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Plasticity of central mechanisms for cough
Abstract
Cough is associated with plasticity of putative cough afferent fibres, but whether plasticity in the brainstem network contributes is less well understood. A key site in the CNS network is the nucleus tractus solitarius (NTS), the first synaptic contact of the primary afferent fibres. We sought to develop a conscious guinea pig model to detect enhanced cough, to focus on the NTS as a potential site for plasticity, and to test a role for substance P in the NTS since the neuropeptide has been implicated in plasticity of the vagal afferent fibres. Guinea pigs were exposed to second-hand tobacco smoke (SHS) or filtered air (FA) from 1-6 weeks of age. At 5 weeks, cannulae were implanted in the NTS. At 6 weeks, either vehicle or a neurokinin 1 (NK-1) receptor antagonist was injected into the NTS of the conscious guinea pigs who were then exposed to citric acid aerosol. SHS exposure significantly enhanced citric acid-induced cough (56%, P<0.05), an effect attenuated by NTS NK-1 receptor blockade (P<0.05). The findings suggest that one possible mechanism for plasticity in cough is related to substance P effects in the NTS. Future studies will be required to investigate the possible mechanisms underlying the role of substance P as well as other mechanisms in generating SHS-induced cough.
... This study is the first to provide evidence that, in contrast to losartan, the ACE inhibitor lisinopril microinjected into the caudal NTS induces a potentiation of the cough reflex evoked by both mechanical and chemical stimulation of the tracheobronchial tree. In our opinion, the main novelty of the present results is that they support the notion of a central action of lisinopril that interferes with the catabolism of bradykinin and substance P at the level of the caudal NTS, i.e., at the level of a neural structure with a very important, or even crucial, role in the medullary regulation of this reflex (e.g., Bolser et al., 2006;Bonham et al., 2004;Mori, 2010, 2011;Mazzone et al., 2005;Mutolo et al., 2007Mutolo et al., , 2008Mutolo et al., , 2009Mutolo et al., , 2012. In other words, the RAS can be suggested to be involved in the central control of the cough reflex. ...
... After binding to the NK 1 receptors, substance P regulates many functions in the central nervous system (for a review, see Munoz and Covenas, 2014). In particular, at the level of the NTS an important role of substance P in the central plasticity induced by vagal afferent fibers as well as in cough potentiation has been suggested (Bonham et al., 2004). Accordingly, substance P microinjections into the caudal NTS potentiate the cough reflex induced by both mechanical and chemical stimulation of the tracheobronchial tree (Mazzone et al., 2005;Mutolo et al., 2007), an effect that was counteracted by intracerebroventricular administration of NK 1 receptor antagonists (Mazzone et al., 2005). ...
... The presynaptic or postsynaptic site of action of bradykinin or substance P in determining cough potentiation is a matter of speculation. However, a probable presynaptic action of bradykinin on sensory C-fibers leading to substance P release (Bhoola et al., 1992;Couture et al., 2001) as well as a postsynaptic action of substance P on NTS neurons of the cough afferent pathway (Bonham et al., 2004 also for further Refs.) can be suggested. ...
... In our opinion, the main novelty of the present results is that they support the notion of a central action of lisinopril that interferes with the catabolism of bradykinin and substance P at the level of the caudal NTS, i.e., at the level of a neural structure with a very important , or even crucial, role in the medullary regulation of this reflex (e.g., Bolser et al., 2006; Bonham et al., 2004; Canning and Mori, 2010, 2011; Mazzone et al., 2005; Mutolo et al., 2007, 2008, 2009, 2012). In other words, the RAS can be suggested to be involved in the central control of the cough reflex. ...
... After binding to the NK 1 receptors, substance P regulates many functions in the central nervous system (for a review, see Munoz and Covenas, 2014). In particular, at the level of the NTS an important role of substance P in the central plasticity induced by vagal afferent fibers as well as in cough potentiation has been suggested (Bonham et al., 2004). Accordingly, substance P microinjections into the caudal NTS potentiate the cough reflex induced by both mechanical and chemical stimulation of the tracheobronchial tree (Mazzone et al., 2005; Mutolo et al., 2007), an effect that was counteracted by intracerebroventricular administration of NK 1 receptor antagonists (Mazzone et al., 2005). ...
... The presynaptic or postsynaptic site of action of bradykinin or substance P in determining cough potentiation is a matter of speculation. However, a probable presynaptic action of bradykinin on sensory C-fibers leading to substance P release (Bhoola et al., 1992; Couture et al., 2001) as well as a postsynaptic action of substance P on NTS neurons of the cough afferent pathway (Bonham et al., 2004 also for further Refs.) can be suggested. ...
We have previously shown that cough potentiation induced by intravenous administration of the AT1 receptor antagonist losartan is lower than that induced by the ACE inhibitor lisinopril in anesthetized and awake rabbits. Since losartan and lisinopril cross the blood-brain barrier, their central action on the cough reflex can be hypothesized. Mechanical stimulation of the tracheobronchial tree and citric acid inhalation were used to induce cough reflex responses in pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Bilateral microinjections (30-50nl) of losartan (5mM), lisinopril (1mM), bradykinin (0.05mM), HOE-140 (0.2mM, a bradykinin B2 receptor antagonist) and CP-99,994 (1mM, an NK1 receptor antagonist) were performed into the caudal nucleus tractus solitarii, the predominant site of termination of cough-related afferents. Lisinopril, but not losartan increased the cough number. This effect was reverted by HOE-140 or CP-99,994. Cough potentiation was also induced by bradykinin. The results support for the first time a central protussive action of lisinopril mediated by an accumulation of bradykinin and substance P.
Copyright © 2015. Published by Elsevier B.V.
... Deux études (expérimentation animale) ont récemment étudié la réponse ventilatoire à une stimulation trachéale mécanique prolongée ( > 5 sec), retrouvant une réponse comprenant un RE dans 54% des cas chez le lapin et dans 68% des cas chez le chat (Poliacek et al., 2008 (Bolser et al., 1999;Fontana and Widdicombe, 2007 Ce travail montre ainsi une différence de réponse défensive selon que la stimulation trachéale mécanique survient à l'inspiration ou à l'expiration. Ce résultat suggère peut être que la commande nerveuse centrale joue un rôle d'intégration des différentes afférences provenant des RARs, des fibres A-δ ainsi que des autres mécanorécepteurs pouvant déclencher et faciliter la toux (Bolser et al., 2006;Bonham et al., 2004;Shannon et al., 2004). (Fontana and Widdicombe, 2007). ...
... La toux est l'expression d'une intégration médullaire de messages afférents, provenant de différents récepteurs et cheminant par l'intermédiaire du nerf vague (Widdicombe et al., 2011). Il a été démontré que le réflexe de toux est capable d'une certaine plasticité que se soit au niveau des récepteurs périphériques impliqués (Carr and Lee, 2006) ou encore au niveau intégratif supérieur (Bonham et al., 2004). Les afférences nerveuses localisées dans la muqueuse nasale ne sont pas capables de déclencher une toux, mais ce réflexe de défense respiratoire peut être sensibilisé dans des conditions expérimentales de rhinite chez l'animal (Brozmanova et al., 2008). ...
Contexte – La stimulation de la muqueuse trachéale peut provoquer une réponse défensive à type de toux. La finalité de cette réponse est la protection des voies aériennes via la clairance du mucus et des particules déposées au sein de l’arbre trachéo-bronchique. La stimulation de la muqueuse nasale est à l’origine de réponses défensives n’incluant toutefois pas la toux. La modulation de la toux suggère de possibles interactions centrales des afférences provenant de localisations anatomiques distinctes. Objectif – Déterminer si une stimulation trachéale mécanique discriminante est capable de provoquer une toux lors d’une apnée provoquée par l’instillation nasale d’eau distillée. Méthodes – Douze lapins anesthésiés et trachéotomisés ont été étudiés. Les stimulations trachéales mécaniques ont été réalisées dans 3 conditions : contrôle, après instillation nasale de sérum physiologique, et lors d’apnée suite à l’instillation d’eau distillée. Résultats – Les paramètres ventilatoires de références ne sont pas différents dans les 3 conditions. Un total de 171 stimulations trachéales a été réalisé. Lors de l’apnée, 81% des réponses sont des réflexes expiratoires et le pic de débit expiré est inférieur (p < 0.0001) à celui observé dans les conditions contrôle et sérum physiologique. L’incidence des réponses comprenant un réflexe de toux est plus faible (p < 0,0001) en cas d’instillation d’eau distillée que dans les 2 autres conditions.Conclusion – La stimulation nasale par l’eau distillée désensibilise les réflexes de défense respiratoire faisant suite à une stimulation trachéale mécanique
... Over the last decade, evidence has accumulated on the complex biomolecular mechanisms related to neural sensitization and plasticity, which are critical for a variety of phenotypic changes in neuron activities [5]. These functional changes are considered to be at the basis both of several physiological events such as memory and learning [5,6] and of many pathological conditions, such as chronic pain syndromes [7]. ...
... Over the last decade, evidence has accumulated on the complex biomolecular mechanisms related to neural sensitization and plasticity, which are critical for a variety of phenotypic changes in neuron activities [5]. These functional changes are considered to be at the basis both of several physiological events such as memory and learning [5,6] and of many pathological conditions, such as chronic pain syndromes [7]. Indeed, enduring neuropathic or inflammatory pain is a well-characterized pathophysiological condition in which a direct parallel between persistent exposure to excitatory/inflammatory neurotransmitters and the increased excitability of spinal post-synaptic neurons has been clearly shown [8][9][10][11]. ...
Allergen exposure may induce changes in the brainstem secondary neurons, with neural sensitization of the nucleus solitary tract (NTS), which in turn can be considered one of the causes of the airway hyperresponsiveness, a characteristic feature of asthma. We evaluated neurofunctional, morphological, and biochemical changes in the NTS of naive or sensitized rats. To evaluate the cell firing activity of NTS, in vivo electrophysiological experiments were performed before and after capsaicin challenge in sensitized or naive rats. Immunohistochemical studies, endocannabinoid, and palmitoylethanolamide quantification in the NTS were also performed. This study provides evidence that allergen sensitization in the NTS induced: (1) increase in the neural firing response to intratracheal capsaicin application, (2) increase of endocannabinoid anandamide and palmitoylethanolamide, a reduction of 2-arachidonoylglycerol levels in the NTS, (3) glial cell activation, and (4) prevention by a Group III metabotropic glutamate receptor activation of neural firing response to intratracheal application of capsaicin in both nave and sensitized rats. Therefore, normalization of ovalbumin-induced NTS neural sensitization could open up the prospect of new treatments based on the recovery of specific brain nuclei function and for extensive studies on acute or long-term efficacy of selective mGlu ligand, in models of bronchial hyperreactivity.
... In chronic hypertussive cough states, normally innocent stimuli that would not under normal circumstances initiate a response, evokes cough 134 . This reaction parallels alterations during chronic pain state, characterized by hyperalgesia and allodynia 135 . ...
... Whereas, it is less clear whether insults that can induce a hypertussive state due to changes in the presynaptic inputs to the nTS, also produces postsynaptic changes indicative of CS 135 . The latter, has been supported by a study in guinea pigs where animals were exposed to tobacco smoke 134 . It was shown, that increased firing in the nTS relay neurons paralleled the increased C-fibres responsiveness to capsaicin, due to increased expression of CRGP and SP in the peripheral nerve endings 134 ...
... In chronic, hypertussive cough states, normally innocuous stimuli that would not normally initiate a response, evoke cough (Bonham et al. 2004). There are clear parallels here with alterations during chronic pain states, characterized by hyperalgesia and allodynia. ...
... In pain pathways, central sensitization involves enhanced efficiency of excitatory synaptic transmission pathways within the CNS, notably in the dorsal horn of the spinal cord at the synapse between the sensory nociceptor fibres and second-order relay neurones (Ji et al. 2003). It has been suggested that central sensitization in the cough reflex loop might also underlie hypertussive states (Bonham et al. 2004(Bonham et al. , 2006a, but to date, there are few data confirming this. ...
Cough is an indispensable defensive reflex. Although generally beneficial, it is also a common symptom of diseases such as asthma, chronic obstructive pulmonary disease, upper respiratory tract infections, idiopathic pulmonary fibrosis and lung cancer. Cough remains a major unmet medical need and although the centrally acting opioids have remained the antitussive of choice for decades, they have many unwanted side effects. However, new research into the behaviour of airway sensory nerves has provided greater insight into the mechanisms of cough and new avenues for the discovery of novel non-opioid antitussive drugs. In this review, the pathophysiological mechanisms of cough and the development of novel antitussive drugs are reviewed.
... The increased substance P expression suggests that substance P could be released both locally in the lungs and airways and also in the central terminals in the NTS to modify synaptic transmission of the sensory information to the NTS. For example, in conscious guinea pigs, exposure to secondhand tobacco smoke significantly increases the cough response to citric acid aerosol (Joad et al. 2007;Bonham et al. 2004). This second-hand tobacco smoke induced enhanced cough is attenuated by microinjection of a substance P NK1 receptor antagonist into the NTS (Joad et al. 2007), providing evidence that plasticity in the NTS in the cough pathway may involve substance P NK1 receptor mechanisms. ...
... In upregulated cough reflex, an increased substance P expression in the vagal neurons may be released at the central terminal in the NTS (Fischer et al. 1996;Chuaychoo et al. 2005). This enhanced substance P release in the NTS could contribute to the enhanced substance P-NK1 receptor mechanism mediating a heightened cough reflex response (Joad et al. 2007;Bonham et al. 2004). The increased substance P released from the primary sensory central terminals is likely to have more focused effect on the NTS second-order neurons, including the inhibitory interneurons. ...
Cough is the most common symptom for which individuals seek medical attention and spend health-care dollars. Despite the burden induced by cough, the current treatments for cough are only partially effective. Delineating the sites and mechanisms in the cough central network for changes in the cough reflex could lead to new therapeutic strategies and drug target sites for more effective treatments. The first synaptic target in the CNS for the cough-related sensory input is the second-order neurons in the nucleus tractus solitarius (NTS); these neurons reorganize the primary sensory information into a coherent output. The NTS neurons have been shown to undergo neuroplasticity under a variety of conditions, such as respiratory disorders, stress, and exposures to environmental pollutants. The NTS contains a rich innervation of substance P immunoreactive nerve terminals, suggesting that substance P might be important in altered cough reflex response. This chapter summarizes our current findings on the role of substance P in enhanced cough reflex as well as the potential NTS targets for the action of substance P.
