The intradermal (i.d.) injection of NK1 receptor antagonists
GR 82334 and
FK 888 (1-50 pmol/paw), in association with
formalin, produced graded inhibition of the early but not the late phase of the
formalin test. The NK2,
SR 48968 and NK3
SR 142801 receptor antagonists (1-50 pmol/paw) were effective in inhibiting both phases of the
formalin model. Co-injection of NK1, (
FK 888,
GR 82334), NK2 (
SR 48968) or NK3 (
SR 142801) receptor antagonists with
capsaicin dose-dependently attenuated
capsaicin-induced licking. In addition, all antagonists were more efficacious when compared with response in the
formalin test. The antinociception caused by i.d. injection of the NK3 receptor antagonist
SR 142801 against both phases of the
formalin test, but not that of NK1 and NK2 receptor antagonists, was significantly reversed by intraperitoneal (i.p.) injection of
naloxone (5 mg/kg). Intracerebroventricular (i.c.v.) injection of NK1, NK2 or NK3 receptor antagonists (15-500 pmol/site), all produced significant and dose-dependent inhibition of both phases of the
formalin and
capsaicin tests. With the exception of the response of
SR 48968, which was equipotent in both models of nociception,
FK 888,
GR 82334 and
SR 142801 were about 2-25-fold less potent at the ID50 level against the
capsaicin-induced
pain. The antinociception caused by i.c.v. injection of NK1, NK2 or NK3 receptor antagonists was reversed by i.p. injection of
naloxone (5 mg/kg). These results indicate that
tachykinin receptor antagonists, acting through NK1, NK2 and NK3 receptors, produce powerful antinociception when injected i.d. or by i.c.v. route against both
formalin- and
capsaicin-induced licking, being more efficacious against the latter model of nociception. The action of NK3 receptor antagonist given i.d. was mediated through an
opioid mechanism sensitive to
naloxone. However, when injected i.c.v., the antinociception caused by NK1, NK2 or NK3 receptor antagonists was largely reversed by
naloxone when assessed in the
formalin test, suggesting a distinct mechanism of action.