Abstract

In this study, the activity of the δ-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the δ-opioid receptor (SB 227122), μ-opioid receptor (codeine and hydrocodone), and κ-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED₅₀ values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The δ-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with β-funaltrexamine (μ-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (κ-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of μ- and κ-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The ς-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a ς-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the δ-opioid receptor.