Brainstem circuitry of tracheal–bronchial cough: c-fos study in anesthetized cats

Jakus, J; Poliaček, Ivan; Halašová, Erika; Muríň, Peter; Knociková, Juliana; Tomori, Z; Bolser, Donald C.

doi:10.1016/j.resp.2007.10.014

Cited by 56 publications

(53 citation statements)

References 41 publications

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“…The results also support the hypothesis (42) that several neural substrates involved in cough regulation (12,16,17,31,44,46,48,56,57) may be sites of action of antitussive drugs. They are consistent with previous suggestions (12,17,42,44,49,51) and extend previous findings on the action of antitussive drugs on the cVRG (42,51).…”

Section: Discussionsupporting

confidence: 88%

“…The tested drugs were the selective -opioid receptor agonist [D-Ala 2 ,N-MePhe 4 ,Gly 5 -ol]-enkephalin (DAMGO), the GABA B receptor agonist baclofen, the neurokinin-1 (NK 1 ) receptor antagonist CP-99,994, and the NK 2 receptor antagonist MEN 10376. We also proposed (42) that several neural substrates involved in the regulation of cough (12,16,17,31,44,46,48,56,57) may be sites of action of antitussive drugs. In agreement with our previous suggestion and preliminary results (17,42,44) as well as the proposal by Bolser and colleagues (12,49), the responsive sites may comprise, in particular, the caudal part of the ventral respiratory column (2), i.e., the so-called caudal ventral respiratory group (cVRG), where bulbospinal expiratory neurons are concentrated (6,30,63).…”

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confidence: 99%

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

Mutolo¹,

Bongianni

Cinelli

et al. 2010

Journal of Applied Physiology

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Mutolo D, Bongianni F, Cinelli E, Pantaleo T. Depression of cough reflex by microinjections of antitussive agents into caudal ventral respiratory group of the rabbit. J Appl Physiol 109: 1002-1010, 2010. First published July 22, 2010 doi:10.1152/japplphysiol.00406.2010.-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-Ala 2 ,N-Me-Phe 4 ,Gly 5 -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 NK 2 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.control of breathing; -opioid receptors; GABAB receptors; neurokinin receptors; expiratory activity -ol]-enkephalin (DAMGO), the GABA B receptor agonist baclofen, the neurokinin-1 (NK 1 ) receptor antagonist CP-99,994, and the NK 2 receptor antagonist MEN 10376. We also proposed (42) that several neural substrates involved in the regulation of cough (12,16,17,31,44,46,48,56,57) may be sites of action of antitussive drugs. In agreement with our previous suggestion and preliminary results (17, 42, 44) as well as the proposal by Bolser and colleagues (12, 49), the responsive sites may comprise, in particular, the caudal part of the ventral respiratory column (2), i.e., the so-called caudal ventral respiratory group (cVRG), where bulbospinal expiratory neurons are concentrated (6,30,63).Several morphological and electrophysiological lines of evidence indicate that cVRG expiratory neurons are probably not involved in respiratory rhythmogenesis since very likely they do not have medullary axon collaterals (6,14,30,41,63). However, microinjections of the broad-spectrum excitato...

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Section: Discussionsupporting

confidence: 88%

mentioning

confidence: 99%

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

Mutolo¹,

Bongianni

Cinelli

et al. 2010

Journal of Applied Physiology

View full text Add to dashboard Cite

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“…Other brain stem regions implicated in the regulation of cough may also be sites of action of these drugs (see Refs. 9,10,27,43,45,47,53,54). As already mentioned, these responsive structures may comprise, in particular, the caudal ventral respiratory group, in agreement with our previous suggestions (11,43) and those by Bolser and colleagues (9,48).…”

Section: Perspectives and Significancesupporting

confidence: 91%

“…Nevertheless, we suggest that the caudal NTS is a drug-sensitive neural substrate subserving the central regulation of cough. Noticeably, high counts of cough-related, Fos-like immunoreactivity were detected in the comNTS of the cat, but they were not increased compared with controls (27). We do not know the meaning of this finding.…”

Section: Perspectives and Significancementioning

confidence: 68%

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

Mutolo¹,

Bongianni²,

Cinelli³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

131

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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-Ala 2 ,N-Me-Phe 4 ,Gly 5 -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.-opioid receptors; GABAB receptors; neurokinin receptors; control of breathing; airway defensive reflexes PREVIOUS STUDIES LED TO THE conclusion that some antitussive drugs act centrally since they inhibit cough when administered by intravertebral arterial or intracerebroventricular route in guinea pigs and cats (7,8). These drugs comprise the opioid receptor agonist codeine, the -opioid receptor agonist morphine, the neurokinin-1 (NK 1 ) receptor antagonist (ϩ)(2R,3R)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), the NK 2 receptor antagonist {(ϩ)-N-methyl-[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-di-dichlorophenyl) butyl]benzamide} (SR48968), and the GABA B receptor agonist baclofen. A prominent central antitussive effect has been proven for the selective -opioid receptor agonist [D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin (DAMGO) by using intracerebroventricular administration in the rat (30). However, the central responsive structures and the mechanism of action of these drugs remain to be investigated.It is widely agreed that tracheobronchial rapidly adapting receptors (RARs) are involved in cough mediation, while the role of bronchopulmonary C-fibers and A␦-nociceptive pulmonary afferent fibers in this reflex is controversial (see e.g., 36, 49, 62; for further references, also see Ref. 43). We have ...

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“…Studies undertaken to provide insights into the neural mechanisms subserving the cough reflex may also provide useful suggestions for novel antitussive therapeutic strategies. The cough reflex involves several brain stem structures that also underlie respiratory rhythm generation (e.g., 7,9,10,19,24,27,[47][48][49]55). …”

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confidence: 99%

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

Mutolo

Cinelli

Bongianni

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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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. airway defensive reflexes; galanin; galanin receptors; galnon; nucleus tractus solitarii COUGH IS A VERY IMPORTANT airway protective reflex and is one of the most common reason why patients seek medical attention. Cough is purposeful and useful under many circumstances, but in case of persistent or chronic cough (e.g., 15) is without an apparent aim and benefit and can results in a wide range of physical and psychological complications including urinary incontinence, insomnia, depression, and anxiety. The efficacy of antitussive drugs is far from clear from the available evidence and, in addition, limited by important side effects. Therefore, further research to find better antitussive approaches is necessary (for reviews see Refs. 4 and 15). Studies undertaken to provide insights into the neural mechanisms subserving the cough reflex may also provide useful suggestions for novel antitussive therapeutic strategies. The cough reflex involves several brain stem structures that also underlie respiratory rhythm generation (e.g., 7,9,10,19,24,27,[47][48][49]55).In particular, the nucleus tractus solitarii (NTS), especially in its caudal aspects, is the main central terminus of cough-related afferents (14, 39 -41, 43, 53 also for further references) and, in addition, a possible strategic site of synaptic plasticity, where cough-related sensory inputs can be modulated (e.g., 10,14,34,39,40,43).In recent years, we and other researchers have focused our attention on the s...

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Brainstem circuitry of tracheal–bronchial cough: c-fos study in anesthetized cats

Cited by 56 publications

References 41 publications

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

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

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

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

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