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 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.
Zaman
S
S
Department of Physiology, St George's Hospital Medical School, Tooting, London, UK.
Woods
A J
AJ
Watson
J W
JW
Reynolds
D J
DJ
Andrews
P L
PL
D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology; D001933:Brain Stem / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D005289:Ferrets; D008139:Loperamide / Q000494:pharmacology*; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000187:drug effects / Q000276:immunology; D011597:Psychomotor Performance / Q000187:drug effects; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism
D000930:Antidiarrheals; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D008139:Loperamide