Suppression of the cough reflex by inhibition of ERK1/2 activation in the caudal nucleus tractus solitarii of the rabbit

2012 ◽  
Vol 302 (8) ◽  
pp. R976-R983 ◽  
Author(s):  
Donatella Mutolo ◽  
Fulvia Bongianni ◽  
Elenia Cinelli ◽  
Maria Grazia Giovannini ◽  
Tito Pantaleo
Keyword(s):  
Tracheobronchial Tree ◽  
Nucleus Tractus Solitarii ◽  
Cough Reflex ◽  
Central Processing ◽  
A Site ◽  
Short Time ◽  
Spontaneously Breathing ◽  
Antitussive Agents ◽  
Inactive Analog

The caudal nucleus tractus solitarii (cNTS), the predominant site of termination of cough-related afferents, has been shown to be a site of action of some centrally acting antitussive agents. A role of ERK1/2 has been suggested in acute central processing of nociceptive inputs. Because pain and cough share similar features, we investigated whether ERK1/2 activation could also be involved in the central transduction of tussive inputs. For this purpose, we undertook the present research on pentobarbital sodium-anesthetized, spontaneously breathing rabbits by using microinjections (30–50 nl) of an inhibitor of ERK1/2 activation (U0126) into the cNTS. Bilateral microinjections of 25 mM U0126 caused rapid and reversible reductions in the cough responses induced by both mechanical and chemical (citric acid) stimulation of the tracheobronchial tree. In particular, the cough number and peak abdominal activity decreased. Bilateral microinjections of 50 mM U0126 completely suppressed the cough reflex without affecting the Breuer-Hering inflation reflex, the pulmonary chemoreflex, and the sneeze reflex. These U0126-induced effects were, to a large extent, reversible. Bilateral microinjections of 50 mM U0124, the inactive analog of U0126, at the same cNTS sites had no effect. This is the first study that provides evidence that ERK1/2 activation within the cNTS is required for the mediation of cough reflex responses in the anesthetized rabbit. These results suggest a role for ERK1/2 in the observed effects via nontranscriptional mechanisms, given the short time involved. They also may provide hints for the development of novel antitussive strategies.

scholarly journals GABAA- and glycine-mediated inhibitory modulation of the cough reflex in the caudal nucleus tractus solitarii of the rabbit

2016 ◽  
Vol 311 (3) ◽  
pp. L570-L580 ◽  
Author(s):  
Elenia Cinelli ◽  
Ludovica Iovino ◽  
Fulvia Bongianni ◽  
Tito Pantaleo ◽  
Donatella Mutolo
Keyword(s):  
Tracheobronchial Tree ◽  
Second Order ◽  
Nucleus Tractus Solitarii ◽  
Glycine Receptors ◽  
Cough Reflex ◽  
C Fibers ◽  
Arterial Blood ◽  
Inhibitory Modulation ◽  
Spontaneously Breathing

Cough-related sensory inputs from rapidly adapting receptors (RARs) and C fibers are processed by second-order neurons mainly located in the caudal nucleus tractus solitarii (NTS). Both GABAA and glycine receptors have been proven to be involved in the inhibitory control of second-order cells receiving RAR projections. We investigated the role of these receptors within the caudal NTS in the modulation of the cough reflex induced by either mechanical or chemical stimulation of the tracheobronchial tree in pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Bilateral microinjections (30–50 nl) of the receptor antagonists bicuculline and strychnine as well as of the receptor agonists muscimol and glycine were performed. Bicuculline (0.1 mM) and strychnine (1 mM) caused decreases in peak abdominal activity and marked increases in respiratory frequency due to decreases in both inspiratory time (Ti) and expiratory time (Te), without concomitant changes in arterial blood pressure. Noticeably, these microinjections induced potentiation of the cough reflex consisting of increases in the cough number associated with decreases either in cough-related Ti after bicuculline or in both cough-related Ti and Te after strychnine. The effects caused by muscimol (0.1 mM) and glycine (10 mM) were in the opposite direction to those produced by the corresponding antagonists. The results show that both GABAA and glycine receptors within the caudal NTS mediate a potent inhibitory modulation of the pattern of breathing and cough reflex responses. They strongly suggest that disinhibition is one important mechanism underlying cough regulation and possibly provide new hints for novel effective antitussive strategies.

