The antitussive activity of delta-opioid receptor stimulation in guinea pigs.
In this study, the activity of the delta-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 delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) 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 delta-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 beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-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 delta-opioid receptor.
Kotzer
C J
CJ
Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Hay
D W
DW
Dondio
G
G
Giardina
G
G
Petrillo
P
P
Underwood
D C
DC
D000818:Animals; D016466:CHO Cells; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D019976:Cloning, Organism; D003061:Codeine / Q000494:pharmacology; D003371:Cough / Q000517:prevention & control*; D006224:Cricetinae; D003915:Dextromethorphan / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006168:Guinea Pigs; D006801:Humans; D006853:Hydrocodone / Q000494:pharmacology; D007977:Levallorphan / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000187:drug effects* / Q000502:physiology*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000187:drug effects / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000187:drug effects / Q000502:physiology
D002227:Carbazoles; D009292:Narcotic Antagonists; D011725:Pyridines; D011758:Pyrroles; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C404151:SB 227122; C088382:BRL 52974; D007977:Levallorphan; D009270:Naloxone; D006853:Hydrocodone; D003915:Dextromethorphan; C034931:rimcazole; D003061:Codeine