The pharmacology of
tachykinin NK receptors varies greatly among species. The aim of the present study was to assess the role of NK(1) and
NK(2) receptors in mediating colorectal distension-evoked nociception and psychological stress-induced defecation in gerbils, a species with human-like NK receptor pharmacology. The effects of the selective NK(1) and
NK(2) receptor antagonists,
aprepitant and
saredutant, on acute (1 h) restraint stress-evoked defecation and plasma adenocorticotropin (
ACTH) levels in gerbils were assessed. The effects of antagonists alone or in combination on colorectal distension-evoked
visceral pain in conscious gerbils were evaluated using the visceromotor response as a
surrogate marker of
pain. Restraint stress increased fecal pellet output 2-3-fold and plasma
ACTH levels 9-fold.
Aprepitant inhibited the defecatory and endocrine responses to stress by 50%, while
saredutant completely normalized the same parameters.
Visceral pain responses during colorectal distension were attenuated by both compounds, but
aprepitant (19+/-6% inhibition, P<0.01) was slightly more effective than
saredutant (10+/-9% inhibition, P<0.05). A combination of both compounds resulted in an additive effect (30+/-10% inhibition, P<0.01). The results demonstrate that NK(1) and
NK(2) receptors are involved in stress-related colonic motor alterations and
visceral pain responses in gerbils and that combined antagonism provides enhanced inhibition of
visceral pain responses. This suggests that for
therapeutic use in for instance
functional gastrointestinal disorders, dual NK(1)/
NK(2) receptor antagonists may provide better clinical outcome than selective compounds.