Endothelin B receptor modulates inflammatory pain and cutaneous inflammation.
The role of endothelin B (ET(B)) receptors in inflammation and nociception was examined using ET(B) receptor knockout mice. Genotyping studies were used with tissues from ET(B)((+/+)), ET(B)((+/-)), and ET(B)((-/-)) mice to confirm the loss of ET(B) receptors. Algesia induced by phenylbenzoquinone was evident in the (+/+) mice, reduced by approximately 80% in the (+/-) mice, and absent in the (-/-) mice. Phenylbenzoquinone-induced algesia in (+/+) mice was inhibited 74% by the ET(B) receptor-selective antagonist A192621 (25 mg/kg p.o.), but unaffected by the ET(A) receptor-selective antagonist SB 234551 (25 mg/kg p.o.). Noninflammatory pain, induced by hotplate, was equivalent between (+/+) and (-/-) mice. The cutaneous inflammatory response to topical arachidonic acid (AA) also was evaluated. Whereas (+/+) mice had a marked inflammatory response to AA, the (+/-), and (-/-) mice had significantly reduced fluid phase responses (37 and 65% inhibition, respectively). Neutrophil infiltration also was reduced in the (+/-) and (-/-) mice (51 and 65% reduction, respectively). Topical administration of A192621 (500 microg/ear) in (+/+) mice inhibited AA-induced swelling (39%), whereas SB 234551 (500 microg/ear) was without effect. Collectively, these results implicate the ET(B) receptor in mediation of inflammatory pain and cutaneous inflammatory responses in mice.
Griswold
D E
DE
Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
Douglas
S A
SA
Martin
L D
LD
Davis
T G
TG
Davis
L
L
Ao
Z
Z
Luttmann
M A
MA
Pullen
M
M
Nambi
P
P
Hay
D W
DW
Ohlstein
E H
EH
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use; D015139:Blotting, Southern; D003872:Dermatitis / Q000188:drug therapy / Q000378:metabolism*; D004149:Dioxoles / Q000494:pharmacology / Q000627:therapeutic use; D065128:Endothelin Receptor Antagonists; D005838:Genotype; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism*
C120508:A 192621; D016227:Benzoquinones; D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; D011720:Pyrazoles; D011759:Pyrrolidines; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C113973:SB 234551; D016718:Arachidonic Acid; C029322:phenylbenzoquinone