... in excitability of central neural pathways involved in processing sensory inputs from the periphery (46,47). Enhanced central nervous system (CNS) processing may involve neuroinflammatory mechanisms that activate glial cells, the primary cells regulating inflammatory states in the brain (117,118). This includes the activation of microglia and astrocytes which release mediators capable of sensitising CNS neurons and evoking molecular and structural plasticity in neurons (117,(119)(120)(121), similar to that described above for the peripheral nervous system during inflammation. ...
Chronic cough is a difficult to treat symptom of many respiratory and some non-respiratory diseases, indicating that varied pathologies can underpin the development of chronic cough. However, clinically and experimentally it has been useful to collate these different pathological processes into the single unifying concept of cough hypersensitivity. Cough hypersensitivity syndrome is reflected by troublesome cough often precipitated by levels of stimuli that ordinarily don't cause cough in healthy people, and this appears to be a hallmark feature in many patients with chronic cough. Accordingly, a strong argument has emerged that changes in the excitability and/or normal regulation of the peripheral and central neural circuits responsible for cough are instrumental in establishing cough hypersensitivity and for causing excessive cough in disease. In this review, we explore the current peripheral and central neural mechanisms that are believed to be involved in altered cough sensitivity and present possible links to the mechanism of action of novel therapies that are currently undergoing clinical trials for chronic cough.
... The pathophysiology of cough during exercise remains unclear but undoubtedly involves numerous mechanisms suggesting that cough exhibits plasticity at both peripheral and central levels (Bonham et al., 2004;Widdicombe and Singh, 2006;Aggarwal et al., 2018). Previous studies have proven that CR is decreased during exercise in healthy subjects (Lavorini et al., 2010;Demoulin-Alexikova et al., 2017) as well as in animal models (Poussel et al., 2014), even the precise underlying mechanisms are still debated. ...
Introduction
Cough is a major symptom frequently experienced during exercise, mainly in asthmatic patients. Inhaled glucocorticoids represent the keystone treatment in the management of asthma, but little is known about interactions between cough and exercise, especially in controlled patients. During exercise, cough reflex (CR) appears downregulated in healthy animal models whereas a lack of desensitization of CR has been shown in ovalbumin-sensitized animal models, mimicking asthmatic disease.
Aims and Objectives
The goal of our study was to clarify the potential modulation of the CR induced by inhaled corticosteroids (CS) in ovalbumin (OVA) sensitized rabbits during artificial limb exercise.
Materials and Methods
Seventeen OVA sensitized rabbits were studied. Among them, 9 were treated with CS delivered intravenously (OVA-Corticoids). The ventilatory response to direct tracheal stimulation, performed at rest and during exercise, was determined to assess the incidence and the sensitivity of the CR. Broncho-alveolar lavage (BAL) and cell counts were performed to determine the level of airway inflammation. Exercise was mimicked by electrically induced hindlimb muscular contractions (EMC).
Results
Compared to rest values, EMC increased minute ventilation by 28% without any decrease in respiratory resistance (Rsr). Among 322 tracheal stimulations, 172 (53%) were performed at rest and 150 (47%) during exercise. The sensitivity of CR decreased during artificial limb exercise compared to baseline in OVA-Corticoids rabbits (p = 0.0313) while it remained unchanged in OVA rabbits (p = NS).
Conclusion
Corticosteroids appear to restore the desensitization of the CR in OVA sensitized rabbits during artificial limb exercise, suggesting the potential role of airway inflammation in the pathophysiology of cough during exercise in asthmatics.
... Chronic cough is a poorly understood and managed clinical problem with a high prevalence rate [21,88]. Recently, sensitization of the cough reflex has been identified as an important mechanism in chronic cough, where cough can result from low level stimulation by chemical, mechanical, or thermal stimuli [12,22]. The term cough hypersensitivity syndrome (CHS) has been coined to describe this phenomenon [73]. ...
Background:
Inhaled bradykinin (BK) has been reported to both sensitize and induce cough but whether BK can centrally sensitize the cough reflex is not fully established. In this study, using a conscious guinea-pig model of cough, we investigated the role of BK in the central sensitization of the cough reflex and in airway obstruction.
Methods:
Drugs were administered, to guinea pigs, by the intracerebroventricular (i.c.v.) route. Aerosolized citric acid (0.2 M) was used to induce cough in a whole-body plethysmograph box, following i.c.v. infusion of drugs. An automated analyser recorded both cough and airway obstruction simultaneously.
Results:
BK, administered by the i.c.v. route, dose-dependently enhanced the citric acid-induced cough and airway obstruction. This effect was inhibited following i.c.v. pretreatment with a B2 receptor antagonist, TRPV1 and TRPA1 channels antagonists and cyclooxygenase (COX) and 12-lipoxygenase (12-LOX) inhibitors. Furthermore, co-administration of submaximal doses of the TRPV1 and TRPA1 antagonists or the COX and 12-LOX inhibitors resulted in a greater inhibition of both cough reflex and airway obstruction.
Conclusions:
Our findings show that central BK administration sensitizes cough and enhances airway obstruction via a B2 receptor/TRPV1 and/or TRPA1 channels which are coupled via metabolites of COX and/or 12-LOX enzymes. In addition, combined blockade of TRPV1 and TRPA1 or COX and 12-LOX resulted in a greater inhibitory effect of both cough and airway obstruction. These results indicate that central B2 receptors, TRPV1/TRPA1 channels and COX/12-LOX enzymes may represent potential therapeutic targets for the treatment of cough hypersensitivity.
... The approach employed in this study could be used to prepare such model of brainstem or possibly other parts of brain and the 3D map of it for other species e.g for guinea pig, or even humans. Guinea pig is nowadays extensively and successfully used in neuroscience (28). Any laboratory animal with stereotaxic coordinates and available data for neuronal localization can be processed that way. ...
Methods that had been applied to study central neuronal circuits regulating cough and respiratory reflexes so far rely on recording performed in vivo, ex vivo, micro injecting and lesion methods. Based on the available data it is clear that this network is complicated, multilevel, holarchical, undergoing reconfiguration under afferent inputs. For many students and researchers it is complicated to get a virtual spatial image of these cooperating neuronal populations. The project was aimed to create graphical three-dimensional computer model of the brainstem using environment MATLAB and the matrix algebra to visualize neuron localization within the brainstem. Relevant data for the model had been taken from recent and also former research papers published in particular areas. This model may help scientists to visualize groups of neurons, help them to find targets for microinjecting or lesion studies together with stereotaxic positioning. The model is upgradeable and highly flexible for future use, research and teaching applications in MATLAB environment. MATLAB is a high-level language and interactive environment that enables you to perform computationally intensive tasks faster than with traditional programming languages
... Only poor information is available regarding to the modulation of cough during human activities [5] but common low-level stimuli such as eating, drinking, talking, laughing, singing or exercising have been shown to cause cough, suggesting the emergence of a new concept (even if little explanation has so far been suggested) where cough is considered as a neuropathic disorder [44] . In the field of exercise (although available information is limited and often contradictory ), present knowledge seems to indicate that the various adaptive responses brought into action by physical activity may modulate the CR [5], supporting that cough reflex exhibits plasticity at peripheral and central levels [45]. In healthy subjects, it has been shown that cough threshold to distilled water aerosol was increased during exercise and voluntary isocapnic hyperpnea [7]. ...
Introduction
Cough is a major symptom of asthma frequently experienced during exercise but little is known about interactions between cough and exercise. The goal of our study was to clarify the potential modulation of the cough reflex (CR) by exercise in a spontaneously breathing anaesthetized animal model of airway eosinophilic inflammation.
Materials & methods
Ten ovalbumin (OVA) sensitized adult rabbits and 8 controls were studied. The ventilatory response to direct tracheal stimulation, performed both at rest and during exercise was determined to quantify the incidence and the sensitivity of the CR.
Broncho-alveolar lavages (BAL) and cell counts were performed to assess the level of the airway inflammation following OVA-induced sensitization. Exercise was mimicked by Electrically induced hindlimb Muscular Contractions (EMC).
Results
Among 494 tracheal stimulations, 261 were performed at rest and 233 at exercise. OVA challenges in sensitized rabbits caused a significant increase in the percentage of eosinophils (p = 0.008) in BAL. EMC increased minute ventilation by 36% and 35% in OVA and control rabbits respectively, compared to rest values. The sensitivity of the CR decreased during exercise compared to baseline in control rabbits (p = 0.0313) while it remained unchanged in OVA rabbits.
Conclusion
The desensitization of the CR during exercise in control rabbits was abolished in OVA rabbits. The precise role of airway inflammation in this lack of CR desensitization needs to be further investigated but it might contribute to the exercise-induced cough in asthmatics.
... However, to date there is no evidence that either an NK1 or an NK2 receptor antagonist have any clinical benefit in the treatment of cough (Fahy et al., 1995), and indeed in other disease areas involving sensory nerves Antitussive Drugs in the periphery such as pain, such drugs have been very disappointing (Hill, 2000). However, it has been suggested that there is a mechanism analogous to the "wind up" mechanism implicated in hyperalgesia and pain involving plasticity of nerves in the CNS (Bonham et al., 2004), and thus, it may be necessary to have a centrally acting NK receptor antagonist or an NK3 receptor antagonist. Therefore, it is noteworthy that a recently reported triple NK receptor antagonist CS-003 has been reported to inhibit cough in the guinea pig (Tsuchida et al., 2008). ...
Cough remains a serious unmet clinical problem, both as a symptom of a range of other conditions such as asthma, chronic obstructive pulmonary disease, gastroesophageal reflux, and as a problem in its own right in patients with chronic cough of unknown origin. This article reviews our current understanding of the pathogenesis of cough and the hypertussive state characterizing a number of diseases as well as reviewing the evidence for the different classes of antitussive drug currently in clinical use. For completeness, the review also discusses a number of major drug classes often clinically used to treat cough but that are not generally classified as antitussive drugs. We also reviewed a number of drug classes in various stages of development as antitussive drugs. Perhaps surprising for drugs used to treat such a common symptom, there is a paucity of well-controlled clinical studies documenting evidence for the use of many of the drug classes in use today, particularly those available over the counter. Nonetheless, there has been a considerable increase in our understanding of the cough reflex over the last decade that has led to a number of promising new targets for antitussive drugs being identified and thus giving some hope of new drugs being available in the not too distant future for the treatment of this often debilitating symptom.
... The left right arrow indicates nasal instillation of water. either the sensor- (Carr and Lee, 2006) or integration level (Bonham et al., 2004). Afferents from the nose per se do not trigger cough, but the reflex is sensitized by experimental rhinitis in animals (Brozmanova et al., 2008), and the post-nasal drip syndrome is also a common cause of chronic cough in humans (Chung and Pavord, 2008;Pratter, 2006). ...
The 'cough center' can be tuned by various afferent inputs, suggesting possible interactions at a central level of neural pathways originating from distant anatomical sites. The present study was designed to determine whether brief mechanical stimulation of the trachea can trigger cough during apnea elicited by nasal instillation of water. Twelve anesthetized, tracheotomized rabbits were studied. Mechanical stimulation of the trachea was performed under 3 conditions: baseline control, after instillation of saline into the nose and during apnea following instillation of water. The baseline breathing pattern did not differ between the 3 conditions. In a series of 171 stimulations, expiration reflex occurred in 81% of stimulations during apnea with a significantly (p<0.0001) lower peak expiratory flow than at baseline or during saline instillation. The incidence of responses comprising a cough reflex was also lower during water instillation than at either baseline or with saline (p<0.0001). These results indicate that stimulation of nasal afferents with distilled water likely down-regulates cough.
... The neurophysiology of these sensors has been extensively reviewed, as have been their putative mechanism(s) of activation by aqueous solutions (23,65). The cough reflex exhibits significant plasticity at the sensory and ganglionic levels, as well as at the level of the central nervous system (8,12). This plasticity usually consists of a sensitization (upregulation) of the reflex, but desensitization (downregulation) may also occur (67). ...
... Many possible mechanisms may underlie neuroplasticity within the cough system, peripherally and centrally. These may include plasticity in the sensory afferent fibers, changes in the release of neurochemicals at the central terminals of vagal afferent neurons such as glutamate and Substance P, or changes in synaptic input (for review see (Bonham et al., 2004)). ...
A function of the abdominal expiratory muscles is the generation of cough, a critical respiratory defense mechanism that is often disrupted following spinal cord injury. We assessed the effects of a lateral T9/10 hemisection on cough production at 4, 13 and 21 weeks post-injury in cats receiving extensive locomotor training. The magnitudes of esophageal pressure as well as of bilateral rectus abdominis electromyogram activity during cough were not significantly different from pre-injury values at all time points evaluated. The results show that despite considerable interruption of the descending pre-motor drive from the brainstem to the expiratory motoneuron pools, the cough motor system shows a significant function by 4 weeks following incomplete thoracic injury.
... Patients with chronic cough very often demonstrate an increased tussive response to inhalation of tussive agents such as capsaicin indicates that there is a sensitisation of the cough reflex [7]. Both peripheral and central causes of this sensitisation have been put forward [8,9]; however, changes observed in the airways of patients with chronic cough indicate that peripheral changes could be involved in the sensitisation of the cough reflex. Thus, there is an increase in mediator expression as measured by increased levels of histamine in bronchoalveolar lavage fluid, and levels of cys-leukotrienes, leukotriene B4, myeloperoxidase and TNF in induced sputum samples from patients with persistent cough [10]. ...
In patients with chronic idiopathic cough, there is a chronic inflammatory response together with evidence of airway wall remodelling and an increase in airway epithelial nerves expressing TRPV-1. We hypothesised that these changes could result from an increase in growth factors such as TGFβ and neurotrophins.
