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Neuroendocrinology Letters incl. Psychoneuroimmunology & Chronobiology

 

NeuroendocrinologyİLetters
ISSNİ0172ñ780X Copyrightİ©İ1997 NeuroendocrinologyİLetters

NEL Vol. 18 No. 2/3
Review Article

1998; 18:85-102
pii: NEL182397R03

 

Neurochemical Markers of Emesis Induced by Anti-Cancer Drugs:
Role of Central Mechanisms

by Parvez, S. H. , Minami, M., Caudy, P., Endo, T., Parvez, S. Hirafuji, M., Hamaue, N., Akita, K., Saito, H., Yoshioka, M., and Qureshi, G.

Introduction

Emesis is an instinctive defense reaction caused by the somato-autonomic nerve reflex, which is integrated in the medulla oblongata. Neurochemical and neuronal mechanisms involved in the emetic response and relevant receptors seem to be rather complicated relative to emetic stimuli. It is well known that dopamine receptor agonists and L-DOPA are effective drugs for the treatment of Parkinson's disease. These drugs, however, frequently (approximately 30%) cause nausea and vomiting as unavoidable side effects by stimulating dopamine receptors in peripheral and brain tissues. The emetic action of dopamine agonists has generally been assumed to be mediated by action on dopamme receptors located in the chemoreceptor trigger zone (CTZ), the tract of the nucleus solitarius (NTS), or the stomach vagus neurons, and to be well inhibited by dopamine receptor antagonists such as metoclopramide and domperidone (Finder et al., 1976; Andrews et al., 1990; Mitchelson, 1992; Andrews and Bhandari, 1993). The emetic effects of talipexole have appeared to be triggered by stimulation of the above dopamine receptors, because haloperidol (Hsu et al., 1986) and metoclopramide dose-dependently .suppress the drug induced vomiting in dogs, which were the animals with the most vigorous vomiting among the examined animal species. Talipexole, an azepine-derivative D2, receptor agonist, showed a greater effectiveness and fewer emetic side effects when compared with bromocriptine, the most widely used dopamine receptor agonist (Nakanishi et al., 1993). Talipexole, in a dose sufficient to produce antiparkinsonian activity, did not induce emesis to the extent found with bromocriptine in cynomolgus monkeys (Kohno et al., 1996a). Recently, Nishio et al. (1996) have found that talipexole has a weak serotonin 5-HT3 receptor blocking effect, while bromocriptine lacks this effect.

Figure 1. A diagram summarizing the pathways involved in emesis. Rache: Nucleus Rache, AP: area postrema, IV: 4 th ventricle, 5-HT: 5-hydroxytryptamine (serotonin), EC: enterochromaffin cell, GI: gastrointestinal.

A number of studies indicate that 5-HT and 5-HT3 receptors are involved in the emetic response. Emetic compounds elevate 5-HT release from intestinal enterochromaffin (EC) cells, activate 5-HT3 receptors on abdominal afferent vagal axons, and evoke an abnormal discharge in the vagal fibers projecting to the area postrema, which in turn cause the vomiting reflex by releasing 5-HT and stimulating 5-HT3 receptors in the area postrema (Fig. 1) (Andrews et al., 1990; Mitchelson, 1992; Andrews and Bhandari, 1993).
Emesis, a distress side effects of cancer chemotherapy, may lead to a patient's refusal of therapy. We have previously reported that cisplatin and copper sulfate increase abdominal afferent vagal activity in a time course parallel to retching and vomiting in ferrets (Endo et al., 1995), and the administration of 5-HT3 receptor antagonist suppress both vagal activity and emesis.

This chapter will discuss the identification of emesis as an unavoidable side effect induced by centrally acting drugs and anti-cancer drugs. This review may be summarized as follows: 1) Cytotoxic drugs or centrally acting emetic drugs have an initial action within the gut that results in histological changes, activation of the biosynthesis of 5-HT, and an increase in the concentration of 5-HT in the gastrointestinal tract. 2) The 5-HT is released from the EC cells of the intestinal mucosa, which in rurn stimulates 5- HT3 receptors on the vagal afferent nerve fibers. 3) This stimulation of vagal afferent fibers results in an increase in 5-HT in the vomiting center rather than a direct action of emetic drugs at this level and leads to emesis. 4) The 5-HT in circulation trapped by platelets is metabolized to 5-hydroxyindole acetic acid (5-HIAA) in the liver and 5-HIAA is excreted in the urine.

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