. The collective data identify differences in the central neuroanatomy that support the disparate roles of vagal and spinal afferent signaling in the facilitation and modulation of colorectal nociceptive responses.QingQing Wang, Sonia Garcia Caraballo, Grigori Rychkov, Alice E.McGovern, Stuart B. Mazzone, Stuart M. Brierley, Andrea M. Harringto
The role of tachykinin receptors in the control of respiration by the nucleus of the solitary tract
No full textThe tachykinins are a family of peptides found extensively throughout the mammalian nervous system. In the brain stem, tachykinins, including substance P (SP) and neurokinin A (NKA), are present in areas involved in the integration of cardiovascular and respiratory reflexes. However, little is known of the role played by tachykinins and tachykinin receptors at such sites. The overall aim of the studies presented in this thesis was to describe the respiratory actions of tachykinins, the identity of the receptors involved and subsequently examine the regulation of tachykinin receptors in the rat brain stem, using both in vivo (respiratory response to microinjection of drugs in to the commissural nucleus of the solitary tract (cNTS)) and in vitro techniques (radioligand binding and autoradiography)
Sensory regulation of the cough reflex
No full textCoughing is a highly coordinated reflex that serves to protect the airways from a variety of potentially harmful stimuli. However, in airways disease the cough reflex threshold is lowered and coughing can become exaggerated and inappropriate. Excessive coughing not only affects an individual's quality of life, but may contribute to the pathology of the disease. Understanding the neural components of the cough reflex is essential for establishing new treatments for cough disorders. This review will summarize the current understanding of the afferent neural pathways mediating cough, including how interactions between airway afferent nerve fibre subtypes may modulate the cough reflex pathway and underlie the manifestation of cough disorders
Neurobiology of Coughing in Children
No full textA cough is one of several defensive responses that protect and clear the airways of inhaled, aspirated or locally produced chemicals and matter. The neural components needed to initiate a cough begin to develop in utero, and at birth the airways and lungs already have a rich supply of sensory and motor-neural innervation. However, a cough is not always the primary defensive response to airway challenge in very young infants, but instead develops in the first postnatal months and matures further into puberty. Consequently, the clinical presentation of a troublesome cough in children may not be the same as in adults, exemplified by important differences in cough sensitivity and hypersensitivity between children and adults. This review will summarise key anatomical and functional concepts in airway neurobiology that may improve understanding of coughs in children
Mechanisms and Rationale for Targeted Therapies in Refractory and Unexplained Chronic Cough
No full textChronic cough, defined as a cough lasting > 8 weeks, is a common medical condition that exerts a substantial physical, mental, and social burden on patients. A subset of patients with chronic cough are troubled with a cough that persists despite optimal treatment of presumed associated common and uncommon conditions (refractory chronic cough; RCC) or in which no diagnosable cause for cough can be identified despite extensive assessment (unexplained chronic cough; UCC). Many of these patients exhibit clinical features of cough hypersensitivity, including laryngeal paresthesia, hypertussia, and allotussia. Over-the-counter cough remedies are ineffective and can lead to intolerable side effects when used for RCC/UCC, and the lack of approved treatments indicated for these conditions reflects a major unmet need. An increased understanding of the anatomy and neurophysiology of protective and pathologic cough has fostered a robust clinical development pipeline of several targeted therapies for RCC/UCC. This manuscript reviews the mechanisms presumed to underly RCC/UCC together with the rationale and clinical evidence for several targeted therapies currently under clinical investigation, including transient receptor potential channel antagonists, P2X3-receptor antagonists, voltage-gated sodium channel blockers, neuromodulators, and neurokinin-1-receptor antagonists. Finally, we provide an overview of targets that have been investigated in preclinical models of cough and other airway diseases that may hold future promise for clinical studies in RCC/UCC. Development of targeted therapies with different sites of action may foster a precision medicine approach to treat this heterogeneous, underserved patient population.</p
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