We recruited 13 patients with persistent non-asthmatic cough despite specific treatment of associated primary cause(s), or without associated primary cause, and 19 normal non-coughing volunteers without cough as controls, who underwent fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsies.
There was a significant increase in the levels of TGFβ in BAL fluid, but not of nerve growth factor(NGF) and brain-derived nerve growth factor(BDNF) compared to normal volunteers. Levels of TFGβ gene and protein expression were assessed in bronchial biopsies. mRNA expression for TGFβ was observed in laser-captured airway smooth muscle and epithelial cells, and protein expression by immunohistochemistry was increased in ASM cells in chronic cough patients, associated with an increase in nuclear expression of the transcription factor, smad 2/3. Subbasement membrane thickness was significantly higher in cough patients compared to normal subjects and there was a positive correlation between TGF-β levels in BAL and basement membrane thickening.
TGFβ in the airways may be important in the airway remodelling changes observed in chronic idiopathic cough patients, that could in turn lead to activation of the cough reflex.
... The cough reflex is not static, but rather the pathways for cough strongly exhibit plasticity at sensory, ganglionic and central nervous levels [2,3]. This usually consists of a sensitization (up-regulation) of the reflex, but down-regulation may also occur [4]. ...
Twelve distinguished scientists attended the workshop, heard three presentations, and took part in the discussions. Fontana first described his unpublished studies on cough in exercise and during hyperventilation with healthy subjects. Both activities depressed cough induced by inhalation of distilled water aerosol (fog). The possible mechanisms were discussed. Gibson then described the successful use of speech therapy to treat chronic cough, and discussed the possible mechanisms, centering on the role of the larynx and its neural control. A comparison was made with the ability of speech and laughter to precipitate cough. Widdicombe discussed the scanty literature on the effect of singing and playing wind instruments on cough, most of the evidence being anecdotal. In the discussion periods several matters for future study arose. It is usually not clear if the modulation of cough, its depression, enhancement or excitation, arose primarily at peripheral sites (reflexes from the airways), or at a cortical level, or both. Nor is it clear whether the same results would be obtained with provoked cough and with spontaneous cough. But all three aspects of 'behavioual' changes in cough sensitivity (exercise, speech and music) could be further explored, and current techniques should make this possible.
... Cough reflex sensitization may occur peripherally and/or centrally[54,55]. As the central processes involved are outside the scope of this review, our intention is to focus on the airway inflammatory events likely to be responsible for the sensitization of cough receptors. ...
Cough reflex hypersensitization is a key feature in patients with troublesome cough. The clinical consequence of this hypersensitive state is typified by bouts of coughing often triggered by low threshold stimuli encountered by the patient during normal daily activities including exposure to aerosols, scents and odours, a change in air temperature and when talking or laughing. These features are often perceived by cough patients to be the most disruptive aspect of their condition and undoubtedly contribute to impaired quality of life. Patients with troublesome cough may describe a range of additional symptoms and sensations including an 'urge to cough' or the feeling of an 'itch' at the back of the throat, or a choking sensation and occasionally chest pain or breathlessness. It is uncertain if these features arise due to the processes responsible for cough reflex sensitization or as a direct consequence of the underlying cough aetiology. In an attempt to understand the clinical features of a sensitized cough reflex, the spectrum of symptoms typically described by cough patients will be reviewed and possible underlying mechanisms considered. Since an intact cough reflex is crucial to airway protection, anti-tussive treatment that attenuates the hypersensitive cough state rather than abolishing the cough reflex completely would be preferable. Identifying such agents remains a clinical, scientific and pharmacological challenge.
... The central pathway for cough is a brainstem reflex linked to control of breathing (the central respiratory pattern generator)[3], which undergoes a maturation process such that the reference values for normal respiratory rate in children are different to those in adults[4]and reaches adult values in adolescence. In early life, cough is related to primitive reflexes (laryngeal chemoreflex), that ...
Worldwide paediatricians advocate that children should be managed differently from adults. In this article, similarities and differences between children and adults related to cough are presented. Physiologically, the cough pathway is closely linked to the control of breathing (the central respiratory pattern generator). As respiratory control and associated reflexes undergo a maturation process, it is expected that the cough would likewise undergo developmental stages as well. Clinically, the 'big three' causes of chronic cough in adults (asthma, post-nasal drip and gastroesophageal reflux) are far less common causes of chronic cough in children. This has been repeatedly shown by different groups in both clinical and epidemiological studies. Therapeutically, some medications used empirically for cough in adults have little role in paediatrics. For example, anti-histamines (in particular H1 antagonists) recommended as a front-line empirical treatment of chronic cough in adults have no effect in paediatric cough. Instead it is associated with adverse reactions and toxicity. Similarly, codeine and its derivatives used widely for cough in adults are not efficacious in children and are contraindicated in young children. Corticosteroids, the other front-line empirical therapy recommended for adults, are also minimally (if at all) efficacious for treating non-specific cough in children. In summary, current data support that management guidelines for paediatric cough should be different to those in adults as the aetiological factors and treatment in children significantly differ to those in adults.
... LUNG AND AIRWAY REFLEXES THROUGH the central nervous system (CNS) play crucial roles in maintaining airway and respiratory function and providing defensive mechanisms. In addition, the reflexes can be modified to give rise to exaggerated and undesired outputs, including airway hyperresponsiveness and persistent cough, implicating them in airway diseases (13,15). Kubin and colleagues (48a) have reviewed the neural pathways in airway reflexes in this Highlighted Topics series. ...
The nucleus tractus solitarius (NTS) is the first central nervous system (CNS) site for synaptic contact of the primary afferent fibers from the lungs and airways. The signal processing at these synapses will determine the output of the sensory information from the lungs and airways to all downstream synapses in the reflex pathways. The second-order NTS neurons bring to bear their own intrinsic and synaptic properties to temporally and spatially integrate the sensory information with inputs from local networks, higher brain regions, and circulating mediators, to orchestrate a coherent reflex output. There is growing evidence that NTS neurons share the rich repertoire of forms of plasticity demonstrated throughout the CNS. This review focuses on existing evidence for plasticity in the NTS, potential targets for plasticity in the NTS, and the impact of this plasticity on lung and airway reflexes.
... 70 This sensitization process may occur peripherally and/or centrally. 71,72 A variety of key sensitizing agents are believed responsible for a number of well recognized cough syndromes outlined briefly below. ...
Chronic cough is a common and disabling symptom. Recent guidelines have attempted to provide direction in the clinical management of cough in both primary and secondary care. They have also provided a critical review of the available literature and identified gaps in current knowledge. Despite this they have been criticized for a reliance on a low quality evidence base. In this review, we summarize the current consensus on the clinical management of chronic cough and attempt to rationalize this based on recent evidence. We have also provided an overview of the likely pathophysiological mechanisms responsible for cough and highlighted areas, where knowledge deficits exist and suggest directions for future research. Such progress will be critical in the search for new and effective treatments for cough.
Bicuculline and saclofen were microinjected into the rostral (rNTS) and caudal nucleus of the solitary tract (cNTS) in 17 anesthetized cats. Electromyograms (EMGs) of the diaphragm (DIA) and abdominal muscles (ABD), esophageal pressures (EP), and blood pressure were recorded and analyzed. Bilateral microinjections of 1mM bicuculline in the rNTS significantly reduced the number of coughs (CN), amplitudes of DIA and ABD EMG, inspiratory and expiratory EP, and prolonged the duration of the cough expiratory phase (CTE) as well as the total cough cycle duration (CTtot). Bilateral microinjections of 2mM saclofen reduced only cough expiratory efforts. Bilateral microinjection of bicuculline in the cNTS significantly reduced CN and amplitudes of ABD EMG and elongated CTE and CTtot. Bilateral microinjections of saclofen in cNTS had no significant effect on analyzed cough parameters. Our results confirm a different GABAergic inhibitory system in the rNTS and cNTS acting on mechanically induced cough in cats.
OBJECTIVE
Endovascular treatment in children, especially neonates, can be more challenging than analogous procedures in adults. This study aimed to describe the clinical and radiological findings, type and timing of endovascular treatment, and early outcomes in children who present with neurovascular malformations, who are treated with embolization, and who weigh less than 5 kg.METHODS
The authors carried out a retrospective review of all consecutively treated children weighing less than 5 kg with neurovascular arteriovenous malformations (AVMs) at a single institution over a 10-year period.RESULTSFifty-two patients were included in the study. Thirty-eight had a vein of Galen aneurysmal malformation, 3 a pial AVM, 6 a pial arteriovenous fistula, and 5 a dural sinus malformation. The endovascular treatment goals were control of cardiac failure or hydrocephalus in cases of nonhemorrhagic malformations or to prevent new bleeding in cases of previous hemorrhage. A hemorrhagic complication occurred in 12 procedures and an ischemic complication in 2. Both complication types were correlated with the age of the infant (age cutoff at 3 months) (p = of 0.015 and 0.049, respectively). No correlation was found with the weight of the infant or the duration of the procedure.CONCLUSIONS
The embolization of AVMs in these patients prevented adverse cardiac effects, hydrovenous disorders, and rebleeding. The risk of major cerebral complications seems mainly correlated with age, with a threshold at 3 months. A multidisciplinary team involved in the treatment of these children may help to improve treatment success and management.
Cough is an important protective reflex that is essential to protect the airways yet can also signify disease as a symptom of airway disease. It is the most common symptom that results in new medical consultations at least in regions where data is available. Both children and adults can cough for a myriad of reasons. This ranges from cough associated with simple viral infections to cough secondary to serious airway or lung disorders. Consequently evaluating causes of cough can be quite challenging.
Bronchial challenge tests are commonly used in clinical medicine and research. The aim of this study was to clarify changes of cough reflex sensitivity before and after exercise challenge testing in asthma children.
42 asthmatic children were submitted to cough reflex sensitivity measurement – capsaicin aerosol in doubling concentrations (from 0.61 to 1250 micromol/l) was inhaled by a single breath method – before and after exercise challenge testing. Concentrations of capsaicin causing two (C2) and five coughs (C5) were reported. Children' (31 boys and 11 girls, mean age 14.05 ± 2.08 yrs) cough reflex sensitivity (median, with the 95% CI) for C2 was before exercise challenge testing 9.77 (6.10–10.99) micromol/l vs. children' C2 after it 7.32 (6.10–14.65) (P = 0.58 for the Wilcoxon two sample paired test). Children' C5 was before exercise challenge testing 19.53 (14.65–80.57) micromol/l vs. C5 after it 39.06 (24.42–58.59) micromol/l (P = 0.09 for the Wilcoxon two sample paired test).
We conclude that cough reflex sensitivity was not significantly changed after exercise challenge testing in children with asthma.
Cough is one of the most common complaints for which sufferers seek medical assistance. However, currently available drugs are not very effective in treating cough, particularly that which follows an upper respiratory tract infection. Nonetheless, there has been a significant increase in our understanding of the mechanisms and pathways of the defensive cough as well as the hypersensitive/pathophysiological cough, both at airway and central nervous system (CNS) levels. Numerous molecules and signaling pathways have been identified as potential targets for antitussive drugs, including neurotrophins (NTs). NTs belong to a family of trophic factors and are critical for the development and maintenance of neurons in the central and peripheral nervous system including sympathetic efferents, sensory neuron afferents, and immune cells. Nerve growth factor (NGF) was the first member of the NT family to be discovered, with wide ranging actions associated with synapse formation, survival, proliferation, apoptosis, axonal and dendritic outgrowth, expression and activity of functionally important proteins such as ion channels, receptors, and neurotransmitters. In addition, NGF has been implicated in several disease states particularly neuropathic pain and most recently in the sensitization of the cough reflex. This review will briefly address the peripheral and central sensitization mechanisms of airway neurons and will then focus on NGF signaling and its role in cough hypersensitivity.
Cough is a normal protective mechanism. Chronic cough in children is different from that of adults and rarely are due to GERD, postnasal dripping or asthma. Treatment should be aimed at the specific causes and symptomatic treatment using the Over-The-Counter is not without disadvantage and is usually not effective. The efficacy of empiric uses of inhaled bronchodilator and corticosteroids may be due to the period effect, withdrawal of such therapy and and re-evaluation may be needed for the confirmation of diagnosis, to avoid the overdiagnosis and overtreatment of bronchial asthma using long-term corticosteroids.
The 'cough network' exhibits plasticity at the sensor and integration levels leading to modulation of the strength or pattern of the cough reflex . Little is known about the interactions between cough and human activities, especially during exercise. The present study was designed to determine whether exercise, mimicked by electrically induced muscle contractions, can modify the incidence and/or strength of cough following mechanical stimulation of the trachea in anesthetized rabbits. Thirteen anesthetized, tracheotomized rabbits were studied by a total of 311 tracheal stimulations: 196 at rest and 115 during exercise. During muscle contractions, the incidence of the cough reflex (CR) decreased and the expiration reflex (ER) increased (p < 0.0001). The sensitivity of the CR and ER both decreased during exercise compared to the sensitivity of the CR at rest (p < 0.02), while the strength of the expulsive response remained unchanged. These results indicate that adjustments occurring during muscle contractions likely downregulate tracheal defensive reflexes in anesthetized rabbits.
Husten ist weltweit eines der häufigsten Symptome, welches zur Konsultation eines Arztes führt. Dabei stellt Husten einen wichtigen neuronalen Reflex dar, der als Schutzfunktion vor körperfremden Mikroorganismen, thermischen und chemischen Reizstoffen, die über die Atemwege eindringen können, dient. Zudem beugt er der Retention von Schleim in den Atemwegen vor.