scholarly journals Inhibitory control of the cough reflex by galanin receptors in the caudal nucleus tractus solitarii of the rabbit

2014 ◽  
Vol 307 (11) ◽  
pp. R1358-R1367 ◽  
Author(s):  
Donatella Mutolo ◽  
Elenia Cinelli ◽  
Fulvia Bongianni ◽  
Tito Pantaleo
Keyword(s):  
Inhibitory Control ◽  
Tracheobronchial Tree ◽  
Nucleus Tractus Solitarii ◽  
Cycle Duration ◽  
Cough Reflex ◽  
Central Processing ◽  
Airway Mucosa ◽  
Galanin Receptors ◽  
Spontaneously Breathing ◽  
Stimulation Of

The caudal nucleus tractus solitarii (NTS) is the main central station of cough-related afferents and a strategic site for the modulation of the cough reflex. The similarities between the characteristics of central processing of nociceptive and cough-related inputs led us to hypothesize that galanin, a neuropeptide implicated in the control of pain, could also be involved in the regulation of the cough reflex at the level of the NTS, where galanin receptors have been found. We investigated the effects of galanin and galnon, a nonpeptide agonist at galanin receptors, on cough responses to mechanical and chemical (citric acid) stimulation of the tracheobronchial tree. Drugs were microinjected (30–50 nl) into the caudal NTS of pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Galnon antitussive effects on cough responses to the mechanical stimulation of the airway mucosa via a custom-built device were also investigated. Bilateral microinjections of 1 mM galanin markedly decreased cough number, peak abdominal activity, and increased cough-related total cycle duration. Bilateral microinjections of 1 mM galnon induced mild depressant effects on cough, whereas bilateral microinjections of 10 mM galnon caused marked antitussive effects consistent with those produced by galanin. Galnon effects were confirmed by using the cough-inducing device. The results indicate that galanin receptors play a role in the inhibitory control of the cough reflex at the level of the caudal NTS and provide hints for the development of novel antitussive strategies.

Modulation of the cough reflex by antitussive agents within the caudal aspect of the nucleus tractus solitarii in the rabbit

2008 ◽  
Vol 295 (1) ◽  
pp. R243-R251 ◽  
Author(s):  
Donatella Mutolo ◽  
Fulvia Bongianni ◽  
Elenia Cinelli ◽  
Giovanni A. Fontana ◽  
Tito Pantaleo
Keyword(s):  
Substance P ◽  
Receptor Antagonist ◽  
Nucleus Tractus Solitarii ◽  
Cycle Duration ◽  
Cough Reflex ◽  
Caudal Portion ◽  
Tracheal Pressure ◽  
Site Of Action ◽  
A Site ◽  
Antitussive Agents

We have previously shown that ionotropic glutamate receptors in the caudal portion of the nucleus tractus solitarii (NTS), especially in the commissural NTS, play a prominent role in the mediation of tracheobronchial cough and that substance P potentiates this reflex. This NTS region could be a site of action of some centrally acting antitussive agents and a component of a drug-sensitive gating mechanism of cough. To address these issues, we investigated changes in baseline respiratory activity and cough responses to tracheobronchial mechanical stimulation following microinjections (30–50 nl) of centrally acting antitussive drugs into the caudal NTS of pentobarbitone-anesthetized, spontaneously breathing rabbits. [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and baclofen decreased baseline respiratory frequency because of increases in the inspiratory time only at the higher concentration employed (5 mM and 1 mM, respectively). DAMGO (0.5 mM) and baclofen (0.1 mM) significantly decreased cough number, peak abdominal activity, peak tracheal pressure, and increased cough-related total cycle duration. At the higher concentrations, these agents suppressed the cough reflex. The effects of these two drugs were counteracted by specific antagonists (10 mM naloxone and 25 mM CGP-35348, respectively). The neurokinin-1 (NK1) receptor antagonist CP-99,994 (10 mM) abolished cough responses, whereas the NK2 receptor antagonist MEN 10376 (5 mM) had no effect. The results indicate that the caudal NTS is a site of action of some centrally acting drugs and a likely component of a neural system involved in cough regulation. A crucial role of substance P release in the mediation of reflex cough is also suggested.

