The present study investigates the influence of
endothelin (ET) related
peptides (0.3-30 pmol/paw) on both phases of nociception and on
edema induced by intraplantar injection of
formalin (0.5% in 20 microL) in the mouse hind paw. The first phase of nociception (0-5 min after injection) was significantly potentiated by simultaneous injection of either ET-1 (10 or 30 pmol/paw) or ET-3 (10 pmol/paw), but not of the selective ET3 receptor agonist
sarafotoxin S6c (
SRTX-c; up to 30 pmol/paw). All three
peptides potentiated the second phase (10-30 min after injection) 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 or 30 pmol/paw) effectively enhanced
edema caused by
formalin (30 min after injection).
Histamine also potentiated all three responses triggered by
formalin, but was 30- to 100-fold less potent than ET-1. Treatment with the mixed ETA/ETB receptor antagonist
bosentan (10 mg/kg i.p., 1 h beforehand) did not influence nociceptive and edematogenic responses 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. These actions are possibly mediated via ETB and ETA receptors, respectively, but their true identity and the mechanisms involved still remain to be fully elucidated.