Targeted Disruption of the Endothelin-B-Receptor Gene Attenuates Inflammatory Nociception and Cutaneous Inflammation in Mice

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Summary: Endothelin-1 (ET-1) has been suggested to have a potential function as an inflammatory mediator. The study reported here assessed the putative inflammatory/nociceptive actions of the ET isopeptides using endothelin-B (ETB)-receptor knockout (KO) mice and ETA- (SB 234551) and ETB- (A192621) selective antagonists. Phenylbenzoquinone (PBQ)-induced algesia was evident in the wild-type (WT) ETB (+/+) mice, attenuated by 80% in the heterozygous ETB (+/−) mice, and absent in the ETB (−/−) homozygotes. This was reproduced pharmacologically in WT ETB (+/+) mice where the algesic effect of PBQ was inhibited 74% by A192621, but unaffected by SB 234551 (both at 25 mg/kg p.o.). Similar observations were made in a model of cutaneous inflammation: ETB (+/+) mice had a marked inflammatory response to topical arachidonic acid, ETB (+/−) and ETB (−/−) mice had significantly reduced edema responses (37% and 65% inhibition). Neutrophil infiltration was reduced in the ETB (+/−) and ETB (−/−) mice (51% and 65% reduction, respectively). Topical administration of A192621 (500 μg/ear) inhibited arachidonic acid-induced swelling (39%) in WT ETB (+/+) mice. Collectively, these results support a role for the ETB-receptor in the mediation of inflammatory pain and cutaneous inflammatory responses. As such, the development of ETB-receptor-selective antagonists may be of therapeutic utility in the treatment of inflammatory disorders.