The site of the
anti-emetic action of the neurokinin1 receptor antagonist
CP-99,994 was studied in the ferret using the centrally acting
opiate receptor agonist
loperamide at a dose (0.5 mg/kg s.c.) which induced
emesis in all animals tested.
CP-99,994 (1 mg/kg, s.c.x2) abolished the
emetic response (retching and
vomiting) and the behaviours (licking, wet dog shakes, mouth scratching and
gagging) induced by
loperamide over a 2-h observation period. The enantiomer of this compound
CP-100,263 (1 mg/kg, s.c.x2) did not have any significant effect on
emesis or related behaviours.
Loperamide (0.5 mg/kg s.c.) administration (but not its vehicle) resulted in dense fos-like immunoreactivity (FLI) mainly throughout the rostro-caudal extent of the nucleus tractus solitarius but not the area postrema. Although
CP-99,994 (1 mg/kgx2) abolished the
loperamide-induced
emesis, it did not have any statistically significant effect on FLI in the brainstem. In
loperamide and
CP-100,263 (1 mg/kg, s.c.x2) treated animals FLI was comparable to that in animals treated with
loperamide and
CP-99,994. The results from this study taken together with those from previous studies indicate that
loperamide exerts its
emetic effect via nucleus tractus solitarius dendrites projecting into the area postrema. The lack of significant effect of
CP-99,994 on the FLI induced by
loperamide in this nucleus suggests that it is acting at a site "deep" in the nucleus tractus solitarius or elsewhere. The marked reduction in behaviours associated with
loperamide administration by
CP-99,994 provides a preliminary indication that NK1 receptor antagonist (as represented by
CP-99,994) may in the clinic have effects on behaviours induced by
emetic agents in addition to their previously described effects on retching and
vomiting.