Depression of cough reflex by microinjections of antitussive agents into caudal ventral respiratory group of the rabbit

2010 ◽  
Vol 109 (4) ◽  
pp. 1002-1010 ◽  
Author(s):  
Donatella Mutolo ◽  
Fulvia Bongianni ◽  
Elenia Cinelli ◽  
Tito Pantaleo
Keyword(s):  
Receptor Antagonist ◽  
Respiratory Activity ◽  
Neural Substrates ◽  
Cough Reflex ◽  
Ventral Respiratory Group ◽  
Tracheal Pressure ◽  
Site Of Action ◽  
A Site ◽  
Antitussive Agents ◽  
Antitussive Drugs

We have previously shown that the caudal nucleus tractus solitarii is a site of action of some antitussive drugs and that the caudal ventral respiratory group (cVRG) region has a crucial role in determining both the expiratory and inspiratory components of the cough motor pattern. These findings led us to suggest that the cVRG region, and possibly other neural substrates involved in cough regulation, may be sites of action of antitussive drugs. To address this issue, we investigated changes in baseline respiratory activity and cough responses to tracheobronchial mechanical stimulation following microinjections (30–50 nl) of some antitussive drugs into the cVRG of pentobarbital-anesthetized, spontaneously breathing rabbits. [d-Ala2, N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and baclofen at the lower concentrations (0.5 mM and 0.1 mM, respectively) decreased cough number, peak abdominal activity, and peak tracheal pressure and increased cough-related total cycle duration (Tt). At the higher concentrations (5 mM and 1 mM, respectively), both drugs abolished the cough reflex. DAMGO and baclofen also affected baseline respiratory activity. Both drugs reduced peak abdominal activity, while only DAMGO increased Tt, owing to increases in expiratory time. The neurokinin-1 (NK1) receptor antagonist CP-99,994 (10 mM) decreased cough number, peak abdominal activity, and peak tracheal pressure, without affecting baseline respiration. The NK2 receptor antagonist MEN 10376 (5 mM) had no effect. The results indicate that the cVRG is a site of action of some antitussive agents and support the hypothesis that several neural substrates involved in cough regulation may share this characteristic.

scholarly journals Hypersensitivity of Airway Reflexes Induced by Hydrogen Sulfide: Role of TRPA1 Receptors

2020 ◽  
Vol 21 (11) ◽  
pp. 3929
Author(s):  
Chi-Li Chung ◽  
You Shuei Lin ◽  
Nai-Ju Chan ◽  
Yueh-Yin Chen ◽  
Chun-Chun Hsu
Keyword(s):  
Hydrogen Sulfide ◽  
Enhancement Effect ◽  
Sodium Hydrosulfide ◽  
Cough Reflex ◽  
Functional Changes ◽  
Intracerebroventricular Infusion ◽  
Airway Reflex ◽  
Airway Hypersensitivity ◽  
Spontaneously Breathing

