Activation Of Airway Sensory Nerves Research Articles

Decoding the role of genetically-distinct sensory nerves in controlling cardiopulmonary reflexes

Activation of airway sensory nerves causes respiratory and autonomic reflexes. The majority of the airway sensory afferents are only sensitive to noxious stimuli, such as inflammation, irritants, and pollutants. Activation of these nociceptive afferents evokes protective mechanisms such as apnea, cough, and bradycardia. These reflexes may contribute to disease morbidity when excessively activated. Airway nociceptors, largely projecting from the vagal ganglia (nodose and jugular ganglion), are heterogeneous with respect to gene expression and neuroanatomy, and our objective is to characterize the reflexes evoked by activation of specific afferent subsets using chemogenetics. To selectively activate vagal afferent subpopulations in vivo, mice were exposed to nebulized selective stimuli such as capsaicin (transient receptor potential (TRP) vanilloid 1 (V1) agonist), allyl isothiocyanate (AITC, TRP ankyrin 1 (A1) agonist), and clozapine-N-oxide (CNO, selective agonist for the designer receptor exclusively activated by designer drug (DREADD) stimulatory receptor hM3Dq). hM3Dq expression by ROSA26-loxP-STOP-loxP mice was selectively expressed in sensory subpopulations by breeding with Cre recombinase-expressing mice: TRPV1 (all nociceptors), Tac1-Cre (peptidergic/jugular-originating nerves), and P2X2-Cre (nodose-originating nerves). An intersectional approach using TRPV1-flp mice and the above Cre mice combined with bilateral vagal injections of an AAV delivering dual recombinase-dependent DREADD constructs was used to express hM3Dq in afferent populations defined by two genes (e.g. TRPV1+ and P2X2+). ECGS were recorded via radiotelemetry, and respiration was measured via whole-body plethysmography. CNO administration in TRPV1-hM3Dq mice, P2X2-hM3Dq mice, and Tac1-hM3Dq mice evoked bradypnea and bradycardia. When CNO was administered in the dual recombinase-dependent ConFon (Cre-On/Flp-On) Tac1-Cre/TRPV1-Flp mouse (selectively activating the vagal jugular nociceptors), a significant bradypnea was evoked; however, when CNO was administered in the dual recombinase-dependent ConFon P2X2-Cre/TRPV1-Flp mouse (selectively activating the nodose nociceptors), no bradypnea was observed. Our preliminary data suggest that functionally-distinct nociceptive subpopulations differentially regulate the cardiopulmonary reflexes. NIH R01: 152219, NIH T32: HL160529. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Activation of select airway afferent subpopulations evokes cardiopulmonary reflexes

Activation of airway sensory nerves causes respiratory and autonomic reflexes. The majority of the sensory nerves are only sensitive to noxious stimuli, such as inflammation, infection, irritants and pollutants. Activation of these nociceptive sensory nerves evokes protective mechanisms such as apnea, cough and bradycardia that can contribute to disease morbidity. Airway nociceptive sensory nerves are heterogeneous with respect to gene expression and neuroanatomy, and our objective is to characterize the specific reflexes evoked by activation of specific afferent subsets. To selectively activate these vagal afferent subpopulations in vivo, mice were exposed to nebulized selective stimuli such as capsaicin (transient receptor potential (TRP) vanillin 1 (V1) agonist), allyl isothiocyanate (AITC, TRP ankyrin 1 (A1) agonist) and clozapine‐N‐oxide (CNO, selective agonist for the designer receptors exclusively activated by designer drugs (DREADD) stimulatory receptor hM3Dq). hM3Dq expression was selectively expressed in sensory subpopulations under the control of cre recombinase in TRPV1‐cre (all nociceptors) and Tac1‐cre (peptidergic nerves). ECGs were recorded via radiotelemetry following implantation of biopotential sensing modules, and respiration was measured via whole body plethysmography. Our data indicate that stimulation of nociceptive subpopulations selectively evokes bradypnea and bradycardia in freely moving wild type mice.

Chapter 11 - Dyspnea

The clinical term dyspnea (a.k.a. breathlessness or shortness of breath) encompasses at least three qualitatively distinct sensations that warn of threats to breathing: air hunger, effort to breathe, and chest tightness. Air hunger is a primal homeostatic warning signal of insufficient alveolar ventilation that can produce fear and anxiety and severely impacts the lives of patients with cardiopulmonary, neuromuscular, psychological, and end-stage disease. The sense of effort to breathe informs of increased respiratory muscle activity and warns of potential impediments to breathing. Most frequently associated with bronchoconstriction, chest tightness may warn of airway inflammation and constriction through activation of airway sensory nerves. This chapter reviews human and functional brain imaging studies with comparison to pertinent neurorespiratory studies in animals to propose the interoceptive networks underlying each sensation. The neural origins of their distinct sensory and affective dimensions are discussed, and areas for future research are proposed. Despite dyspnea's clinical prevalence and impact, management of dyspnea languishes decades behind the treatment of pain. The neurophysiological bases of current therapeutic approaches are reviewed; however, a better understanding of the neural mechanisms of dyspnea may lead to development of novel therapies and improved patient care.

