5‐HT3 receptor antagonists injected into the area postrema inhibit cisplatin‐induced emesis in the ferret

Abstract

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 μg; GR65630A, 0.001–0.1 μg; MDL72222, 0.1–10 μg. 5 Cisplatin-induced emesis was not inhibited by discrete injection of ketanserin (30 μg) or methiothepin (30 μg) 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.