Suppression of the cough reflex byα₂-adrenergic receptor agonists in the rabbit

Abstract

The α2-adrenergic receptor agonist clonidine has been shown to inhibit citric acid-induced cough responses in guinea pigs when administered by aerosol, but not orally. In contrast, oral or inhaled clonidine had no effect on capsaicin-induced cough and reflex bronchoconstriction in humans. In addition, intravenous administration of clonidine has been shown to depress fentanyl-induced cough in humans. We investigated the effects of the α2-adrenergic receptor agonists, clonidine and tizanidine, on cough responses induced by mechanical and chemical (citric acid) stimulation of the tracheobronchial tree. Drugs were microinjected (30–50 nL) into the caudal nucleus tractus solitarii (cNTS) and the caudal ventral respiratory group (cVRG) as well as administered intravenously in pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Bilateral microinjections of clonidine into the cNTS or the cVRG reduced cough responses at 0.5 mmol/L and abolished the cough reflex at 5 mmol/L. Bilateral microinjections of 0.5 mmol/L tizanidine into the cNTS completely suppressed cough responses, whereas bilateral microinjections of 5 mmol/L into the cVRG only caused mild reductions in them. Depressant effects on the cough reflex of clonidine and tizanidine were completely reverted by microinjections of 10 mmol/L yohimbine. Intravenous administration of clonidine (80–120 μg/kg) or tizanidine (150–300 μg/kg) strongly reduced or completely suppressed cough responses. These effects were reverted by intravenous administration of yohimbine (300 μg/kg). The results demonstrate that activation of α2-adrenergic receptors in the rabbit exerts potent inhibitory effects on the central mechanism generating the cough motor pattern with a clear action at the level of the cNTS and the cVRG.

The cough reflex is upregulated by lisinopril microinjected into the caudal nucleus tractus solitarii of the rabbit

“…The average values of cough-related variables were taken as single measurements for subsequent statistical analysis (GraphPad Prism 5, La Jolla, CA, USA). On some occasions, an expiration reflex could occur as the first motor event in a cough epoch (Korpáš and Tomori, 1979;Widdicombe and Fontana, 2006 for further details see Tatar et al, 2008;Mutolo et al, 2007Mutolo et al, , 2008Mutolo et al, , 2009Mutolo et al, , 2012Cinelli et al, 2013). Expiration reflexes were not considered for data analysis.…”

Downregulation of the cough reflex by aclidinium and tiotropium in awake and anesthetized rabbits

“…As proposed in our previous reports ( [8,11,28] also for further Refs), cough and nociception share similar central and peripheral features. This led to the proposal that agents involved in the control of pain sensation could be also effective in the cough regulation and viceversa (see e.g.…”

“…It was scheduled to ensure the complete development of bronchodilator effects (see Methods). It is noteworthy that changes in the ongoing respiratory activity or in arterial blood pressure, that have been proved to affect the timing and intensity of cough responses [8,24,37], were not induced by the two employed LAMAs.…”

“…Expiration reflexes were not considered for data analysis. For a discussion on the expiration reflex, see our previous reports [8,9,11,25,26].…”

“…The diameter of the droplets ranged from 0.5 to 8 mm and the nebulizer output was always set at 1 mL/min. The opening of the tracheal cannula, through which the rabbits were spontaneously breathing, was exposed to a steady stream of the nebulized MCh solution for 30 s. In preliminary trials (two rabbits), MCh was delivered at increasing concentrations (8,16 and 32 mg/mL) as previously reported [30] to select the dose able to induce a submaximal increase of R L . The selected dose was 16 mg/mL.…”