Characterization of cardiovascular reflexes evoked by airway stimulation with allylisothiocyanate, capsaicin, and ATP in Sprague-Dawley rats.

Acute inhalation of airborne pollutants alters cardiovascular function and evidence suggests that pollutant-induced activation of airway sensory nerves via the gating of ion channels is critical to these systemic responses. Here, we have investigated the effect of capsaicin [transient receptor potential (TRP) vanilloid 1 (TRPV1) agonist], AITC [TRP ankyrin 1 (TRPA1) agonist], and ATP (P2X2/3 agonist) on bronchopulmonary sensory activity and cardiovascular responses of conscious Sprague-Dawley (SD) rats. Single fiber recordings show that allyl isothiocyanate (AITC) and capsaicin selectively activate C fibers, whereas subpopulations of both A and C fibers are activated by stimulation of P2X2/3 receptors. Inhalation of the agonists by conscious rats caused significant bradycardia, atrioventricular (AV) block, and prolonged PR intervals, although ATP-induced responses were lesser than those evoked by AITC or capsaicin. Responses to AITC were inhibited by the TRP channel blocker ruthenium red and the muscarinic antagonist atropine. AITC inhalation also caused a biphasic blood pressure response: a brief hypertensive phase followed by a hypotensive phase. Atropine accentuated the hypertensive phase, while preventing the hypotension. AITC-evoked bradycardia was not abolished by terazosin, the α1-adrenoceptor inhibitor, which prevented the hypertensive response. Anesthetics had profound effects on AITC-evoked bradycardia and AV block, which was abolished by urethane, ketamine, and isoflurane. Nevertheless, AITC inhalation caused bradycardia and AV block in paralyzed and ventilated rats following precollicular decerebration. In conclusion, we provide evidence that activation of ion channels expressed on nociceptive airway sensory nerves causes significant cardiovascular effects in conscious SD rats via reflex modulation of the autonomic nervous system.

Targeting TRP channels for chronic cough: from bench to bedside.

Cough is currently the most common reason for patients to visit a primary care physician in the UK, yet it remains an unmet medical need. Current therapies have limited efficacy or have potentially dangerous side effects. Under normal circumstances, cough is a protective reflex to clear the lungs of harmful particles; however, in disease, cough can become excessive, dramatically impacting patients' lives. In many cases, this condition is linked to inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD), but can also be refractory to treatment and idiopathic in nature. Therefore, there is an urgent need to develop therapies, and targeting the sensory afferent arm of the reflex which initiates the cough reflex may uncover novel therapeutic targets. The cough reflex is initiated following activation of ion channels present on vagal sensory afferents. These ion channels include the transient receptor potential (TRP) family of cation-selective ion channels which act as cellular sensors and respond to changes in the external environment. Many direct activators of TRP channels, including arachidonic acid derivatives, a lowered airway pH, changes in temperature, and altered airway osmolarity are present in the diseased airway where responses to challenge agents which activate airway sensory nerve activity are known to be enhanced. Furthermore, the expression of some TRP channels is increased in airway disease. Together, this makes them promising targets for the treatment of chronic cough. This review will cover the current understanding of the role of the TRP family of ion channels in the activation of airway sensory nerves and cough, focusing on four members, transient receptor potential vanilloid (TRPV) 1, transient receptor potential ankyrin (TRPA) 1, TRPV4, and transient receptor potential melastatin (TRPM) 8 as these represent the channels where most information has been gathered with relevance to the airways. We will describe recent data and highlight the possible therapeutic utility of specific TRP channel antagonists as antitussives in the clinic.

Effect of Nociceptin in Acid-evoked Cough and Airway Sensory Nerve Activation in Guinea Pigs