The activation of capsaicin-sensitive lung vagal (CSLV) afferents can elicit airway reflexes. Hypersensitivity of these afferents is known to contribute to the airway hypersensitivity during airway inflammation. Hydrogen sulfide (H2S) has been suggested as a potential therapeutic agent for airway hypersensitivity diseases, such as asthma, because of its relaxing effect on airway smooth muscle and anti-inflammatory effect. However, it is still unknown whether H2S affects airway reflexes. Our previous study demonstrated that exogenous application of H2S sensitized CSLV afferents and enhanced Ca2+ transients in CSLV neurons. The present study aimed to determine whether the H2S-induced sensitization leads to functional changes in airway reflexes and elevates the electrical excitability of the CSLV neurons. Our results showed that, first and foremost, in anesthetized, spontaneously breathing rats, the inhalation of aerosolized sodium hydrosulfide (NaHS, a donor of H2S; 5 mg/mL, 3 min) caused an enhancement in apneic response evoked by several stimulants of the CSLV afferents. This enhancement effect was found 5 min after NaHS inhalation and returned to control 30 min later. However, NaHS no longer enhanced the apneic response after perineural capsaicin treatment on both cervical vagi that blocked the conduction of CSLV fibers. Furthermore, the enhancing effect of NaHS on apneic response was totally abolished by pretreatment with intravenous HC-030031 (a TRPA1 antagonist; 8 mg/kg), whereas the potentiating effect was not affected by the pretreatment with the vehicle of HC-030031. We also found that intracerebroventricular infusion pretreated with HC-030031 failed to alter the potentiating effect of NaHS on the apneic response. Besides, the cough reflex elicited by capsaicin aerosol was enhanced by inhalation of NaHS in conscious guinea pigs. Nevertheless, this effect was entirely eliminated by pretreatment with HC-030031, not by its vehicle. Last but not least, voltage-clamp electrophysiological analysis of isolated rat CSLV neurons showed a similar pattern of potentiating effects of NaHS on capsaicin-induced inward current, and the involvement of TRPA1 receptors was also distinctly shown. In conclusion, these results suggest that H2S non-specifically enhances the airway reflex responses, at least in part, through action on the TRPA1 receptors expressed on the CSLV afferents. Therefore, H2S should be used with caution when applying for therapeutic purposes in airway hypersensitivity diseases.

β-Endorphin, An Endogenous Depressor Agent in the Rat?

1981 ◽  
Vol 61 (s7) ◽  
pp. 339s-342s ◽  
Author(s):  
M. A. Petty ◽  
J. M. A. Sitsen ◽  
W. De Jong
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Subcutaneous Administration ◽  
Nucleus Tractus Solitarii ◽  
Variable Effect ◽  
A Site ◽  
Renal Hypertensive Rats

1. The role of opiates in cardiovascular regulation has been investigated. 2. In urethane-anaesthetized renal hypertensive rats (two-kidney, one-clip Goldblatt model), intracerebroventricular β-endorphin (10 μg) caused a greater fall in mean arterial pressure than in sham-operated controls. 3. Unilateral injection of β-endorphin into the nucleus tractus solitarii of the urethane-anaesthetized rat resulted in a U-shaped dose—response relationship, with a fall in mean arterial pressure and heart rate occurring at low doses. Doses above 10 ng caused a rise in pressure, accompanied by a variable effect on heart rate. 4. The fall in blood pressure and heart rate was prevented by prior subcutaneous administration of naloxone. Naloxone caused an increase in blood pressure when administered alone. 5. These results suggest a depressor role of an endogenous brain opiate, possibly β-endorphin; a site of action is probably the nucleus tractus solitarii.

The Return of Alsace to France, 1918-1939

2018 ◽  
Author(s):  
Alison Carrol
Keyword(s):  
National Policy ◽  
Third Republic ◽  
French Society ◽  
German Empire ◽  
Cross Border ◽  
The First World War ◽  
German Speaking ◽  
A Site ◽  
First World

In 1918 the end of the First World War triggered the return of Alsace to France after almost fifty years of annexation into the German Empire. Enthusiastic crowds in Paris and Alsace celebrated the homecoming of the so-called lost province, but return proved far less straightforward than anticipated. The region’s German-speaking population demonstrated strong commitment to local cultures and institutions, as well as their own visions of return to France. As a result, the following two decades saw politicians, administrators, industrialists, cultural elites, and others grapple with the question of how to make Alsace French again. The answer did not prove straightforward; differences of opinion emerged both inside and outside the region, and reintegration became a fiercely contested process that remained incomplete when war broke out in 1939. The Return of Alsace to France examines this story. Drawing upon national, regional, and local archives, it follows the difficult process of Alsace’s reintegration into French society, culture, political and economic systems, and legislative and administrative institutions. It connects the microhistory of the region with the macro levels of national policy, international relations, and transnational networks, and with the cross-border flows of ideas, goods, people, and cultural products that shaped daily life in Alsace. Revealing Alsace to be a site of exchange between a range of interest groups with different visions of the region’s future, this book underlines the role of regional populations and cross-border interactions in forging the French Third Republic.

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