Central antitussive activity of the NK₁ and NK₂ tachykinin receptor antagonists, CP‐99,994 and SR 48968, in the guinea‐pig and cat

Abstract

1 The purpose of this study was to investigate the antitussive activity and sites of action of the NK 1 and NK 2 tachykinin receptor antagonists, 994, SR 48968, and the racemate of SR 48968, SR 48212A in the cat and guinea-pig. 2 Guinea-pigs were dosed subcutaneously (s.c.) with CP-99,994, SR 48212A or SR 48968 one hour before exposure to aerosols of capsaicin (0.3 mM) to elicit coughing. Coughs were detected with a microphone and counted. 3 Intracerebroventricular (i.c.v.) cannulae were placed in the lateral cerebral ventricles of anaesthetized guinea-pigs. Approximately one week later, the animals were dosed with 994 or SR 48212A (i.c.v.) and exposed to aerosols of capsaicin (0.3 mM) to elicit coughing. 4 Cough was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was monitored from electromyograms of respiratory muscle activity. Cannulae were placed for intravenous (i.v.) or, in separate groups of animals, intravertebral arterial (i.a.) administration of CP-99,994, SR 48212A or SR 48968. Dose-response relationships for i.v. and i.a. administration of each drug were generated to determine a ratio of i.v. ED 50 to i.a. ED 50 , known as the e ective dose ratio (EDR). The EDR will be 20 or greater for a centrally active drug and less than 20 for a peripherally active drug. 5 In the guinea-pig, CP-99,994 (0.1 ± 30 mg kg 71 , s.c.), SR 48212A (1.0 ± 30 mg kg 71 , s.c.), and SR 48968 (0.3 ± 3.0 mg kg 71 , s.c.) inhibited capsaicin-induced cough in a dose-dependent manner. Capsaicininduced cough was also inhibited by i.c.v. administration of CP-99,994 (10 and 100 mg) or SR 48212A (100 mg). 6 In the cat, both CP-99,994 (0.0001 ± 0.3 mg kg 71 , i.a., n=5; 0.003 ± 3.0 mg kg 71 , i.v., n=5) and SR 48212A (0.003 ± 1.0 mg kg 71 , i.a., n=5; 0.01 ± 3.0 mg kg 71 , i.v., n=5) inhibited mechanically induced cough by either the i.v. or i.a. routes in a dose-dependent manner. SR 48968 (0.001 ± 0.3 mg kg 71 , i.a., n=5; 0.03 ± 1.0 mg kg 71 , i.v., n=5) inhibited cough when administered by the i.a. route in a dosedependent manner, but had no e ect by the i.v. route up to a dose of 1.0 mg kg 71 . Intravenous antitussive potencies (ED 50 , 95% con®dence interval (CI)) of these compounds were: CP-99,994 (0.082 mg kg 71 , 95% CI 0.047 ± 0.126), SR 48212A (2.3 mg kg 71 , 95% CI 0.5 ± 20), and SR 48968 (41.0 mg kg 71 , 95% CI not determined). The intra-arterial potencies of these compounds were: CP-99,994 (1.0 mg kg 71 , 95% CI 0.4 ± 1.8), SR 48212A (25 mg kg 71 , 95% CI 13 ± 52), and SR 48968 (8.0 mg kg 71 , 95% CI 1 ± 32). The derived EDRs for each compound were: 994, 82; SR 48212A, 92; and SR 48968, 4125. 7 We concluded that CP-99,994 and SR 48968 inhibit cough in the guinea-pig and cat by a central site of action. In the cat, the antitussive action of these compounds appears to be solely by a central site.

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

“…Several brain stem Varied results have been obtained with CP-99,994 or different NK 1 receptor antagonists in anesthetized and unanesthetized animals of different species as well as in asthmatic patients (e.g., and for further references, see Refs. 1,7,8,17,28,40 ). In particular, our results on the effects of CP-99,994 on cough are consistent with those previously described by Bolser and colleagues (7,8) and with those of a recent study by Chapman et al (17) in dogs orally dosed with this antagonist.…”

“…1,7,8,17,28,40 ). In particular, our results on the effects of CP-99,994 on cough are consistent with those previously described by Bolser and colleagues (7,8) and with those of a recent study by Chapman et al (17) in dogs orally dosed with this antagonist. On the contrary, they are at variance with those obtained by Mazzone et al (40).…”

“…-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.…”

Inhibiting Effect of Ammonia on Citric Acid‐Induced Cough in Pigs: A Possible Involvement of Substance P

“…Both capsaicin and citric acid are thought to act through the release of neurokinins, especially substance P, from Cfibers. Furthermore, neurokinin receptor (NK1, NK2, NK3) antagonists inhibit the cough reflex, and in guinea pigs, cats, and humans, citric acid-induced coughing is enhanced by inhibitors of two enzymes involved in substance P degradation: neutral endopeptidase and angiotensin-converting enzyme (Ujiie et al 1993;Fox et al 1996;Sekizawa et al 1996;Advenier et al 1997;Bolser et al 1997). These facts support the view that substance P plays a role in the cough reflex.…”

Inflammation-Induced Plasticity of the Afferent Innervation of the Airways

“…Nevertheless, pharmacologic studies have demonstrated that the NK receptors NK 1 , NK 2 , and NK 3 are present in secondary neurons within the nucleus of the solitary tract, and stimulation of these receptors can profoundly affect vagal reflex physiology (85). Also consistent with a role for tachykinins in modulating airway reflexes, the NK 1 receptor-selective antagonist CP-99,994 and SR-48968, an NK 2 receptor-selective antagonist, were able to inhibit mechanically induced cough in the guinea pig and cat by an action in the central nervous system (86).…”