Endothelins contribute towards nociception induced by antigen in ovalbumin-sensitised mice.
1. The contribution of endogenous endothelins to nociceptive responses elicited by ovalbumin (OVA) in the hind-paw of mice sensitised to this antigen (50 microg 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 microg; 152.6+/-35.6 s at 1 microg) than nonsensitised animals (29.3+/-7.4 s at 1 microg). Nocifensive responses of sensitised mice to 0.3 microg 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 micromol kg(-1)) or A-122722.5 (selective ET(A) receptor antagonist; 6 micromol 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 micromol 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 microg, i.pl.) induced nocifensive responses per se and potentiated those induced by i.pl. capsaicin (0.1 microg). 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.
Piovezan
Anna P
AP
Department of Pharmacology, CCB, Universidade Federal de Santa Catarina, R Ferreira Lima 82, Florianópolis 88015-420, SC, Brazil.
D'Orléans-Juste
Pedro
P
Frighetto
Monica
M
Souza
Glória E P
GE
Henriques
Maria G M O
MG
Rae
Giles A
GA
D000818:Animals; D000941:Antigens / Q000276:immunology / Q000494:pharmacology*; D000077300:Bosentan; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000502:physiology*; D006930:Hyperalgesia / Q000503:physiopathology*; D006967:Hypersensitivity / Q000503:physiopathology*; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology*; D010146:Pain / Q000503:physiopathology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
D000941:Antigens; D016232:Endothelins; D007202:Indicators and Reagents; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D013449:Sulfonamides; D014757:Viper Venoms; C057354:sarafotoxins s6; D003189:p-Methoxy-N-methylphenethylamine; C086539:BQ 788; D010047:Ovalbumin; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)