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The contribution of endogenous endothelins to nociceptive responses elicited by ovalbumin (OVA) in the hind-paw of mice sensitised to this antigen (50 μg OVA+5 mg Al(OH)3, s.c., 14 days beforehand) was investigated. Sensitised mice exhibited greater nocifensive responsiveness to intraplantar (i.pl.) OVA (total licking time over first 30 min: 85.2±14.6 s at 0.3 μg; 152.6±35.6 s at 1 μg) than nonsensitised animals (29.3±7.4 s at 1 μg). Nocifensive responses of sensitised mice to 0.3 μg OVA were inhibited by morphine (3 mg kg−1, s.c.) or local depletion of mast cells (four daily i.pl. injections of compound 48/80). Pretreatment with i.v. bosentan (mixed ETA/ETB receptor antagonist; 52 μmol kg−1) or A-122722.5 (selective ETA receptor antagonist; 6 μmol kg−1) reduced OVA-induced licking from 124.8±20.6 s to 45.7±13.0 s and 64.2±12.1 s, respectively, whereas A-192621.1 (selective ETB receptor antagonist; 25 μmol kg−1) enhanced them to 259.2±39.6 s. Local i.pl. pretreatment with BQ-123 or BQ-788 (selective ETA or ETB receptor antagonists, respectively, each at 3 nmol) reduced OVA-induced licking (from 106.2±15.2 to 57.0±9.4 s and from 118.6±10.5 to 76.8±14.7 s, respectively). Sarafotoxin S6c (selective ETB receptor agonist, 30 pmol, i.pl., 30 min after OVA) induced nocifensive responses in OVA-sensitised, but not in nonsensitised, animals. Compound 48/80 (0.3 μg, i.pl.) induced nocifensive responses per se and potentiated those induced by i.pl. capsaicin (0.1 μg). Treatment with BQ-123 (3 nmol, i.pl.) reduced only the hyperalgesic effect of compound 48/80, whereas BQ-788 (3 nmol) was ineffective. Thus, immune-mediated Type I hypersensitivity reactions elicit mast cell- and endothelin-dependent nociception in the mouse hind-paw, which are mediated locally by both ETA and ETB receptors. The nocifensive response to antigen is amenable to blockade by systemic treatment with dual ETA/ETB or selective ETA receptor antagonists, but is sharply potentiated by systemic selective ETB receptor antagonist treatment. The apparently distinct roles played by ETB receptors in this phenomenon at local and other sites remain to be characterised. British Journal of Pharmacology (2004) 141, 755–763. doi:10.1038/sj.bjp.0705663 |
