Effect of the two tachykinin antagonists, SR 48968 and SR 140333, on cough induced by citric acid in the unanaesthetized guinea pig

Abstract

E Ef ff fe ec ct t o of f t th he e t tw wo o t ta ac ch hy yk ki in ni in n a an nt ta ag go on ni is st ts s, , S SRIn conclusion, our results demonstrate that NK 2 -receptor stimulation plays a predominant role in the regulation of cough reflex, at least in the guinea-pig, as shown by the high potency and efficacy of SR 48968, a tachykinin NK 2 -receptor antagonist. SR 140333, a NK 1 -receptor antagonist is unable to inhibit cough by itself, but it potentiates SR 48968 in terms of efficiency. Finally, as salbutamol did not modify the effect of SR 48968, it may be suggested that the antitussive effect of SR 48968 is not related to the inhibition of citric acid-induced bronchoconstriction.

The diagnosis and management of chronic cough

“…Gamma aminobutyric acid (GABA) B receptor agonists have a similar inhibitory profile on the tussive response [112]. NK-receptor antagonists, such as the NK 2 -receptor antagonist, SR 48968, inhibit citric acidinduced cough in conscious guinea pigs [113], possibly via both a central and/or peripheral mechanism of action [114]. The NK 3 -receptor competitive antagonist, SB 235375, is also effective against citric acid-induced cough and an NK 1 /NK 2 / NK 3 -receptor antagonist, SCH 206272, inhibits capsaicininduced cough in the guinea-pig [115].…”

Pharmacology of Bradykinin-Evoked Coughing in Guinea Pigs

“…In favor of their utility in cough and in controlling other aberrant respiratory reflexes and sensations, we and others have shown previously that, in guinea pigs, NK receptor antagonists inhibit capsaicin-evoked and citric acid-evoked coughing, reflex bronchospasm evoked by tracheal/laryngeal C-fiber activation, and the reflex bronchospasm evoked by bradykinin following cyclooxygenase inhibition (Girard et al, 1995;Bolser et al, 1997;Canning et al, 2001;Mazzone and Canning, 2002;El-Hashim et al, 2004). NK receptor antagonists also inhibit coughing evoked in rabbits, cats, and dogs (reviewed in Canning, 2009), and a recent preliminary report suggests modest cough suppression in lung cancer patients by the NK 1 receptor antagonist aprepitant (Harle et al, 2015).…”

SSR240600 [(R)-2-(1-{2-[4-{2-[3,5-Bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl}- 4-piperidinyl)-2-methylpropanamide], a Centrally Active Nonpeptide Antagonist of the Tachykinin Neurokinin-1 Receptor: I. Biochemical and Pharmacological Characterization

“…The in vivo pharmacological profile of SSR240600 was investigated in three animal models in which the role of tachykinin NK 1 receptor has been well characterized: hypotension, bronchoconstriction, and plasma extravasation induced by substance P or specific agonists of the tachykinin NK 1 receptor (Regoli et al, 1994;Quartara and Maggi, 1998). Furthermore, the activity of SSR240600 was studied in a model of cough provoked by inhalation of citric acid, where endogenous tachykinins and their receptors play an important role Ujiie et al, 1993;Girard et al, 1995;Yasumitsu et al, 1996;Daoui et al, 1998).…”

“…SSR240600 was administered by the intraperitoneal route at various times before the aerosol challenge. Coughs were counted by a trained observer, and recognized by the characteristic animal posture and the pressure variation in the body plethysmograph Girard et al, 1995;Daoui et al, 1998).…”

“…SSR240600 was then studied in an animal model where endogenous tachykinins through their respective receptors are suspected to play a major role: citric acid-induced cough in unanesthetized guinea pigs (Widdicombe, 1995;Advenier and Emonds-Alt, 1996;Advenier et al, 1997). Either tachykinin NK 2 Girard et al, 1995;Yasumitsu et al, 1996;Emonds-Alt et al, 1997) or NK 3 (Daoui et al, 1998;Emonds-Alt et al, 2002) receptor antagonists have been reported to have potent antitussive activity in this model. Regarding the effect of nonpeptide tachykinin NK 1 receptor antagonists in this model, the results are controversial.…”