Probable involvement of the 5-hydroxytryptamine(4) receptor in methotrexate-induced delayed emesis in dogs

J Pharmacol Exp Ther. 2000 Mar;292(3):1002-7.

Abstract

Delayed emesis in cancer patients undergoing chemotherapy remains a significant problem. The pathogenesis of delayed emesis is still obscure. It was recently demonstrated that methotrexate (MTX), an anticancer drug, evoked delayed emesis in dogs in a manner similar to its actions in humans. We evaluated the antiemetic activity of FK1052, a potent antagonist for both the 5-hydroxytryptamine (HT)(3) and 5-HT(4) receptors, on delayed emesis induced by MTX in beagle dogs. Animal behavior was recorded for 3 days using a video camera. Delayed emesis lasting up to 72 h was observed in dogs treated with MTX (2.5 mg/kg i.v.), but acute emesis did not occur. The following antiemetics, at the dose that prevents cisplatin-induced acute emesis in dogs, were administered i.v. as multiple injections every 12 h during days 2 to 3. FK1052 (1 and 3.2 mg/kg) significantly reduced the emetic episodes caused by MTX, whereas ondansetron (1 mg/kg), a selective 5-HT(3) receptor antagonist, was not effective. The emetic episodes induced by MTX were also inhibited by another 5-HT(3/4) receptor antagonist, tropisetron (1 mg/kg). CP-122,721 (0. 1 mg/kg), a potent selective tachykinin NK(1) receptor antagonist, significantly reduced the emetic responses to MTX. Copper sulfate-induced emesis in dogs was also prevented by FK1052, tropisetron, and CP-122,721 but not by ondansetron. FK1052, tropisetron, and ondansetron had negligible affinity for the NK(1) receptor at 1 microM. These results suggest that the 5-HT(4) receptor may be in part involved in the production of delayed emesis induced by MTX in dogs and that FK1052 may be a useful drug against both acute and delayed emesis induced by cancer chemotherapy.

MeSH terms

  • Animals
  • Antiemetics / pharmacology*
  • Cisplatin / toxicity
  • Copper Sulfate / pharmacology
  • Dogs
  • Female
  • Imidazoles / pharmacology*
  • Indoles / pharmacology*
  • Male
  • Methotrexate / toxicity*
  • Piperidines / pharmacology
  • Receptors, Neurokinin-1 / physiology
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin, 5-HT3
  • Receptors, Serotonin, 5-HT4
  • Serotonin Antagonists / pharmacology*
  • Time Factors
  • Vomiting / chemically induced*
  • Vomiting / prevention & control

Substances

  • Antiemetics
  • Imidazoles
  • Indoles
  • Piperidines
  • Receptors, Neurokinin-1
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Serotonin Antagonists
  • FK 1052
  • Receptors, Serotonin, 5-HT4
  • Copper Sulfate
  • Cisplatin
  • (2S,3S)-2-phenyl-3-((5-trifluoromethoxy-2-methoxy)benzylamino)piperidine
  • Methotrexate