The effect of the NK1 receptor antagonist CP-99,994 on emesis and c-fos protein induction by loperamide in the ferret

The site of the anti-emetic action of the neurokinin, receptor antagonist C P-99,994 was studied in the ferret using the centrally acting opiate recept or agonist loperamide at a dose (0.5 mg/kg s.c.) which induced emesis in al l 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 i n dense fos-like immunoreactivity (FLI) mainly throughout the rostro-caudal extent of the nucleus tractus solitarius but nor the area postrema. Althou gh CP-99,994 (1 mg/kgx2) abolished the loperamide-induced emesis, it did no t have any statistically significant effect on FL in the brainstem. In lope ramide and CP-100,263 (1 mg/kg, s.c.x2) treated animals FLI was comparable to that in animals heated 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 soli tarius dendrites projecting into the area postrema. The lack of significant effect of CP-99,994 on the FLI induced by loperamide in this nucleus sugge sts that it is acting at a site "deep" in the nucleus tractus solitarius or elsewhere. The marked reduction in behaviours associated with loperamide a dministration by CP-99,994 provides a preliminary indication that NK, recep tor antagonist (as represented by CP-99,994) may in the clinic have effects on behaviours induced by emetic agents in addition to their previously des cribed effects on retching and vomiting. (C) 2000 Elsevier Science Ltd. All rights reserved.