Evidence that 5-hydroxytryptamine3 receptors mediate cytotoxic drug and radiation-evoked emesis

Abstract

Summary The involvement of 5-hydroxytryptamine (5-HT) 5-HT3 receptors in the mechanisms of severe emesis evoked by cytotoxic drugs or by total body irradiation have been studied in ferrets. Anti-emetic compounds tested were domperidone (a dopamine antagonist), metoclopramide (a gastric motility stimulant and dopamine antagonist at conventional doses, a 5-HT3 receptor antagonist at higher doses) and BRL 24924 (a potent gastric motility stimulant and a 5-HT3 receptor antagonist). Domperidone or metoclopramide prevented apomorphine-evoked emesis, whereas BRL 24924 did not. Similar doses of domperidone did not prevent emesis evoked by cis-platin or by total body irradiation, whereas metoclopramide or BRL 24924 greatly reduced or prevented these types of emesis. Metoclopramide and BRL 24924 also prevented emesis evoked by a combination of doxorubicin and cyclophosphamide. These results are discussed in terms of a fundamental role for 5-HT3 receptors in the mechanisms mediating severely emetogenic cancer treatment therapies.There have recently been two important advances relating to the improvement of anti-emetic treatment given to patients undergoing anti-cancer therapies. Firstly, it was found that, unlike conventional doses of metoclopramide (Maxolon; Beecham Pharmaceuticals) which antagonise dopamine receptors and stimulate gastric motility, high doses of the drug greatly reduced cis-platin-evoked emesis (Gralla et al., 1981). In contrast, even high doses of the dopamine antagonists, domperidone (Motilium; Janssen Pharmaceuticals) or alizapride, have little or no ability to prevent cis-platininduced emesis (Tonato et al., 1985;Saller & Hellenbrecht, 1985). Mechanisms other than dopamine receptor antagonism have therefore been implicated in this antiemetic action of metoclopramide (McRitchie et al., 1984).Secondly, metoclopramide is an antagonist of 5-hydroxytryptamine (5-HT) acting on 5-HT3 receptors (previously known as 5-HT M-receptors; see Bradley et al., 1986 for definition of this receptor) located in the peripheral nervous system (Fozard, 1984a); the effective concentrations of metoclopramide are higher than those required to antagonise dopamine receptors or to stimulate gut motility (Sanger, 1984). We subsequently suggested that such high doses of metoclopramide may prevent cis-platin-induced emesis by means of antagonising 5-HT3 receptors .The involvement of 5-HT3 receptors in the mechanisms of emesis have now been further investigated using chemo-and radio-emetic stimuli in the ferret. The ferret has previously been shown to be suitable for studying emesis evoked by cisplatin (Florczyk et al., 1982;), a combination of doxorubicin and cyclophosphamide (Schurig et al., 1984) or by whole-body irradiation (Andrews et al., 1986;Gylys & Gidda, 1986

5-Hydroxyindoleacetic acid (5-HIAA) and cortisol excretion as predictors of chemotherapy-induced emesis

“…The combination of 5-hydroxytryptamine-3-receptor (5-HT3) antagonists with corticosteroids represents the most effective anti-emetic treatment in platinum-based and cyclophosphamide-based chemotherapy (Roila et al, 1991;Italian Group for Antiemetic Research, 1995). These clinical experiences as well as experimental data (Cubeddu et al, 1990;Schworer et al, 1991;Miner et al, 1987;Fredrickson et al, 1992) indicate a role for serotonin and corticosteroid metabolism in the pathophysiology of emesis. The mechanism of anti-emetic action of the 5-HT3 antagonists mainly reflects their capability of blocking 5-HT3 receptors which are believed to play a crucial role in the afferent part of the emetic reflex.…”

The agonist properties of m‐chlorophenylbiguanide and 2‐methyl‐5‐hydroxytryptamine on 5‐HT3 receptors in N1E‐115 neuroblastoma cells

“…5-HT3 receptors directly gate a cation channel (Derkach et al, 1989); activation of 5-HT3 receptors in vertebrate neurones causes rapid depolarization (Wallis & Nash, 1981;Ireland & Tyers, 1987) and single channel characteristics of these receptors have been described in guinea-pig submucous plexus (Derkach et al, 1989). Interest in 5-HT3 receptors in the central nervous system has been stimulated by evidence suggesting that drugs acting at this receptor have potential in the treatment of emesis, anxiety and various psychotic illnesses (Costall et al, 1987;Miner et al, 1987;Jones et al, 1988). 5-HT3 receptors are present at relatively low density in CNS tissue (Kilpatrick et al, 1987), but are present in much greater concentrations in certain neuronal cell lines, including NIE-1 15 neuroblastoma cells, NG108-15 neuroblastoma-glioma hybrid cells and NCB-20 neuroblastoma hybrid cells (Neijt et al, 1988;Hales et al, 1988;Yakel & Jackson, 1988 (Lummis et al, 1990).…”

Casopitant: a novel NK1-receptor antagonist in the prevention of chemotherapy-induced nausea and vomiting

“…10 The fundamental role for serotonin and 5-HT 3 _ receptors in the emetic pathway was discovered in the mid 1980s, giving rise to the development of 5-HT 3 -receptor antagonists. 13 Recently, the role of substance P and the neurokinin 1 (NK 1 ) receptors in the emetic pathway has been investigated, resulting in development of the NK 1 receptor antagonists.…”