Der Husten-Reflex wird durch die Aktivierung verschiedener Husten-Rezeptoren initiiert. Diese Husten-Rezeptoren lassen sich hinsichtlich ihrer elektrophysiologischen Konfiguration in 3 Gruppen unterteilen, nämlich in die beiden Aδ-Fasern-Typen „schnell adaptierende (RAR) Mechanorezeptoren“ und „langsam adaptierende (SAR) Mechanorezeptoren“ und die C-Faser-Rezeptoren. Der Reiz wird durch die Husten-Rezeptoren über vagal-sensible Neuronen an das Husten-Zentrum im Gehirn weitergegeben. Der Husten selbst wird danach über Motoneuronen efferenter Nerven ausgebildet. Der Hustenreflex besteht somit aus 5 [1] funktionell aufeinander folgenden Teilen, nämlich den Husten-Rezeptoren [2], den primären afferenten Bahnen des N. vagus [3] [4] [5], N. trigeminus und N. glossopharyngeus [1], dem Hustenzentrum in der Medulla oblongata (N. tractus solitarius) [6] [7] [8], den afferenten Bahnen des N. phrenicus, des Spinalnervs und des N. laryngeus recurrens und den Muskeln des Rachens sowie dem Zwerchfell und der abdominalen, intercostalen und laryngealen Muskulatur. Die Hustenrezeptoren befinden sich hauptsächlich in Larynx, Trachea und Hauptbronchien [2].
Der Vorgang des Hustens kann in 4 Phasen eingeteilt werden. Auf die erste Phase der schnellen Inspiration mit geöffneter Glottis folgen die Kompression mit geschlossener Glottis und ansteigendem trachealen Druck, die Akzeleration, bei der sich die Glottis öffnet, und schließlich die Exspiration/Expulsion mit geöffneter Glottis [9]. Gemäß seiner Charakteristik kann Husten in zwei distinkte Typen aufgeteilt werden, zum einen den „unfreiwilligen, lauten Aspirations-Husten“, und zum anderen den kratzenden, reizenden und in seiner Intensität langsam ansteigenden kontrollierten Husten [10].
Akuter Husten entsteht häufig als Reaktion auf eine Infektion des respiratorischen Systems [11] [12] [13] und endet meist spontan nach 4 Wochen. Bis zu 8 Wochen hingegen kann Husten in chronischer Form durch einen infektiösen Befall mit Pathogenen wie Adenovirus, Bordetella pertussis und Mykoplasmen andauern [12] [13] [14]. Zur Unterteilung des Hustens nach seiner Ursache kann er auch nach Art und Weise differenziert werden. Zu unterscheiden sind trockener und Schleim-produzierender Husten.
Mit dieser Übersicht sollen die neuronalen Vorgänge und Mechanismen sowie Diagnostik und Therapie chronischen Hustens dargestellt werden. Dabei wird auch die Effizienz etablierter und potenzieller, noch nicht etablierter Antitussiva betrachtet.
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.
Substance P (SP) is involved in the pathogenesis of cough in animal models. However, few studies in humans have been reported and the roles of SP in clinical cough remain obscure.
To clarify the relevance of plasma levels of SP in patients with persistent cough.
We studied 82 patients with cough persisting for at least 3 weeks and 15 healthy controls. Patients were classified as having asthmatic cough (cough-variant asthma and cough-predominant asthma; n = 61) or nonasthmatic cough (n = 21; postinfectious cough, n = 6; gastroesophageal reflux disease, n = 5; idiopathic cough, n = 5, and others, n = 5). Correlations were evaluated between plasma SP levels as measured with ELISA and methacholine airway hyperresponsiveness (airway sensitivity and airway reactivity), capsaicin cough sensitivity, sputum eosinophil and neutrophil counts, and pulmonary function.
Plasma SP levels were significantly elevated in patients with both asthmatic and nonasthmatic cough compared with controls [31.1 pg/ml (range 18.0-52.2) and 30.0 pg/ml (range 15.1-50.3) vs. 15.4 pg/ml (range 11.3-23.7); p = 0.003 and p = 0.038, respectively] but did not differ between the two patient groups (p = 0.90). Plasma SP levels correlated with airway sensitivity (threshold dose of methacholine) in the patients with asthmatic cough (r = -0.37, p = 0.005) but not with airway reactivity, cough sensitivity, FEV1 values, or sputum eosinophil and neutrophil counts in either group.
Increased levels of SP in plasma are associated with persistent cough in humans and might be related to airway sensitivity in asthmatic cough.
Chronic intermittent hypoxia (CIH) is a frequent concomitant of sleep apnea, which can increase sympathetic nerve activity through mechanisms involving chemoreceptor inputs to the commissural nucleus of the solitary tract (cNTS). These chemosensory inputs co-store glutamate and substance P (SP), an endogenous ligand for neurokinin-1 (NK(1)) receptors. Acute hypoxia results in internalization of NK(1) receptors, suggesting that CIH also may affect the subcellular distribution of NK(1) receptors in subpopulations of cNTS neurons, some of which may express tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis (TH). To test this hypothesis, we examined dual immunolabeling for the NK(1) receptor and TH in the cNTS of male mice subjected to 10days or 35days of CIH or intermittent air. Electron microscopy revealed that NK(1) receptors and TH were almost exclusively localized within separate somatodendritic profiles in cNTS of control mice. In dendrites, immunogold particles identifying NK(1) receptors were prevalent in the cytoplasm and on the plasmalemmal surface. Compared with controls, CIH produced a significant region-specific decrease in the cytoplasmic (10 and 35days, P<0.05, unpaired Student t-test) and extrasynaptic plasmalemmal (35days, P<0.01, unpaired Student t-test) density of NK(1) immunogold particles exclusively in small (<0.1microm) dendrites without TH immunoreactivity. These results suggest that CIH produces a duration-dependent reduction in the availability of NK(1) receptors preferentially in small dendrites of non-catecholaminergic neurons in the cNTS. The implications of our findings are discussed with respect to their potential involvement in the slowly developing hypertension seen in sleep apnea patients.
The management of cough in children should be etiologically based. This requires that all children with cough should be carefully evaluated and managed differently than adults because the etiologic factors and treatment in children are significantly different than that in adults. In all children with cough, exacerbation factors should be sought and intervention options for cessation advised or initiated. Parental expectations and specific concerns should also be sought and addressed.
Stimuli within the lung can cause the sensations of pain, ache, irritation and urge-to-cough. In general these are abolished or inhibited by vagal section or vagal anaesthesia, or local anaesthesia within the airways. They are present in patients with functional high cervical spinal cord transaction and after general neuromuscular paralysis. There are at least nine sensors in the bronchopulmonary system, studied almost entirely in animals. It is at present impossible to link any one sensor with any one pattern of sensation. It is reasonable to suppose that urge-to-cough arises from sensors what mediate cough, but there are at least five sensors involved in this reflex, and how they relate to unpleasant sensation is unknown. The problem is that sensation can almost only be studied in humans, and the vagal neural mechanisms almost only in other species. Vagal sensors can also ameliorate the sensation of air hunger, and this is probably due to the action of slowly adapting pulmonary stretch receptors (SARs). The same sensors may give rise to the awareness of lung volume and its changes. Many sensors in the lungs can be sensitized or desensitized by natural or imposed conditions, and this could underlie the sensitization and desensitization of dyspnoeic sensations that have been described.
Chronic cough is a common and frequently disruptive symptom which can be difficult to treat with currently available medicines. Asthma/eosinophilic airway disease and gastro-oesophageal reflux disease are most commonly associated with chronic cough but it may also trouble patients with chronic obstructive pulmonary disease, pulmonary fibrosis and lung cancer. Over the last three decades there have been a number of key advances in the clinical approach to cough and a number of international guidelines on the management of cough have been developed. Despite the undoubted benefit of such initiatives, more effective treatments for cough are urgently needed. The precise pathophysiological mechanisms of chronic cough are unknown but central to the process is sensitization (upregulation) of the cough reflex. One well-recognized clinical consequence of this hypersensitive state is bouts of coughing triggered by apparently trivial provocation such as scents and odours and changes in air temperature. The main objective of new treatments for cough would be to identify ways to downregulate this heightened cough reflex but yet preserve its crucial role in protecting the airway. The combined efforts of clinicians, scientists and the pharmaceutical industry offer most hope for such a treatment breakthrough. The aim of this chapter is to provide some rationale for the current treatment recommendations and to offer some reflections on the management of patients with chronic cough.
Chronic and uncontrollable cough is one of the most common and debilitating symptoms found in patients with chronic airway diseases. The physical trauma and stresses of chronic cough on the airway mucosa and respiratory muscles can further worsen the deteriorating process of the airway diseases. The articles presented in this section focus primarily on the effect of chronic cough on the cell structure and protective function of the airway mucosa, the mechanisms underlying the hypersensitivity of chronic cough, and new target areas for antitussive drug development. A major emphasis has been placed on the neuronal plasticity found at the peripheral and central sites of the neural pathway mediating the cough reflex, and its potential role in the development of chronic cough is discussed. A number of new and important questions concerning the physiological and pharmacological mechanisms underlying chronic cough have emerged in these presentations. Further studies are required to answer these questions, which should bring a better understanding of the pathogenic mechanisms of chronic cough and lead to the development of new therapeutic strategies.
Recent clinical studies have emphasized the up-regulation (sensitization) of cough in pathological conditions of the airways. However there are also many situations where voluntary and reflex cough can be down-regulated. These include: (1) chemical stimulation of breathing by hypercapnia or hypoxia or both, establishing that cough sensitivity can be inversely related to drive to breathing; (2) voluntary inhibition of cough, probably similar in mechanism to the depression of cough that can be induced by hypnosis and other branches of alternative medicine; (3) the placebo effect of many antitussive treatments; (4) sleep; (5) general anaesthesia; (6) central nervous disorders such as coma, stroke, Parkinson's disease and several other conditions where the defect in the protective reflexes may lead to aspiration pneumonia; (7) increased activity in various afferent inputs from viscera in the thorax and abdomen; (8) a number of bronchopulmonary clinical disorders. The list is long, but regrettably the nervous mechanisms of these down-regulations have been little studied. In addition there are a number of situations, such as exercise, coitus, talking and singing which, while important to coughing humans, have been not investigated in relation to cough. Most of the studies have been with experimental animals, and their extension to human research is desirable. In view of the importance of cough and other defensive reflexes in maintaining human well-being, far more research is needed. The field is wide-open.
Tachykinins such as substance P are localized in unmyelinated slow-conducting C fibers that can be activated by noxious stimuli and tissue inflammation. Substance P is seldom expressed in fast-conducting large-diameter (A-fiber) vagal sensory neurons. We have previously found that allergic inflammation causes a phenotypic change in tachykinergic innervation of the trachea such that the production of substance P is induced in large-diameter sensory neurons projecting mechanosensitive A fibers to the trachea.
To evaluate whether allergic inflammation also induces substance P synthesis in large-diameter sensory stretch-receptor neurons innervating guinea pig lungs, and to investigate potential mechanisms by which this may occur.
Sensitized guinea pigs were exposed to allergen (ovalbumin) aerosol. One day later, immunohistochemical analysis was performed on vagal sensory neurons that had been retrogradely labeled from the lungs.
Ovalbumin inhalation caused a significant increase in substance P expression in large-diameter neurofilament-positive nodose ganglion neurons that innervate the lungs (P < .05). This effect was decreased by ipsilateral vagotomy. Exposing isolated nodose ganglia to the sensitizing antigen, ovalbumin, also significantly increased substance P expression compared with control.
Allergic inflammation induces substance P synthesis in large-diameter (A-fiber) nodose ganglion neurons innervating guinea pig lungs. This could contribute to the hyperreflexia seen in allergic airway disease. The full expression of this phenotypic switch in vagus nodose ganglion neurons requires intact vagus nerve, but if allergen reached the systemic circulation in sufficient quantities, it could also affect substance P synthesis by local activation of vagal ganglionic mast cells.
An intact cough reflex is important to protect the lung from injurious substances and to clear excess secretions. A blunted cough reflex may be harmful or even fatal in respiratory disease. Hypoxia is common in respiratory disorders and has been shown to have depressant effects on respiratory sensation and ventilation. We hypothesized that it might also suppress the cough reflex.
To determine if acute hypoxia increases cough threshold and cough tachyphylaxis to inhaled capsaicin.
On two occasions, 16 healthy subjects inhaled a saline control followed by doubling doses of capsaicin aerosol (range, 0.49-500 microM) every minute for 15 s during controlled ventilation (approximately 190% baseline) with isocapnic hypoxia (SpO2, approximately 80%) or isocapnic normoxia, in random order. When a subject responded to a dose with five or more coughs, the next doubling dose of capsaicin was administered continuously for 60 s to assess acute tachyphylaxis.
The capsaicin concentration required to elicit five coughs was significantly higher during isocapnic hypoxia compared with normoxia (29.6 +/- 16.0 vs. 23.4 +/- 15.6 microM, p = 0.01). During continuous capsaicin inhalation, significantly more coughs were evoked in the first 10 s compared with the last (2.3 +/- 0.3 vs. 1.3 +/- 0.3, p < 0.01), indicating cough tachyphylaxis. However, the decrease was the same during hypoxia and normoxia (-1.3 +/- 0.4 vs. -0.9 +/- 0.6, p = 0.54).
Acute isocapnic hypoxia suppresses cough reflex sensitivity to inhaled capsaicin. This finding raises the possibility that the cough reflex may be impaired during acute exacerbations of hypoxic-respiratory disorders.
Cough is the commonest symptom of clinical importance and the most frequent reason for new consultations with a doctor. Although therapy directed at any underlying cause for cough can be effective there is a clinical need for new treatments specifically directed at the cough itself. A major obstacle to the development of such therapy has been an imprecise understanding of the pathophysiological mechanisms responsible for cough. In this article, we review the important clinical aspects of both acute and chronic cough, offer practical insight into the existing treatment options, highlight the current understanding of cough pathophysiology and identify important areas for future research effort.
Cough is comprised of three phases (inspiratory, compressive and expiratory) and serves as a vital defensive mechanism for lung health. It prevents pulmonary aspiration, promotes ciliary activity and clears airway debris. The importance of an intact cough mechanism is reflected in the occurrence of pulmonary problems when cough is inefficient. Cough efficiency is dependent on physical/mechanical aspects (respiratory muscles, mucus, airway calibre and larynx) and integrity of the neurophysiological pathway of cough. The understanding of the latter has progressed significantly (albeit mostly in animals) with the discovery of vanniloid receptors (and subtypes) and, more recently, by the characterisation of distinct cough receptors. However, the relative contributions of previously described airway afferents/receptors to cough are still disputed. Plasticity of the peripheral and central afferent pathways in cough has recently been shown to be important in pathological states associated with increased cough. To date, little is known of the developmental aspects of cough.
