Vagal afferent fibers and peripheral 5-HT3 receptors mediate cisplatin-induced emesis in dogs.
The involvement of visceral afferent fibers and 5-HT3 receptors in the emesis induced by cisplatin was studied in beagle dogs. The emesis induced by cisplatin (3 mg/kg, i.v.) was inhibited by the intravenous administration of ICS205930 (2 x 0.01 or 2 x 0.1 mg/kg) and MDL72222 (2 x 0.5 mg/kg), 5-HT3 receptor antagonists, but not by the intravenous administration of metoclopramide (2 x 0.5 mg/kg), a dopamine D2 receptor antagonist. The cisplatin-induced emesis was also suppressed by the intravenous administration of para-chlorophenylalanine (300 mg/kg/day for 3 days), an inhibitor of 5-HT synthesis. On the other hand, the administration of ICS205930 into the IVth ventricle (2 x 0.01 mg/animal) had no effects on the cisplatin-induced emesis. The cisplatin-induced emesis was completely inhibited by abdominal vagotomy and splanchnicectomy, but not by splanchnicectomy alone. On the contrary, the emesis induced by apomorphine was suppressed by the intravenous (0.1 mg/kg) or intracerebroventricular (0.05 mg/animal) administration of metoclopramide, but not by visceral nerve section. These results strongly suggest that cisplatin evokes emesis mainly by acting on the vagal afferent terminals through the release of 5-HT and that peripheral 5-HT3 receptors are involved in this action.
Fukui
H
H
Drug Safety Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan.
Yamamoto
M
M
Sato
S
S
D000344:Afferent Pathways / Q000503:physiopathology; D000818:Animals; D002945:Cisplatin / Q000633:toxicity*; D004285:Dogs; D005260:Female; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008787:Metoclopramide / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology; D014326:Tropanes / Q000494:pharmacology; D000077526:Tropisetron; D014630:Vagus Nerve / Q000503:physiopathology; D014839:Vomiting / Q000139:chemically induced* / Q000503:physiopathology
D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D014326:Tropanes; D000077526:Tropisetron; D008787:Metoclopramide; C042253:bemesetron; D002945:Cisplatin