Oral antinociception and oedema inhibition produced by NPC 18884, a non-peptidic bradykinin B2 receptor antagonist.
This study investigates the antinociceptive and the oedema inhibition properties of the novel non-peptide bradykinin (BK) B2 receptor antagonist, NPC 18884. Given by i.p. or p.o. routes NPC 18884 produced graded and long-lasting (at least 2.5h and 5.0h, respectively, for i.p. and p.o. administration) inhibition of acetic acid-induced abdominal constrictions in mice, with mean ID50 values of 8.3 nmol/kg and 439.9 nmol/kg. NPC 18884 also inhibited kaolin-induced abdominal constrictions (44+/-9% and 48+/-3% of inhibition, for i.p. and p.o. routes, respectively). Given by i.p. or p.o. routes NPC 18884 attenuated both phases of formalin-induced licking, as well as formalin-induced oedema formation. At similar doses NPC 18884 produced significant inhibition of capsaicin-induced nociception. NPC 18884, like HOE 140 given i.p., prevented the nociception caused by BK with mean ID50 values of 0.85 nmol/kg and 0.44 nmol/kg, respectively. Given orally NPC 18884, but not HOE 140, caused graded inhibition of BK-induced nociception (mean ID50 value of 50 nmol/kg). In rats, NPC 18884 given i.p. prevented BK and carrageenan-induced hyperalgesia (mean ID50 values of 6 nmol/kg and 13 nmol/kg), without affecting the hyperalgesia induced by des-Arg9-bradykinin (DABK) or by prostaglandin E2 (PGE2). NPC 18884 given i.p. inhibited the mouse paw oedema induced by tyrosine8-bradykinin or by carrageenan, but had no effect on DABK-induced oedema in mice pre-treated with Escherichia coli endotoxin, or that induced by PGE2. Thus, the novel non-peptide BK B2 receptor antagonist NPC 18884 produces rapid onset, potent and relatively long-lasting oral antinociceptive and oedema inhibition properties. The anti-BK actions of NPC 18884 are quite selective towards the BK B2 receptor-mediated responses.
de Campos
R O
RO
Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
Alves
R V
RV
Ferreira
J
J
Kyle
D J
DJ
Chakravarty
S
S
Mavunkel
B J
BJ
Calixto
J B
JB
D019342:Acetic Acid / Q000009:adverse effects; D000284:Administration, Oral; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001920:Bradykinin / Q000009:adverse effects / Q000031:analogs & derivatives; D065168:Bradykinin Receptor Antagonists; D002211:Capsaicin / Q000009:adverse effects; D002351:Carrageenan / Q000009:adverse effects; D015232:Dinoprostone / Q000009:adverse effects; D004151:Dipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control*; D005557:Formaldehyde / Q000009:adverse effects; D006614:Hindlimb; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2; D013997:Time Factors
D000700:Analgesics; D065168:Bradykinin Receptor Antagonists; D004151:Dipeptides; C117759:NPC 18884; D043782:Receptor, Bradykinin B2; C024626:bradykinin, des-Arg(9)-; D005557:Formaldehyde; D002351:Carrageenan; D015232:Dinoprostone; D019342:Acetic Acid; D002211:Capsaicin; D001920:Bradykinin