Nociceptin/orphanin FQ has been reported to inhibit capsaicin- and mechanically provoked cough in animal models, but the mechanism of this effect has not been elucidated. The objectives of this study were to determine whether nociceptin inhibits acid-evoked cough in conscious animals and to evaluate the mechanism of this effect. We tested the effect of nociceptin on acid-induced cough in conscious guinea pigs and acid-induced nerve activation in airway-specific vagal sensory neurons using calcium imaging techniques and the gramicidin-perforated patch clamp technique. Nociceptin (3 mg/kg, intraperitoneal) effectively inhibited acid-evoked cough in guinea pigs by nearly 70%. Acid (pH 5) increased intracellular free calcium in acutely dissociated vagal jugular ganglionic neurons. The acid-induced increase in intracellular calcium was inhibited by a selective transient receptor potential vanilloid-1 antagonist, 5-iodo-resiniferatoxin (1 microM, approximately 80% reduction). The inhibitory effect of 5-iodo-resiniferatoxin on acid-induced increases in calcium was mimicked by nociceptin (0.1 microM). In gramicidin-perforated patch clamp recordings on airway-specific capsaicin-sensitive jugular ganglion neurons, acid (pH 5) induced two distinct inward currents. A transient current was evoked that was inhibited by amiloride and a sustained current was evoked that was inhibited by 5-iodo-resiniferatoxin. Nociceptin selectively inhibited only the sustained component of acid-induced inward current. These results indicate that the inhibitory effect of nociceptin on acid-induced cough may result from a direct inhibitory effect on peripheral C-fiber activity caused by the selective inhibition of acid-induced transient receptor potential vanilloid-1 activation.

Ionotropic and metabotropic receptor mediated airway sensory nerve activation

There are several receptors capable of inducing activating generator potentials in cough-associated afferent terminals in the airways. The chemical receptors leading to generator potentials can be subclassified into ionotropic and metabotropic types. An ionotropic receptor has an agonist-binding domain, and also serves directly as an ion channel that is opened upon binding of the agonist. Examples of ionotropic receptors found in airway sensory nerve terminals include receptors for serotonin (5-HT 3 receptors), ATP (P2X receptors), acetylcholine (nicotinic receptors), receptors for capsaicin and related vanilloids (TRPV1 receptors), and acid receptors (acid sensing ion channels). Afferent nerve terminals can also be depolarized via activation of metabotropic or G-protein coupled receptors (GPCRs). Among the GPCRs that can lead to activation of airway afferent fibers include bradykinin B 2 and adenosine A1 receptors. The signaling events leading to GPCR-mediated membrane depolarization are more complex than that seen with ionotropic receptors. The GPCR-mediated effects are thought to occur through classical second messenger systems such as activation of phospholipase C. This may lead to membrane depolarization through interaction with specific ionotropic receptors (such as TRPV1) and/or various types of calcium activated channels.

The human nasal response to capsaicin

Airway sensory nerves play a role in reactions to inhaled allergens, irritants, and physical stimuli. Capsaicin, the pungent principle of hot peppers, stimulates a subcategory of sensory nerves. To study the consequences of selective activation of airway sensory nerves in the human nose, we administered capsaicin nasal challenges to eight volunteers (four normal subjects and four subjects with perennial allergic rhinitis). Capsaicin (20 μmol/L), when sprayed into the nose, induced burning, rhinorrhea, and lacrimation. Capsaicin also induced a significant increase in total protein content of nasal lavage fluid after challenge compared with vehicle (increase from before challenge to 1 minute after challenge, 172 ± 55 vs 46 ± 29 μg/ml, p < 0.001). In contrast to many animal studies, capsaicin did not increase vascular permeability in the airway, because albumin content of nasal lavage fluid was not increased (p = 0.86). On the other hand, lactoferrin, a marker of glandular secretion, was increased (p < 0.005). Repetitive capsaicin challenge every 10 minutes led to tachyphylaxis of symptoms, total protein secretion, and lactoferrin secretion. Compared with vehicle, unilateral capsaicin (6 mmol/L) disk challenge induced significant secretion both ipsilateral (21.3 ± 4.2 vs 4.9 ± 2.1 mg, p < 0.01) and contralateral (18.2 ± 4.4 vs 7.4 ± 1.9 mg, p < 0.04) to challenge. Thus we have shown that capsaicin challenge to the human nose leads to airway sensory nerve activation. Further, we have demonstrated that capsaicin stimulates a predominantly central neuronal response and that the induced secretory response is of glandular rather than vascular origin. (J ALLERGY CLIN IMMUNOL 1994;94:1035-45.)

Inhibition of low pH evoked activation of airway sensory nerves by capsazepine, a novel capsaicin-receptor antagonist

Low pH is a well known sensory irritant in pathological conditions such as inflammation. The mechanisms underlying this low pH effect were therefore studied in the guinea pig. Acid exposure caused marked nasal irritation via a specific subset of sensory nerves sensitive to capsaicin. Futhermore, acid caused bronchoconstriction via release of neuropeptides from capsaicin sensitive afferents. Interestingly, capsazepine, a recently developed competitive capsaicin receptor antagonist, selectively inhibited these responses to low pH. Ruthenium red, which blocks the cation channel associated with the capsaicin receptor, had effects similar to those of capsazepine. Therefore, acid irritation of the airway mucosa may involve capsaicin-receptor mechanisms and capsazepine represents a novel protective agent.