Endothelin‐1‐induced ETA receptor‐mediated nociception, hyperalgesia and oedema in the mouse hind‐paw: modulation by simultaneous ETB receptor activation

• Published in: British journal of pharmacology Vol. 129; no. 5; pp. 961 - 968
• Main Authors: Piovezan, Anna P, D'Orléans‐Juste, Pedro, Souza, Glória E P, Rae, Giles A
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.03.2000; Nature Publishing
• Subjects: Biological and medical sciences; capsaicin; Endothelin; endothelin receptor antagonist; hyperalgesia; inflammation; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; nociception; oedema; pain; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Edema; Agonist; Capsaicin; Toxicity; Rodentia; Activation; Endothelin 1; Inflammation; Hyperalgesia; Vertebrata; Mammalia; Pain; Mouse; Animal; Peptidergic receptor; Antagonist; Mechanism of action
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0703154

Endothelin‐1 causes ETA receptor‐mediated enhancement of capsaicin‐induced nociception in mice. We have assessed if this hyperalgesic effect of endothelin‐1 is also accompanied by other pro‐inflammatory effects, namely nociception and oedema, and characterized the endothelin ET receptors involved. Intraplantar (i.pl.) hind‐paw injection of endothelin‐1 (0.3–30 pmol) induced graded nociceptive responses (accumulated licking time: vehicle, 20.5±3.3 s; endothelin‐1 at 30 pmol, 78.1±9.8 s), largely confined to the first 15 min. Endothelin‐1 (1–10 pmol) potentiated ipsilateral capsaicin‐induced (0.1 μg, i.pl.; at 30 min) nociception (vehicle, 40.2±2.6 s; endothelin‐1 at 10 pmol, 98.4±5.8 s, but 30 pmol was inactive), and caused oedema (increase in paw weight 5 min after capsaicin: vehicle, 46.3±2.3 mg; endothelin‐1 at 30 pmol, 100.3±6.1 mg). Selective ETB receptor agonists sarafotoxin S6c (up to 30 pmol) and IRL 1620 (up to 100 pmol) were inactive, whereas endothelin‐3 (up to 30 pmol) induced only modest oedema. ETA receptor antagonists BQ‐123 (1 nmol, i.pl.) or A‐127722‐5 (6 μmol kg−1, i.v.) prevented all effects of endothelin‐1 (10 pmol), but the ETB receptor antagonist BQ‐788 (1 or 10 nmol, i.pl.) was ineffective. BQ‐788 (10 nmol, i.pl.) unveiled hyperalgesic effects of 30 pmol endothelin‐1 and endothelin‐3. Sarafotoxin S6c (30 pmol, i.pl.) did not modify endothelin‐1‐induced (10 pmol) nociception or oedema, but abolished hyperalgesia. Thus, endothelin‐1 triggers ETA receptor‐mediated nociception, hyperalgesia and oedema in the mouse hind‐paw. Simultaneous activation of ETB receptors by endothelin‐1 or selective agonists can limit the hyperalgesic, but not the nociceptive or oedematogenic, effects of the peptide. British Journal of Pharmacology (2000) 129, 961–968, doi:10.1038/sj.bjp.0703154