We have reviewed the role of afferent inputs and blood chemical changes to the central nervous system, and the way in which they modify the cough and expiration reflexes (CR and ER). Slowly adapting pulmonary stretch receptors (SARs) augment the CR, insofar as when their activity is abolished the CRs from the tracheobronchial (TB) tree and larynx are abolished or weakened. However, stimulation of SARs by lung inflation has an inconsistent effect on the CR. Activation of SARs strongly potentiates the ER from the vocal folds, by a reflex mechanism, and inhibition of SARs weakens the ER. Bronchopulmonary C-fibre receptors inhibit the CR, as do capsaicin-sensitive afferents from the heart and splanchnic bed, cutaneous cold receptors and those that respond to chest wall vibration. Nasal receptors responsive to the irritant agent capsaicin potentiate the reflex. Acute hypoxia also augments the CR, and the reflex is down-regulated by carotid body resection. On the other hand, the CR is inhibited by prolonged hypoxia and hyperoxia, and by hypercapnia. Thus different inputs to the cough-controlling mechanism in the brainstem have very varied effects on the CR. We conclude that the sensitivities of the CR and ER can be modified in a large variety of physiological and clinical conditions, and that there is no clear relationship between the reflexes and changes in breathing caused by the interventions.
Historical aspects of respiratory reflexes from the lungs and airways are reviewed, up until about 10 yr ago. For most of the 19th century, the possible reflex inputs into the "respiratory center," the position of which had been identified, were very speculative. There was little concept of reflex control of the pattern of breathing. Then, in 1868, Breuer published his paper on "The self-steering of respiration via the Nervus Vagus." For the first time this established the role of vagal inflation and deflation reflexes in determining the pattern of breathing. Head later extended Breuer's work, and Kratschmer laid a similar basis for reflexes from the nose and larynx. Then, 50-60 yr later, the development of the thermionic valve and the oscilloscope allowed recording action potentials from single nerve fibers in the vagus. In 1933, Adrian showed that slowly adapting pulmonary stretch receptors were responsible for the inflation reflex. Later, Knowlton and Larrabee described rapidly adapting receptors and showed that they mediated deep augmented breaths and the deflation reflex. Still later, it was established that rapidly adapting receptors were, at least in part, responsible for cough. In 1954, Paintal began his study of C-fiber receptors (J receptors), work greatly extended by the Coleridges. Since approximately 10 yr ago, when the field of this review stops, there has been an explosion of research on lung and airway receptors, many aspects of which are dealt with in other papers in this series.
We review cough from premature birth, mature neonatal life, in childhood and adult life, and in old age. There is a regrettable lack of definitive studies, but many clues in the literature. The cough reflex seems weak in premature infants, but develops with maturity. It is pronounced in childhood, but there seem to be no studies comparing its strength then with that in adulthood. In old age the cough may weaken, as indicated by the prevalence of aspiration pneumonia. These changes are presumably related to the development and degeneration of the afferent and central nervous pathways for cough, which may be reflected in the changes in laryngeal muscle function with age. There is much evidence that age influences the development of the respiratory system in general, and of the immune system which would affect the degree, frequency and clinical issues of cough. Other factors that limit our understanding of the changes in cough with age include the reporting of cough by parents in infants and carers in old age and the use of different diagnostic criteria throughout life. Age-related variation in cough sensitivity seems to be well established, but its quantitation and mechanisms require much further research.
In a survey of 1,355 children six- to 12 years of age, the risk of hospitalization for respiratory illness among children before age two years was increased when gas was used for cooking at home (p less than 0.001) or at least one of the parents smoked (p less than 0.02). The occurrence of cough with colds in children also was significantly increased when one or both parents smoked (p less than 0.001). Small but significant increases (p less than .05) in the mean values of forced expiratory volume at one second, the flow rate at 75 percent of the forced vital capacity, and the forced expiratory flow rate from 25 percent to 75 percent of the vital capacity (FEF25-75) were seen after administering inhaled isoproterenol to children whose parents smoked (n = 94) but not among children whose parents did not smoke (n = 89); this was not seen in association with gas cooking. Thus, exposure of children during the first two years of life to gas cooking or cigarette smoking appears to be associated with an increased risk of hospitalization for respiratory illness, and cigarette smoking appears to be associated with a more consistent response to inhaled bronchodilator among six- to 12-year-old children with no other history of chronic respiratory illness.
Noxious skin stimuli which are sufficiently intense to produce tissue injury, characteristically generate prolonged post-stimulus sensory disturbances that include continuing pain, an increased sensitivity to noxious stimuli and pain following innocuous stimuli. This could result from either a reduction in the thresholds of skin nociceptors (sensitization) or an increase in the excitability of the central nervous system so that normal inputs now evoke exaggerated responses. Because sensitization of peripheral receptors occurs following injury, a peripheral mechanism is widely held to be responsible for post-injury hypersensitivity. To investigate this I have now developed an animal model where changes occur in the threshold and responsiveness of the flexor reflex following peripheral injury that are analogous to the sensory changes found in man. Electrophysiological analysis of the injury-induced increase in excitability of the flexion reflex shows that it in part arises from changes in the activity of the spinal cord. The long-term consequences of noxious stimuli result, therefore, from central as well as from peripheral changes.
Substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP) have potent proinflammatory effects in the airways. They are released from sensory nerve endings originating in jugular and dorsal root ganglia. However, the major sensory supply to the airways originates from the nodose ganglion. In this study, we evaluated changes in neuropeptide biosynthesis in the sensory airway innervation of ovalbumin-sensitized and -challenged guinea pigs at the mRNA and peptide level. In the airways, a three- to fourfold increase of SP, NKA, and CGRP, was seen 24 h following allergen challenge. Whereas no evidence of local tachykinin biosynthesis was found 12 h after challenge, increased levels of preprotachykinin (PPT)-A mRNA (encoding SP and NKA) were found in nodose ganglia. Quantitative in situ hybridization indicated that this increase could be accounted for by de novo induction of PPT-A mRNA in nodose ganglion neurons. Quantitative immunohistochemistry showed that 24 h after challenge, the number of tachykinin-immunoreactive nodose ganglion neurons had increased by 25%. Their projection to the airways was shown. Changes in other sensory ganglia innervating the airways were not evident. These findings suggest that an induction of sensory neuropeptides in nodose ganglion neurons is crucially involved in the increase of airway hyperreactivity in the late response to allergen challenge.
The primary hypothesis of this study was that the cough motor pattern is produced, at least in part, by the medullary respiratory neuronal network in response to inputs from "cough" and pulmonary stretch receptor relay neurons in the nucleus tractus solitarii. Computer simulations of a distributed network model with proposed connections from the nucleus tractus solitarii to ventrolateral medullary respiratory neurons produced coughlike inspiratory and expiratory motor patterns. Predicted responses of various "types" of neurons (I-DRIVER, I-AUG, I-DEC, E-AUG, and E-DEC) derived from the simulations were tested in vivo. Parallel and sequential responses of functionally characterized respiratory-modulated neurons were monitored during fictive cough in decerebrate, paralyzed, ventilated cats. Coughlike patterns in phrenic and lumbar nerves were elicited by mechanical stimulation of the intrathoracic trachea. Altered discharge patterns were measured in most types of respiratory neurons during fictive cough. The results supported many of the specific predictions of our cough generation model and suggested several revisions. The two main conclusions were as follows: 1) The Bötzinger/rostral ventral respiratory group neurons implicated in the generation of the eupneic pattern of breathing also participate in the configuration of the cough motor pattern. 2) This altered activity of Bötzinger/rostral ventral respiratory group neurons is transmitted to phrenic, intercostal, and abdominal motoneurons via the same bulbospinal neurons that provide descending drive during eupnea.
We sought to determine whether glutamate acting at both N-methyl-D-aspartate (NMDA) and non-NMDA receptors transmits area postrema (AP) excitatory inputs to nucleus tractus solitarii (NTS) neurons in the aortic baroreceptor or vagal afferent pathways in vivo. In alpha-chloralose-anesthetized rabbits, we recorded extracellular NTS neuronal responses to low-frequency aortic depressor nerve (ADN), vagus nerve, and AP stimulation and to iontophoresis of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and NMDA during control, iontophoresis of 2, 3-dihdroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), DL-2-amino-5-phosphonovaleric acid (AP5), or both, and recovery conditions. In neurons receiving AP and ADN inputs, NBQX attenuated AP- and ADN-evoked responses by 46 (P = 0.0206) and 49% (P = 0.0042). AP5 attenuated AP- and ADN-evoked responses by 39 (P = 0.0270) and 40% (P = 0.0157). NBQX + AP5 attenuated AP- and ADN-evoked responses by 74 (P = 0.0040) and 75% (P = 0.0028). In neurons receiving AP and vagal inputs, AP transmission was attenuated by 58, 60, and 98%; vagal transmission was attenuated by 62, 35, and 83% during NBQX, AP5, and both antagonists, respectively. These data suggest that both non-NMDA and NMDA receptors transmit AP input to NTS neurons in aortic baroreceptor or vagal afferent pathways.
With increasing frequencies of autonomic afferent input to the nucleus tractus solitarii (NTS), postsynaptic responses are depressed. To test the hypothesis that a presynaptic mechanism contributes to this frequency-dependent depression, we used whole cell, voltage-clamp recordings in an NTS slice. First, we determined whether solitary tract stimulation (0.4-24 Hz) resulted in frequency-dependent depression of excitatory postsynaptic currents (EPSCs) in second-order neurons. Second, because decreases in presynaptic glutamate release result in a parallel depression of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) receptor-mediated components of EPSCs, we determined whether the magnitude, time course, and recovery from the depression were the same in both EPSC components. Third, to determine whether AMPA receptor desensitization contributed, we examined the depression during cyclothiazide. EPSCs decreased in a frequency-dependent manner by up to 76% in second- and 92% in higher-order neurons. AMPA and NMDA EPSC components were depressed with the same magnitude (by 83% and 83%) and time constant (113 and 103 ms). The time constant for the recovery was also not different (1.2 and 0.8 s). Cyclothiazide did not affect synaptic depression at >/=3 Hz. The data suggest that presynaptic mechanism(s) at the first NTS synapse mediate frequency-dependent synaptic depression.
Electrophysiological and morphological properties of a direct projection from the nucleus of the tractus solitarius (NTS) to the ventrolateral medulla (VLM) were investigated. NTS neurons projecting to the VLM exhibit a monosynaptic excitatory response followed by an inhibitory one after the tractus solitarius stimulation. These neurons show spontaneous inhibitory postsynaptic currents, and have medium to large soma (14-26 microm in diameter). It is concluded that the projection from the NTS to the VLM is mediated mostly by medium to large neurons that are inhibited locally by GABAergic interneurons within the NTS.
Acute ozone exposure evokes adverse respiratory responses, particularly in children. With repeated ozone exposures, however, despite the persistent lung inflammation and increased sensory nerve excitability, the central nervous system reflex responses, i.e., rapid shallow breathing and decreased lung function, adapt, suggesting changes in central nervous system signaling. We determined whether repeated ozone exposures altered the behavior of nucleus tractus solitarius (NTS) neurons where reflex respiratory motor outputs are first coordinated. Whole cell recordings were performed on NTS neurons in brain stem slices from infant monkeys exposed to filtered air or ozone (0.5 ppm, 8 h/day for 5 days every 14 days for 11 episodes). Although episodic ozone exposure depolarized the membrane potential, increased the membrane resistance, and increased neuronal spiking responses to depolarizing current injections (P < 0.05), it decreased the excitability to vagal sensory fiber activation (P < 0.05), suggesting a diminished responsiveness to sensory transmission, despite overall increases in excitability. Substance P, implicated in lung and NTS signaling, contributed to the increased responsiveness to current injections but not to the diminished sensory transmission. The finding that NTS neurons undergo plasticity with repeated ozone exposures may help to explain the adaptation of the respiratory motor responses.
Substance P modulates the reflex regulation of respiratory function by its actions both peripherally and in the CNS, particularly in the nucleus tractus solitarii (NTS), the first central site for synaptic contact of the lung and airway afferent fibres. There is considerable evidence that the actions of substance P in the NTS augment respiratory reflex output, but the precise effects on synaptic transmission have not yet been determined. Therefore, we determined the effects of substance P on synaptic transmission at the first central synapses by using whole-cell voltage clamping in an NTS slice preparation. Studies were performed on second-order neurons in the slice anatomically identified as receiving monosynaptic input from sensory nerves in the lungs and airways. This was done by the fluorescent labelling of terminal boutons after 1,1'-dioctadecyl-3,3,3',3'-tetra-methylindocarbo-cyanine perchlorate (DiI) was applied via tracheal instillation. Substance P (1.0, 0.3 and 0.1 microM) significantly decreased the amplitude of excitatory postsynaptic currents (eEPSCs) evoked by stimulation of the tractus solitarius, in a concentration-dependent manner. The decrease was accompanied by an increase in the paired-pulse ratio of two consecutive eEPSCs, and a decrease in the frequency, but not the amplitude, of spontaneous EPSCs and miniature EPSCs, findings consistent with a presynaptic site of action. The effects were consistently and significantly attenuated by a neurokinin-1 (NK1) receptor antagonist (SR140333, 3 muM). The data suggest a new site of action for substance P in the NTS (NK1 receptors on the central terminals of sensory fibres) and a new mechanism (depression of synaptic transmission) for regulating respiratory reflex function.
Children raised with extended exposure to environmental tobacco smoke (ETS) experience increased cough and wheeze. This study was designed to determine whether extended ETS exposure enhances citric acid-induced cough and bronchoconstriction in young guinea pigs via a neurokinin-1 (NK-1) receptor mechanism at the first central synapse of lung afferent neurons, the nucleus tractus solitarius. Guinea pigs were exposed to ETS from 1 to 6 weeks of age. At 5 weeks of age, guide cannulae were implanted bilaterally in the medial nucleus tractus solitarius at a site that produced apnea in response to the glutamate agonist D,L-homocysteic acid. At 6 weeks of age, either vehicle or a NK-1 receptor antagonist, SR 140333, was injected into the nucleus tractus solitarius of the conscious guinea pigs who were then exposed to citric acid aerosol. ETS exposure significantly enhanced citric acid-induced cough by 56% and maximal Penh (a measure of airway obstruction) by 43%, effects that were attenuated by the NK-1 receptor antagonist in the nucleus tractus solitarius. We conclude that in young guinea pigs extended exposure to ETS increases citric acid-induced cough and bronchoconstriction in part by an NK-1 receptor mechanism in the nucleus tractus solitarius.
