ABSTRACT
The effects of a novel tachykinin NK1-receptor antagonist HSP-117 [(2S,3S)-3-[(5-isopropyl-2,3-dihydrobenzofuran-7-yl)methyl]amino-2-phenylpiperidine dihydrochloride] on cisplatin-induced pica, i.e., the eating of nonnutritive substances such as kaolin were examined in rats. HSP-117 inhibited kaolin intake in a dose-dependent manner for 2 days. The 5-HT3-receptor antagonist ondansetron inhibited only on the first day, but not on the second day. These results indicate that the cisplatin-induced kaolin intake on the first day is related to both 5-HT3- and NK1 receptors, while only the NK1 receptor is involved on the second day. Thus, cisplatin-induced continuous pica in rats represents a useful model of not only acute but also delayed emesis.
Subject(s)
Antineoplastic Agents/adverse effects , Benzofurans/pharmacology , Cisplatin/adverse effects , Neurokinin-1 Receptor Antagonists , Pica/chemically induced , Piperidines/pharmacology , Vomiting/prevention & control , Animals , Humans , Rats , Rats, Wistar , Vomiting/chemically inducedABSTRACT
The role of tachykinin NK-1 receptors in the area postrema (AP) in emesis was examined in ferrets. Strong c-fos-like immunoreactivity was observed in the AP and nucleus tractus solitalius (NTS) in cisplatin (10 mg/kg, i.p.)-treated animals, but not in control animals. The number of the central emetogen morphine-induced vomits and retches was remarkably reduced (95%) and that of the peripheral emetogen copper sulphate-induced vomits was significantly (54%) reduced by AP lesion. Pretreatment with the tachykinin NK-1 receptor antagonists HSP-117 (1.0 microg) and CP-99,994 (7.5 microg) into the AP decreased the numbers of vomits and retches induced by morphine and copper sulphate. These results suggest that NK-1 receptors in the AP are involved in the mechanism of emesis induced by morphine and copper sulphate.
Subject(s)
Chemoreceptor Cells/drug effects , Chemoreceptor Cells/metabolism , Fourth Ventricle/drug effects , Fourth Ventricle/metabolism , Medulla Oblongata/drug effects , Medulla Oblongata/metabolism , Receptors, Neurokinin-1/drug effects , Receptors, Neurokinin-1/metabolism , Tachykinins/metabolism , Vomiting/physiopathology , Animals , Antiemetics/pharmacology , Antineoplastic Agents/pharmacology , Benzofurans/pharmacology , Chemoreceptor Cells/cytology , Cisplatin/pharmacology , Copper Sulfate/pharmacology , Drug Interactions/physiology , Ferrets , Fourth Ventricle/cytology , Male , Medulla Oblongata/cytology , Morphine/pharmacology , Narcotics/pharmacology , Neurokinin-1 Receptor Antagonists , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Piperidines/pharmacology , Proto-Oncogene Proteins c-fos/drug effects , Proto-Oncogene Proteins c-fos/metabolism , Radioligand Assay , Solitary Nucleus/cytology , Solitary Nucleus/drug effects , Solitary Nucleus/metabolism , Substance P/metabolism , Substance P/pharmacology , Tachykinins/antagonists & inhibitors , Tritium , Vomiting/drug therapyABSTRACT
Substance P (SP) is a member of the tachykinin family of bioactive peptides and has highest affinity for the NK-1 receptor. We have developed the non-peptide compound HSP-117 as a selective antagonist of the NK-1 receptor. Binding of 3H-SP to the membranes of IM-9 cells was inhibited by the antagonists HSP-117 and CP-99,994, the inhibitory activity of HSP-117 being 50-fold that of CP-99,994. The SP-induced firing responses of single neuron activity in slices of the nucleus tractus solitarius of ferrets were inhibited by 10 microM HSP-117. Intracerebroventricular injection of HSP-117 significantly inhibited retching and vomiting induced by copper sulphate and morphine and the inhibitory effect of HSP-117 on emesis was greater than that of CP-99,994. Moreover, emesis induced by copper sulphate and morphine were inhibited by the microinjection of HSP-117 and CP-99,994 into the area postrema and by lesion of the area postrema. These results indicate that HSP-117 is a potent anti-emetic agent, blocking NK-1 receptors in the area postrema and that NK-1 receptors in the area postrema play an important role in emesis induced by broad-spectrum emetic stimuli.
Subject(s)
Antiemetics/pharmacology , Benzofurans/pharmacology , Medulla Oblongata/chemistry , Piperidines/pharmacology , Receptors, Neurokinin-1/physiology , Vomiting/physiopathology , Animals , Copper Sulfate , Ferrets , Morphine , Receptors, Neurokinin-1/analysis , Solitary Nucleus/drug effects , Stereoisomerism , Vomiting/chemically inducedABSTRACT
We have developed a non-peptide compound, HSP-117, antagonist of the tachykinin NK-1 receptor. Binding of 3H-substance P (SP) to the membranes of IM-9 cells was inhibited by the antagonists HSP-117 and CP-99,994, the inhibitory activity of HSP-117 being about 50-fold that of CP-99,994. The SP-induced firing responses of single neuron activity in slices of the nucleus tractus solitarius of ferrets were inhibited by 10 microM HSP-117. Intracerebroventricular injection of HSP-117 significantly inhibited retching and vomiting induced by copper sulphate and morphine and the inhibitory effect of HSP-117 on emesis was greater than that of CP-99,994. These results indicate that (1) HSP-117 is a potent anti-emetic agent, blocking NK-1 receptors in the nucleus tractus solitarius and (2) NK-1 receptors in the nucleus tractus solitarius play an important role in emesis induced by broad-spectrum emetic stimuli.