ENDOTHELINS POTENTIATE FORMALIN-INDUCED NOCICEPTION AND PAW EDEMA IN MICE

The present study investigates the influence of endothelin (ET) relate d peptides (0.3-30 pmol/paw) on both phases of nociception and on edem a induced by intraplantar injection of formalin (0.5% in 20 mu L) in t he mouse hind paw. The first phase of nociception (0-5 min after injec tion) was significantly potentiated by simultaneous injection of eithe r ET-1 (10 or 30 pmol/paw) or ET-3 (10 pmol/paw), but not of the selec tive ETB receptor agonist sarafotoxin S6c (SRTX-c; up to 30 pmol/paw). All three peptides potentiated the second phase (10-30 min after inje ction) of formalin-induced nociception (at 3-30, 1-30, and 10-30 pmol/ paw for ET-1, ET-3, and SRTX-c, respectively), whereas only ET-1 (10 o r 30 pmol/paw) effectively enhanced edema caused by formalin (30 min a fter injection). Histamine also potentiated all three responses trigge red by formalin, but was 30- to 100-fold less potent than ET-1. Treatm ent with the mixed ETA/ETB receptor antagonist bosentan (10 mg/kg i.p. , 1 h beforehand) did not influence nociceptive and edematogenic respo nses to formalin or their potentiation by histamine (3 nmol/paw), but did inhibit the potentiations induced by ET-1 (10 pmol/paw). Thus, ET- 1 potentiates formalin-induced nociception and edema in the mouse. The se actions are possibly mediated via ETB and ETA receptors, respective ly, but their true identity and the mechanisms involved still remain t o be fully elucidated.