5-HT3 receptor antagonists injected into the area postrema inhibit cisplatin-induced emesis in the ferret.
1. The purpose of the present study was to identify and investigate the role of 5-hydroxytryptamine3 (5-HT3) receptors in the area postrema in the control of cisplatin-induced emesis in the ferret. 2. Homogenate binding and autoradiography experiments using the high affinity 5-HT3 receptor ligand, [3H]-GR65630, identified the presence of a high concentration of 5-HT3 receptors in the area postrema of the ferret. 3. Intraperitoneal injection of the 5-HT3 receptor antagonists, GR38032F, GR65630A and MDL72222, at doses of 1, 0.1 and 1 mg kg-1 respectively, inhibited emesis induced by cisplatin, 9 mg kg-1 i.p. 4. Discrete injection of low doses of the 5-HT3 receptor antagonists directly into the area postrema region also inhibited cisplatin-induced (9 mg kg-1 i.p.) emesis. The dose ranges used were: GR38032F, 0.01-1 microgram; GR65630A, 0.001-0.1 microgram; MDL72222, 0.1-10 micrograms. 5. Cisplatin-induced emesis was not inhibited by discrete injection of ketanserin (30 micrograms) or methiothepin (30 micrograms) into the area postrema. Injection of the 5-HT3 receptor agonist, 2-methyl-5-HT, directly into the area postrema produced an incomplete emetic response. 6. These results confirm a role of 5-HT, and in particular 5-HT3 receptors, in the control of cisplatin-induced emesis, and show that at least one functional site for these receptors in modulating the emetic response is the area postrema, the locus of the chemoreceptor trigger zone.
Higgins
G A
GA
Department of Neuropharmacology, Glaxo Group Research Ltd., Herts.
Kilpatrick
G J
GJ
Bunce
K T
KT
Jones
B J
BJ
Tyers
M B
MB
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001345:Autoradiography; D001923:Brain Chemistry; D002335:Carnivora / Q000502:physiology*; D002945:Cisplatin / Q000037:antagonists & inhibitors*; D005260:Female; D005289:Ferrets / Q000502:physiology*; D007276:Injections, Intraventricular; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008719:Methiothepin / Q000494:pharmacology; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014839:Vomiting / Q000139:chemically induced*
D012702:Serotonin Antagonists; D012701:Serotonin; D008719:Methiothepin; C045918:2-methyl-5-HT; D007650:Ketanserin; D001058:Apomorphine; D002945:Cisplatin