SUBSTANCE P (SP) modulates the activity of taste-responsive neurons in the gustatory zone of the nucleus of the solitary tract (NST) in the hamster. The distribution of the neurokinin-1 (NK1) receptor (i.e, the SP receptor) was mapped and compared with the distribution of SP immunoreactivity to identify the sites of ligand-receptor interactions. NK1-immunoreactive puncta and somata were located mostly in the rostral lateral, upper half of the rostral central and medial NST subnuclei. These subnuclei also contained intense SP-immunoreactive puncta, and are known to receive substantial inputs via gustatory and somatosensory afferent fibers. The ventral subnucleus, which is involved in visceromotor reflexes accompanying ingestion, contained little NK1 or lighter SP-immunoreactivity. These findings suggest that SP modulates taste activity destined for the ascending gustatory pathway at the level of the first central synapse in the gustatory pathway. NeuroReport 10:1003-1006 (C) 1999 Lippincott Williams & Wilkins.
We present a systematic seismic reservoir characterization workflow that integrates log and seismic data using an artificial neural network. Seismic attributes are examined both qualitatively and quantitatively to determine the best discriminators of rock and fluid properties. These attributes are systematically classified using an artificial neural network, the Kohonen self-organizing map (K-SOM) algorithm. Ultimately, the classified litho-facies volume is calibrated to available well control by applying the K-SOM technology to well- derived data. The product is a seismic-scale rock and fluid properties reservoir model that is consistent with borehole and surface seismic data. The workflow is applied to the characterization of a Vicksburg-age reservoir in South Texas.
Injections of the fluorescent retrograde axonal tracer, True Blue, into the solitary complex (a visceral and taste center in the medulla) labeled pyramidal cell bodies deep in the medial, prefrontal cortex and especially lateral prefrontal (or insular) cortex of the rat. Injections of the anterograde axonal tracer (wheat germ agglutinin conjugated to horseradish peroxidase) into the prefrontal cortex produced bilateral labeling throughout much of the solitary nucleus. The distribution of prefrontal cortical cells projecting directly to the solitary nucleus may provide one clear anatomical criterion for identifying regions of cerebral cortex that may influence visceral function.
Acute exposure to ozone causes changes in breathing pattern and lung function which may be caused in part by stimulation of rapidly adapting receptors (RARs). The consequences of repeated daily ozone exposure on RAR responsiveness are unknown, although ozone-induced changes in pulmonary function diminish with repeated exposure. Accordingly, we investigated whether repeated daily ozone exposure diminishes the general responsiveness of RARs. Guinea pigs (n = 30) were exposed to 0.5 parts/million ozone or filtered air (8 h/day for 7 days). The animals were then anesthetized, and RAR impulse activity, dynamic compliance (Cdyn), and lung resistance were recorded at baseline and in response to four stimuli: substance P, methacholine, hyperinflation, and removal of positive end-expiratory pressure. Repeated daily ozone exposure exaggerated RAR responses to substance P, methacholine, and hyperinflation without causing physiologically relevant effects on baseline or substance P- and methacholine-induced changes in Cdyn and lung resistance. Because agonist-evoked changes in RAR activity preceded Cdyn changes, the data suggest that repeated daily ozone exposure enhances RAR responsiveness via a mechanism other than changes in Cdyn.
Immunoreactivity for the calcium binding protein, calretinin (calretinin-ir), was demonstrated in cell bodies of vagal and glossopharyngeal sensory ganglia (jugular, petrosal, and nodose ganglia) and in associated nerve fibers. In the jugular and petrosal ganglia, many calretinin-ir neurons were also immunoreactive for calcitonin gene-related peptide and substance P. In the nodose ganglion, most of the calretinin-ir neurons lacked these peptides. None of the calretinin-ir neurons in these ganglia were also immunoreactive for tyrosine hydroxylase.
The differentiated cytoarchitecture, neurochemistry, and capillary organization of the rat dorsal vagal complex prompted this comprehensive investigation of microvascular physiology in 11 subdivisions of area postrema, 5 subnuclei of nucleus tractus solitarii (NTS), the dorsal motor nucleus of the vagus nerve, and 4 other gray matter structures in the dorsal medulla oblongata. Microvascular exchangeable volume (residual plasma volume), capillary blood and plasma flow, and unidirectional transfer constants for a tracer amino acid, [14C]alpha-aminoisobutyric acid (AIB), varied considerably among the structures analyzed. Exchangeable volume, largest in area postrema medial zones (about 29 microliters.g-1) and smallest in medullary gray matter (7-11 microliters.g-1), correlated directly with subregional densities of capillaries and rates of tissue glucose metabolism. Capillary blood flow (range of 1,430-2,147 microliters.g-1.min-1), plasma flow, and tissue glucose metabolism (range of 0.48-0.71 mumol.g-1.min-1) were linearly related in the dorsal vagal complex. The most striking quantitative difference among structures in this brain region were the rates of transcapillary influx and derived permeability X surface area (PS) products of [14C]AIB, which has physicochemical properties resembling those of hormones. PS products for AIB were negligible in most medullary gray matter regions (less than 1 microliter.g-1.min-1, indicative of blood-brain barrier properties), but were 20-59X and 99-402X higher in NTS subnuclei and area postrema, respectively. An extraordinary feature of the microcirculation in area postrema was the long-duration transit of tracer sucrose and blood, a characteristic that would amplify the sensing ability of area postrema as it monitors the composition of the circulation.
Nucleus tractus solitarius (NTS), an aggregate of several individual nuclear groups in the dorsal medulla oblongata, is involved in virtually all autonomic functions as the first synaptic site in the brain for many peripheral viscerosomatic inputs. We found morphological evidence that dorsocaudal subregions of rat NTS (approximately 800 microns caudal from obex) had fenestrated capillaries and enlarged Virchow-Robin (perivascular) spaces that were similar to those in area postrema but unlike capillaries elsewhere in the medulla oblongata. Complexes of microvessels, consisting of up to 10 small vessels with smooth muscle layers (luminal diameters of 10-45 microns) and several capillaries (average luminal diameter of 4.5 microns), were located in the dorsal midline of NTS within large Virchow-Robin spaces measuring some 2,000 microns 2 in area. In physiological studies, we determined that most of NTS had a definable blood-brain barrier [permeability-surface area (PS) products for a neutral amino acid near 0], but medial and lateral aspects of the commissural subnucleus of NTS had PS products of 16-63 microliters.g-1.min-1 for alpha-[14C]aminoisobutyric acid 12 s after intravenous injection. Microvascular differentiations permitting such brisk tracer influx from blood resemble those of area postrema and appear to afford the rich neuropil of commissural NTS with a constant stream of blood-borne information for expediting its regulation of viscerosensory and autonomic functions.
Neurons in the ventral region of the nucleus tractus solitarius (NTS) of guinea pigs were studied using an in vitro brainstem slice preparation. One group of neurons was characterized electrophysiologically by a delay between the onset of a depolarizing stimulus and the first spike. This delay could be as large as 760 ms and was modulated by the membrane potential level preceding the stimulus. The firing rate during the depolarizing stimulus was also modulated by the preceding membrane potential level. A fast transient outward current, similar to A-current in molluscan neurons, appeared to be responsible for the delay in firing while a slower calcium-activated potassium current affected the firing rate. These data suggest that intrinsic membrane properties may play an important role in determining the firing pattern of NTS neurons. In vivo, inhibitory synaptic inputs could modulate the expression of these intrinsic properties during subsequent excitation.
The projections of the rat area postrema were analysed using anterograde and retrograde axonal transport techniques. Discrete injections of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) into the area postrema produced anterograde labeling in specific medullary and pontine nuclei. In the medulla, anterograde labeling was present in the internal solitary zone and dorsal division of the medial solitary nucleus, both of which also contained a small number of retrogradely labeled perikarya. Prominent projections to the dorsal motor nucleus of the vagus were seen only if the WGA-HRP injections in the area postrema invaded dorsal solitary nuclei. In the pons, anterograde labeling was present in the parabrachial nuclei, the dorsolateral tegmental nucleus, and the pericentral division of the dorsal tegmental nucleus. By far the major pontine projection was to the dorsolateral region of the middle one-third of the rostrocaudal extent of the parabrachial nuclei. Retrograde fluorescent tracing studies indicated that most area postrema neurons take part in this parabrachial projection. The area postrema projection to the parabrachial nuclei was bilaterally distributed, whereas that from the dorsal solitary nuclei was primarily ipsilateral. The external solitary zone, immediately subadjacent to the area postrema, neither received area postrema projections nor participated in the projections to the parabrachial nuclei. Fluorescent retrograde double labeling studies confirmed the bilateral nature of the area postrema projection to the parabrachial nuclei. In addition, because no doubly labeled neurons were observed it appears that individual area postrema neurons project to either side but not both sides of the dorsal pons. Thus, numerous neuronal pathways exist for the transfer of blood-borne information (that cannot cross the blood-brain barrier) from the area postrema to other brain regions.
Direct projections from the forebrain to the nucleus of the solitary tract (NTS) and dorsal motor nucleus of the vagus in the rat medulla were mapped in detail using both retrograde axonal transport of the fluorescent tracer True Blue and anterograde axonal transport of wheat germ agglutinin conjugated to horseradish peroxidase (WGA‐HRP). In the retrograde tracing studies, cell groups in the medial prefrontal cortex, lateral prefrontal cortex (primarily ventral and posterior agranular insular cortex), bed nucleus of the stria terminalis, central nucleus of the amygdala, paraventricular, arcuate, and posterolateral areas of the hypothalamus were shown to project to the NTS and in some cases also to the dorsal motor nucleus of the vagus. The prefrontal cortical areas projecting to the NTS apparently overlap to a large degree with those cortical areas receiving mediodorsal thalamic and dopaminergic input. The retrogradely labeled cortical cells were situated in deep layers of the rat prefrontal cortex.
The anterograde tracing studies revealed a prominent topography in the mediolateral termination pattern of forebrain projections to the rostral part of the NTS and to the dorsal pons. The projections to the NTS were generally bilateral, except for projections from the central nucleus of the amygdala and bed nucleus of the stria terminalis which were predominantly ipsilateral. The prefrontal cortical projections to the NTS travel through the cerebral peduncle and pyramidal tract and terminate throughout the rostrocaudal extent of the NTS. Specifically, the prefrontal cortex innervates dorsal portions of the NTS (lateral part of the dorsal division of the medial solitary nucleus, dorsal part of the lateral solitary nucleus and the caudal midline region of the commissural nucleus), areas which receive relatively sparse subcortical projections. These dorsal portions of the NTS receive major primary afferent projections from the vagal and glossopharyngeal nerves. In contrast, the subcortical projections, which travel through the midbrain and pontine tegmentum, terminate most heavily in the ventral portions of the NTS, i.e., the area immediately dorsal and lateral to the dorsal motor nucleus of the vagus. Only the paraventricular hypothalamic nucleus has substantial terminals throughout the dorsal motor nucleus of the vagus. Hypothalamic cell groups innervate the area postrema and, along with the prefrontal cortex, innervate the zone subjacent to the area postrema.
We suggest that direct projections to the NTS and dorsal motor nucleus of the vagus are one criterion that can be used to define the visceral fore‐brain. The organization of the forebrain terminations in the solitary complex described here may eventually allow a better understanding of how the brain controls visceral function.
The respiratory health of a large group of Arizona school children who have been exposed to indoor pollutants--tobacco smoke and home cooking fumes--is reported. A significant relationship was found between parental smoking and symptoms of cough, wheeze, and sputum production. Also, children in homes where gas cooking fuel was used had higher rates of cough than children in homes where electricity was used. No differences in pulmonary function or yearly lung growth rates occurred among subjects grouped by exposure to tobacco smoke or cooking fuel. Thus, parental smoking and home cooking fuel affected cross-sectional respiratory symptom rates in a large group of Arizona school children. Study of pulmonary function, however, revealed no lung function or lung growth effects during 4 yr of study.
The influence of specific antigen challenge on the excitability of C-cells in nodose ganglia isolated from actively sensitized guinea pigs was evaluated using intracellular recording techniques. Antigen (ovalbumin) caused a significant depolarization (approximately 8 mV) of the resting membrane potential. Antigen exposure had differing effects on the membrane input impedance; decreasing it in 15 neurons, increasing it in 6 neurons, and having no effect in 8 neurons. About 20% of guinea pig nodose C-cells reveal a long-lasting after-spike hyperpolarization (AHPslow). Antigen challenge reversibly blocked the AHPslow in 4 of 18 neurons studied in 18 ganglia. About 30% of the nodose ganglion neurons display a time- and voltage-dependent inward rectification at membrane potentials more negative than -75 mV. Exposing the ganglion to the sensitizing antigen consistently blocked this response in 8 of 8 neurons. Histological assessment of toluidine blue stained cells revealed that the nodose ganglion contained approximately 100 mast cells. Exposing the ganglion to ovalbumin stimulated mast cell degranulation, as measured by a decrease in number of stained cells, and evoked the release of histamine, PGD2, and immunoreactive peptidoleukotrienes from the tissue. The results support the hypothesis that endogenous inflammatory mediators released during the immediate hypersensitivity (allergic) reactions can modulate the excitability of primary C-fiber afferents. Mechanisms underlying antigen-induced neuromodulation of these neurons include depolarization of the resting membrane potential, changes in membrane resistance, blockade of a time- and voltage-dependent anomalous rectifier, and, in some cells, blockade of the AHPslow.
