Endothelins contribute towards nociception induced by antigen in ovalbumin-sensitised mice

Abstract

1 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. 2 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). 3 Pretreatment with i.v. bosentan (mixed ET A/ET B receptor antagonist; 52 μmol kg -1) or A-122722.5 (selective ET A 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 ET B receptor antagonist; 25 μmol kg -1) enhanced them to 259.2 ± 39.6 s. 4 Local i.pl. pretreatment with BQ-123 or BQ-788 (selective ET A or ET B 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. 5 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. 6 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 ET A and ET B receptors. The nocifensive response to antigen is amenable to blockade by systemic treatment with dual ET A/ET B or selective ET A receptor antagonists, but is sharply potentiated by systemic selective ET B receptor antagonist treatment. The apparently distinct roles played by ET B receptors in this phenomenon at local and other sites remain to be characterised.