Chronic pain is characterized by abnormal sensitivity, which is due to the generation of pain in response to the activation of the low-threshold mechanoreceptive A beta fibres that normally generate innocuous sensations. Three different processes in the spinal cord can account for this dramatic alteration in sensory processing in the somatosensory system: increased excitability, decreased inhibition and structural reorganization. All have been shown to occur and each may contribute separately or together to the wide range of chronic inflammatory and neuropathic pain disorders. The unravelling of the cellular mechanisms involved both offers the potential for developing novel therapeutic strategies, which reduce functional synaptic plasticity and prevent central atrophic and regenerative responses in injured neurones, and illustrates the capacity of the adult nervous system for maladaptive modification.
The pattern of synaptic interactions between neurons of the nucleus tractus solitarius (NTS) has been analyzed using whole cell recording in rat brainstem slices. Following tractus solitarius (TS) stimulation 15/55 neurons presented a prolonged (up to 300 ms) increased excitability (PIE neurons) and 40/55 neurons presented a prolonged (up to 200 ms) reduced excitability (PRE neurons). In the absence of afferent sensory input all neurons showed spontaneous synaptic activity. Ongoing synaptic activity in PIE cells was glutamatergic and characterized by the absence of detectable inhibitory potentials while in PRE cells it was 90% GABAergic and 10% glutamatergic. Glutamatergic synaptic currents in PIE cells and GABAergic synaptic currents in PRE were studied using probability density and intensity functions. Distribution of time intervals between synaptic events indicated the latter were generated, in both PIE and PRE cells, by two simultaneous processes: (1) a close to Poisson process generating independent events; and (2) a subsidiary re-excitatory process generating synaptic events separated by intervals shorter than 20 ms. Blockade of glutamatergic transmission by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM) or blockade of action potentials by tetrodotoxin (TTX; 1 microM) suppressed the subsidiary process. In conclusion, we propose that PIE cells (1) form a re-excitatory network contributing to generation of excitatory activity in the NTS and (2) are located presynaptically with respect to PRE cells.
The presence and coexistence of tyrosine hydroxylase (TH), vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP), substance P (SP) and galanin (GAL) were studied in the petrosal and jugular neurons innervating the carotid body and carotid sinus of the rat. The retrograde labeling of the carotid sinus nerve with Fluoro-gold (FG) demonstrated that most (94.5%) FG-labeled ganglionic neurons were observed in the petrosal ganglion. Fewer (5.2%) FG-labeled neurons were seen in the jugular ganglion and very few (0.3%) were observed in the nodose ganglion. Immunohistochemistry revealed that subpopulations of TH-, VIP-, CGRP-, SP- and GAL-immunoreactive (-ir) neurons in the petrosal ganglion projected to the carotid sinus nerve. Approximately 4% of FG-labeled neurons contained TH-ir and were predominantly found in the caudal portion of the petrosal ganglion. Nearly 90% of total TH-ir neurons in the petrosal ganglion were labeled with FG. Less than 1% of FG-labeled neurons were immunoreactive for VIP in this ganglion. In the petrosal ganglion, 25% of FG-labeled neurons contained CGRP-ir, and 16.7% of FG-labeled neurons contained SP-ir. 30% of CGRP-ir or SP-ir neurons in the petrosal ganglion were labeled with FG. In the jugular ganglion, no TH- or VIP-ir neurons projected to the carotid sinus nerve and only small populations of CGRP- or SP-ir neurons projected to the carotid sinus nerve. Many FG-labeled and GAL-ir neurons were observed in the petrosal and jugular ganglia.(ABSTRACT TRUNCATED AT 250 WORDS)
We determined the effect of sidestream tobacco smoke (SS) exposure on responses of lung rapidly adapting receptors (RARs), peak tracheal pressure (Ptr), and arterial blood pressure (ABP) to substance P in young guinea pigs. Guinea pigs were exposed to SS or filtered air from day 8 to days 41-45 of life. They were then anesthetized and given three doses of intravenous substance P (1.56-4.94 nmol/kg). SS exposure augmented substance P-evoked increases in RAR activity (P = 0.029 by analysis of variance) but not substance P-evoked increases in peak Ptr or decreases in ABP. Neurokinin 1-receptor blockade (CP-96345, 400 nmol/kg) attenuated substance P-evoked increases in RAR activity (P = 0.001) and ABP (P = 0.009) but not in peak Ptr (P = 0.06). This chronic exposure to SS in young guinea pigs exaggerates RAR responsiveness to substance P. The findings may help explain the increased incidence of airway hyperresponsiveness and cough in children chronically exposed to environmental tobacco smoke.
The focus of this review is work that supports a model of the medullary neuronal network that is involved in producing the cough motor pattern of inspiratory and expiratory pump muscles. Evidence is presented that supports the following hypotheses: (1) Bulbospinal drive to respiratory motoneurons during cough arises, at least in part, from the same medullary neurons involved in providing drive during eupnoea. (2) Medullary Bötzinger/ rostral ventral respiratory group neurons implicated in generating and shaping the eupnoeic pattern of breathing are also involved in producing the central cough motor pattern. The results were not consistent with a "cough centre" separate from the BOT/VRG. Observed neurons (in cats) included most of all previously identified respiratory modulated "types". The results showed that there were alterations in discharge patterns of all respiratory neurons during fictive cough. Many "types" responded as predicted by cough model network simulations. Based on neuron behaviours in our studies and inferred synaptic actions among BOT/VRG neurons, we propose a preliminary model for cough generation by the BOT/rVRG network.
Area postrema (AP) modulates cardiovascular function through excitatory projections to neurons in nucleus tractus solitarius (NTS), which also process primary sensory (including cardiovascular-related) input via the solitary tract (TS). The neurotransmitter(s) and their receptors in the AP-NTS pathway have not been fully characterized. We used whole cell recordings in voltage- and current-clamp modes in the rat brain stem slice to examine the role of ionotropic glutamatergic receptors and alpha2-adrenergic receptors in the pathway from AP to NTS neurons receiving visceral afferent information via the TS. In neurons voltage clamped at potentials from -100 to +80 mV, AP stimulation (0. 2 Hz) evoked excitatory postsynaptic currents having a fast component blocked by the non-N-methyl-D-aspartate (NMDA) receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2, 3-dioxobenzoquinoxaline-7-sulfonamide (NBQX; 3 microM, n = 7) and a slow component blocked by the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV; 50 microM, n = 8). Although NBQX (3 microM, n = 14) abolished AP-evoked action potentials, APV (50 microM, n = 9 or 500 microM, n = 6) or yohimbine, (200 nM, n = 5 or 2 microM, n = 10) did not. Thus, although AP stimulation activates both non-NMDA and NMDA receptors on NTS neurons receiving TS input, only non-NMDA receptors are required for synaptic transmission.
This study investigates the influence of allergic inflammation in airway sensory innervation. We conclude that allergic inflammation in the guinea pig leads to both an increase in excitability, as manifested by an increase in the mechanical sensitivity of the airway nerve endings, and an induction of substance P production in airway sensory neurons. The data are consistent with the hypothesis that the induction of substance P occurs in fast conducting nodose sensory neurons that were previously devoid of this neuropeptide. Thus, allergen challenge is associated with a phenotypic change in the airway tachykinergic innervation. We also provide evidence that nerve growth factor is a potentially important mediator for these effects, and that it is elevated in the bronchoalveolar lavage of asthmatic subjects.
Substance P (SP) modulates the activity of taste-responsive neurons in the gustatory zone of the nucleus of the solitary tract (NST) in the hamster. The distribution of the neurokinin-1 (NK1) receptor (i.e. the SP receptor) was mapped and compared with the distribution of SP immunoreactivity to identify the sites of ligand-receptor interactions. NK1-immunoreactive puncta and somata were located mostly in the rostral lateral, upper half of the rostral central and medial NST subnuclei. These subnuclei also contained intense SP-immunoreactive puncta, and are known to receive substantial inputs via gustatory and somatosensory afferent fibers. The ventral subnucleus, which is involved in visceromotor reflexes accompanying ingestion, contained little NK1 or lighter SP-immunoreactivity. These findings suggest that SP modulates taste activity destined for the ascending gustatory pathway at the level of the first central synapse in the gustatory pathway.
Children chronically exposed to environmental tobacco smoke (ETS) have more coughs, wheezes, and airway obstruction, which may result in part from stimulation of lung C fibers. We examined the effect of chronic exposure to sidestream tobacco smoke (SS, a surrogate for ETS) on lung C-fiber responsiveness in guinea pigs, in which dynamic compliance (Cdyn), lung resistance, tracheal pressure, arterial blood pressure, and heart rate were also monitored. Guinea pigs were exposed to SS (1 mg/mm(3) total suspended particulates) or filtered air 5 days/wk from 1 to 6 wk of age. They were then anesthetized, and lung C fibers (n = 55), identified by a conduction velocity of <2.0 m/s, were tested for responsiveness to chemical and mechanical stimuli. SS exposure doubled C-fiber responsiveness to left atrial capsaicin (P = 0.02) and lung hyperinflation (P = 0.03) but had no effect on responsiveness to inhaled capsaicin or bradykinin or on baseline activity. The data indicate that chronically exposing young guinea pigs to SS enhances C-fiber sensitivity to certain stimuli and may help explain respiratory symptoms in children exposed to ETS.
Extracellular field potential (FP) recording of dendritic depolarizations evoked by afferent stimulation is widely used as a quantitative measure of excitatory synaptic transmission in brain slices in-vitro for structures with high neuronal density and regularity such as hippocampus, neocortex and cerebellum. On the other hand, FP recordings of somatic depolarizations induced by orthodromic or antidromic stimulation of afferent or efferent nerves have been used in some in-vivo preparations for mapping the central projections of these nerves. In this study, we examined the applicability of somatic FPs as a measure of excitatory synaptic transmission in a sparse and irregular brain structure. Excitatory FPs were induced in nucleus tractus solitarius (NTS) in the dorsal medulla by electrical impulse stimulation of primary afferent fibers in the tractus solitarius (TS) in rat brainstem slices in vitro. The evoked FP was rapid and biphasic, and was stimulus-intensity dependent and saturable. The morphology of these somatic FPs resembled the dendritic FPs found in hippocampal and neocortical slices, with an excitatory postsynaptic component that exhibited similar pharmacological and stimulus frequency-dependent properties as found in NTS cells with intracellular or whole-cell recordings. Simultaneous FP and whole-cell recordings revealed that the postsynaptic component of FP was associated with neuronal firing rather than subthreshold membrane depolarizations. We conclude that somatic FP recording provides a simple and reliable measure of excitatory neurotransmission in the TS-NTS pathway and is a useful alternative or adjunct to intracellular or whole-cell recordings especially for studies of long-term synaptic plasticity in spiking neurons. This technique may also be applicable to other brain regions that lack the regular and dense organization of hippocampal and neocortical structures.
Many children are exposed to smoking both prenatally and postnatally. Prenatal exposure to mainstream smoke from the mother and even to environmental tobacco smoke (ETS) from the mother in utero has been shown to change fetal lung development and cause airflow obstruction and airway hyperresponsiveness. Children exposed to ETS postnatally have more symptoms of cough, wheeze, respiratory illnesses, decreases in lung function, and increases in airway responsiveness. Smoke exposure is associated with the early development of asthma, increased severity of asthma, and the development of allergy. Finally smoke exposure is associated with sudden infant death and airway obstruction. This article reviews the spectrum of effects of cigarette smoke exposure on the respiratory health of infants and children and highlights basic science research exploring the mechanisms of these effects.
Intravenous phenylephrine (PE) activates neurons in the nucleus of the solitary tract (NTS) whose distribution conforms to those of central projections of the carotid sinus and aortic depressor nerves. This was exploited to permit fine structural characterization of cells presumed to compose the first station in the processing of arterial baroreceptor input, and their responses to stimulation. Rats were perfused at varying intervals after PE injection, and sections through the baroreceptor afferent zone of the NTS prepared for preembedding immunolocalization of Fos-immunoreactivity. Labeled neurons composed a continuous strip extending from the dorsal part of the commissural NTS (NTScom) to the dorsal subnucleus at the level of the area postrema (NTSap). PE-sensitive neurons in these regions were medium-sized, round to ovoid in shape, with scant cytoplasm and an unremarkable complement of organelles. Distinctive features included extensively invaginated nuclei and well-developed Golgi apparati; Fos-ir cells in the NTSap were distinguished from those in NTScom by virtue of better-developed rough endoplasmic reticulum and Golgi, and less convoluted nuclei. Proximal synaptic input to PE-sensitive neurons was sparse and was provided by terminals containing predominantly small, clear synaptic vesicles that formed mainly symmetric junctions with somata and primary dendrites. Prolonged stimulation was accompanied by accentuation of nuclear invaginations, marked accumulation of heterochromatin at their apices, and evidence of enhanced Golgi activity (vesicular budding). These may represent adaptations to facilitate changes in gene expression, to maintain neurotransmitter availability, or both, in the face of a persistent hypertensive challenge.
This review describes results from in vivo experiments on brain stem network mechanisms that control breathing. Multi-array recording technology and computational methods were used to test predictions derived from simulations of respiratory network models. This highly efficient approach has the advantage that many simultaneously recorded neurons are subject to shared stimulus, history, and state-dependent conditions. Our results have provided evidence for concurrent or parallel network interactions in the generation and modulation of the respiratory motor pattern. Recent data suggest that baroreceptors, chemoreceptors, nociceptors, and airway cough receptors shape the respiratory motor pattern, at least in part, through a system of shared coordinated 'multifunctional' neurons distributed in the brain stem. The 'gravity method' for the analysis and representation of multi-neuron data has demonstrated respiratory phase-dependent impulse synchrony among neurons with no respiratory modulation of their individual firing rates. The detection of this emergent property motivated the development of pattern detection methods that subsequently identified repeated transient configurations of these 'correlational assemblies'. These results support the view that information can be 'coded' in the nervous system by spike timing relationships, in addition to firing rate changes that traditionally have been measured by neurophysiologists.
Bronchopulmonary C fibers defend the lungs against injury from inhaled agents by a central nervous system reflex consisting of apnea, cough, bronchoconstriction, hypotension, and bradycardia. Glutamate is the putative neurotransmitter at the first central synapses in the nucleus of the solitary tract (NTS), but substance P, also released in the NTS, may modulate the transmission. To test the hypothesis that substance P in the NTS augments bronchopulmonary C fiber input and hence reflex output, we stimulated the C fibers with left atrial capsaicin (LA CAP) injections and compared the changes in phrenic nerve discharge, tracheal pressure (TP), arterial blood pressure (ABP), and heart rate (HR) in guinea pigs before and after substance P injections (200 microM, 25 nl) in the NTS. Substance P significantly augmented LA CAP-evoked increases in expiratory time by 10-fold and increases in TP and decreases in ABP and HR by threefold, effects prevented by neurokinin-1 (NK1) receptor antagonism. Thus substance P acting at NTS NK1 receptors can exaggerate bronchopulmonary C fiber reflex output. Because substance P synthesis in vagal airway C fibers may be enhanced in pathological conditions such as allergic asthma, the findings may help explain some of the associated respiratory symptoms including cough and bronchoconstriction.
The activation of primary afferent neurons that innervate the airways leads to homeostatic and defensive reflexes. The anatomic and physiologic characteristics of these afferent fibers do not appear to be static properties but rather appear to change rapidly in response to inflammation. The threshold for activation of airway afferent neurons to various stimuli, for example, is not fixed; these fibers can be become sensitized during inflammation. A subset of nociceptive-like (C-fibers) airway afferent neurons not only participates in centrally mediated reflexes but is also thought to release neuropeptides at their peripheral terminals, leading to neurogenic inflammation. An increase in the content of tachykinins is commonly seen in inflamed tissues, and there is accumulating evidence that irritation and inflammation of the airways is associated with the induction of tachykinin synthesis in non-nociceptive airway afferent fibers that under normal conditions do not contain neuropeptides. The release of neurokinins from the peripheral terminals in the airways and their central terminals in the brain stem may contribute to the symptoms of inflammatory airway diseases. Elevated release of neurokinins from peripheral terminals may promote local inflammatory responses, and the release of neurokinins in the brainstem, together with inflammation-induced increases in the excitability of afferent fibers, may culminate in altered visceral autonomic reflex activity, changes in breathing pattern, and cough.
Extended exposure to allergen exacerbates asthma symptoms, in part via complex interactions between inflammatory cells and mediators. One consequence of these interactions is the triggering of local and central nervous system (CNS) neuronal activity that might further exacerbate the asthma-like symptoms by causing bronchoconstriction, mucous secretion, increased microvascular leak, and cough. One CNS region that might be particularly important is the caudomedial nucleus tractus solitarius (NTS). NTS neurons not only integrate primary afferent inputs from lung sensory nerve fibers but also have direct exposure to inhaled allergens and allergen-induced blood-borne inflammatory mediators via a deficient blood-brain barrier. Given the capacity of CNS neurons to undergo plasticity, allergen-induced changes in NTS neuronal properties could contribute to the exaggerated respiratory responses to extended allergen exposure.
In a recently developed rhesus monkey model of allergic asthma, we tested the hypothesis that extended exposure to allergen increases the intrinsic excitability of NTS neurons.
Three adult monkeys were sensitized and then repeatedly exposed to aerosols of house dust mite allergen; 4 monkeys served as controls. Whole-cell current-clamp recordings were made to measure 3 indices of excitability: resting membrane potential, input resistance, and number of action potentials evoked by current injections.
Extended allergen exposure depolarized the resting membrane potential by 14% and increased the number of action potentials evoked by current injections (5-fold).
The finding that NTS neurons in a primate model of allergic asthma undergo intrinsic increases in excitability suggests that CNS mechanisms might contribute to the exaggerated symptoms in asthmatic individuals exposed to allergen.
Painful stimuli can evoke dramatic responses in the cardiovascular and respiratory systems. We have assessed the role of both the sympathetic and parasympathetic nervous system in mediating the reflex tachycardia that accompanies somatic nociception. We describe a major role for the nucleus tractus solitarii (NTS) as a site for integrating nociceptive and cardiorespiratory afferents. Since cardiorespiratory and nociceptive afferents terminate in the NTS, this nucleus offers a powerful opportunity for central modulation. We show that the NTS plays a major role in mediating the reflex tachycardia evoked by somatic noxious stimulation. Similar noxious stimulation attenuates the cardiac component of the peripheral chemoreceptor reflex and inhibits the peripheral chemoreceptor-evoked excitatory synaptic response of some NTS neurones. The functional interpretation we propose is that by depressing homeostatic reflexes at the NTS, noxious stimulation-evoked cardiorespiratory changes can be expressed and maintained, which may be essential for the survival of the animal.
In the vagal-sensory system, neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) are synthesized nearly exclusively in small-diameter nociceptive type C-fiber neurons. By definition, these neurons are designed to respond to noxious or tissue-damaging stimuli. A common feature of visceral inflammation is the elevation in production of sensory neuropeptides. Little is known, however, about the physiological characteristics of vagal sensory neurons induced by inflammation to produce substance P. In the present study, we show that allergic inflammation of guinea pig airways leads to the induction of substance P and CGRP production in large-diameter vagal sensory neurons. Electrophysiological and anatomical evidence reveals that the peripheral terminals of these neurons are low-threshold Adelta mechanosensors that are insensitive to nociceptive stimuli such as capsaicin and bradykinin. Thus inflammation causes a qualitative change in chemical coding of vagal primary afferent neurons. The results support the hypothesis that during an inflammatory reaction, sensory neuropeptide release from primary afferent nerve endings in the periphery and central nervous system does not require noxious or nociceptive stimuli but may also occur simply as a result of stimulation of low-threshold mechanosensors. This may contribute to the heightened reflex physiology and pain that often accompany inflammatory diseases.
Recent studies evaluating the effects of pulmonary afferents, chemoreceptors, and antitussive drugs on the cough motor pattern indicate that this reflex is regulated in a different manner than breathing. Furthermore, regulatory differences exist between tracheobronchial and laryngeal cough. We propose a functional model of the brainstem elements participating in the production of cough that accounts for these regulatory differences. The model incorporates known brainstem interneuronal pathways as well as novel regulatory elements for tracheobronchial and laryngeal cough. Each of these novel regulatory elements controls the excitability of a common motor pattern generation network. Given that cough and breathing are associated with profoundly different spatiotemporal alterations in motor drive to respiratory motoneurons, brainstem elements common to the generation of both behaviours must be capable of a high degree of plasticity.
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.
Hypothalamic nuclei, particularly the paraventricular nuclei (PVN), are important brain sites responsible for eliciting stress responses following a systemic immune challenge. The activation of PVN cells by a systemic immune challenge is critically dependent on the integrity of inputs from brainstem cells situated in the nucleus tractus solitarius (NTS) and ventrolateral medulla (VLM). Interestingly, a descending pathway from the PVN to the brainstem, recruited by systemic immune challenge, might also exist. It is well documented that PVN neurons innervate the NTS and VLM and recent evidence from our laboratory shows that lesions of the PVN reduce brainstem cell responses elicited by a systemic bolus of the proinflammatory cytokine interleukin-1beta (IL-1beta). Although a number of different PVN divisions are candidates for the source of inputs to the brainstem, we have demonstrated that the majority of descending PVN projections recruited by systemic IL-1beta arise from cell bodies localized in the medial and lateral parvocellular PVN. These findings suggest that central nervous system responses to an immune challenge are likely to involve complex reciprocal connections between the PVN and the brainstem, whereby brainstem cell populations could essentially act as integratory sites for descending and ascending immune signals. For instance, these brainstem pathways may have significant implications not only for the regulation of central hypothalamic and extra-hypothalamic targets but also the autonomic nervous system.
The interstitial nucleus of the posterior limb of the anterior commissure (IPAC) receives inputs from several autonomic/limbic regions in the forebrain, including the agranular insular cortex, bed nucleus of the stria terminalis, the amygdaloid complex, and the lateral hypothalamic area. We sought to identify the distribution of afferent sources to the IPAC and to determine whether these IPAC projection fibers issue collaterals to the nucleus of the solitary tract (NTS), the principal relay of primary visceral afferents. Two fluorescent tracers, FluoroGold and FluoroRed, were centered stereotaxically on the IPAC and the NTS on chloral hydrate-anesthetized Sprague-Dawley rats. Although the majority of IPAC and NTS afferents were spatially segregated, small but substantial numbers of dually labeled neurons (three to four cells/section) were observed in the dorsal bank of the posterior agranular insular cortex, exclusively in layer V. Collateral projection neurons were also found in the posterior part of the lateral hypothalamic area (two to six cells/section). The branching projections identified here may represent a potential link between affective or motivated behavior and viscerosensory processing.
Xu-Friedman, Matthew A., and Wade G. Regehr. Structural Contributions to Short-Term Synaptic Plasticity. Physiol Rev 84: 69–85, 2004; 10.1152/physrev.00016.2003.—Synaptic ultrastructure is critical to many basic hypotheses about synaptic transmission. Various aspects of synaptic ultrastructure have also been implicated in the mechanisms of short-term plasticity. These forms of plasticity can greatly affect synaptic strength during ongoing activity. We review the evidence for how synaptic ultrastructure may contribute to facilitation, depletion, saturation, and desensitization.
Memory is central to many aspects of behaviour, but in spite of a long interest in its neural basis, empirical evidence of the nature of the hypothetical pathway that is left in the vertebrate central nervous system by learning has been elusive. An important impediment has been the difficulty of localizing a brain region in which information is stored, but this difficulty has largely been overcome in the case of the learning process of visual imprinting. Most theories of memory suppose that an experience or event leads to the formation or strengthening of particular pathways in the brain. The evidence that is derived from imprinting partly supports this view, but the processes involved are more complex and more interesting than has been supposed.
Environmental contaminants within the polycyclic aromatic hydrocarbon (PAH) and halogenated aromatic hydrocarbon class have been shown to cross the placenta exposing the fetus to the contaminant body burden of the mother. Consequently, a gestational exposure to environmental contaminants may result in increased adverse health outcomes, possibly affecting cognitive performance. Benzo(a)pyrene [B(a)P] and 2,3,7,8, tetrachlorodibenzo-p-dioxin (TCDD) are two prototypical environmental contaminants. A systematic review of the literature suggests that there may be a relationship between vulnerability in susceptible populations and health disparities. The purpose of this mini-review is to provide a point of reference for neurotoxicological studies of environmental contaminant mixture effects on indices of development in general, and on neurodevelopment in particular. Environmental contaminant-mixture-induced decrements in (1) birth index, (2) N-methyl-D-aspartate receptor (NMDA) mRNA expression, (3) long-term potentiation (LTP), (4) fixed-ratio performance learning behavior, and (5) experience-dependent activity related cytoskeletal-associated protein (Arc) mRNA and protein expression collectively support associations between neurobehavioral deficits and gestational exposure to environmental levels of these contaminants. Collectively, data are presented in this mini-review evaluating the effect of gestational exposure to environmental contaminant-mixtures on specific indices of learning and memory, including hippocampal-based synaptic plasticity mechanisms. These indices serve as templates for learning and memory, and as such, from a vulnerability perspective, may serve as targets for dysregulation during development in susceptible populations that have been disproportionately exposed to these contaminants. Included in this review is also a discussion of the relevance of developing biomarkers for use within the framework of cumulative risk-assessment.
Twenty-five years ago, very little was known about chemical communication in the afferent limb of the baroreceptor reflex arc. Subsequently, considerable anatomic and functional data exist to support a role for the tachykinin, substance P (SP), as a neuromodulator or neurotransmitter in baroreceptor afferent neurons. Substance P is synthesized and released from baroreceptor afferent neurons, and excitatory SP (NK1) receptors are activated by baroreceptive input to second-order neurons. SP appears to play a role in modulating the gain of the baroreceptor reflex. However, questions remain about the specific role and significance of SP in mediating baroreceptor information to the central nervous system (CNS), the nature of its interaction with glutaminergic transmission, the relevance of colocalized agents, and complex effects that may result from mediation of non-baroreceptive signals to the CNS.
Ionotropic glutamate receptors (iGluRs) are postsynaptic ion channels involved in excitatory neurotransmission. iGluRs play important roles in development and in forms of synaptic plasticity that underlie higher order processes such as learning and memory. Neurobiological and biochemical studies have long characterized iGluRs in detail. However, the structural basis for the function of iGluRs has not yet been investigated, because there is insufficient information about their three-dimensional structures. In 1998, a crystal structure called S1S2 lobes was first solved for the extracellular bilobed ligand-binding domain of the GluR2 subunit. Since then, the crystal structures for the S1S2 lobes both in the apo and in various liganded states have been reported, and recent biophysical studies have further elucidated the dynamic aspects of the structure of the S1S2 lobes. In this review, the dynamic structures of the S1S2 lobes and their ligands are summarized, and the importance of their structural flexibility and fluctuation is discussed in light of the mechanisms of ligand recognition, activation, and desensitization of the receptor.
It is generally believed that spatio-temporal configurations of distributed activity in the brain contribute to the coding of neuronal information and that synaptic contacts between nerve cells could play a central role in the formation of privileged pathways of activity. Synaptic plasticity is not the only mode of regulation of information processing in the brain and persistent regulations of ionic conductances in some specialized neuronal areas such as the dendrites, the cell body and the axon could also modulate, in the short- and the long-term, the propagation of information in the brain. Persistent changes in intrinsic excitability have been reported in several brain areas in which activity is modified during a classical conditioning. The role of synaptic activity seems to be determinant in the induction but the learning rules and the underlying mechanisms remain to be defined. This review discusses the role of neuronal activity in the induction of intrinsic plasticity in cortical, hippocampal and cerebellar neurons. Activation and inactivation properties of ionic channels in the axon determine the short-term dynamics of axonal propagation and synaptic transmission. Activation of glutamate receptors initiates a long-term modification in neuronal excitability that may represent the substrate for the mnesic engram and for the stabilization of the epileptic state. Similarly to synaptic plasticity, long-lasting intrinsic plasticity appears to be reversible and to express a certain level of input or cellular specificity. These non-synaptic forms of plasticity affect the signal propagation in the axon, the dendrites and the soma. They not only share common learning rules and induction pathways with the better known synaptic plasticity such as NMDA receptor-dependent LTP and LTD but also contribute in synergy with these synaptic changes to the formation of a coherent mnesic engram.