CISPLATIN-EVOKED INDUCTION OF C-FOS PROTEIN IN THE BRAIN-STEM OF THE FERRET - THE EFFECT OF CERVICAL VAGOTOMY AND THE ANTIEMETIC 5-HT3 RECEPTOR ANTAGONIST GRANISETRON (BRL-43694)

We have monitored the expression of c-fos protein in the medulla oblongata of the ferret, using immunocytochemistry, to identify the brainstem pathways involved in the mediation of nausea and vomiting caused by the antineoplastic drug cisplatin. Cisplatin administration resulted in c-fos-like immunoreactivity (FLI) in the area postrema, the nucleus of the solitary tract, and in scattered cells within the ependymal lining of the fourth ventricle. Unilateral cervical vagotomy greatly reduced FLI in the ipsilateral nucleus of the solitary tract but did not significantly affect reactivity in the contralateral solitary tract nucleus or in the area postrema. Pretreatment of the animals with the 5-HT3 antagonist granisetron (BRL 43694) abolished the retching and vomiting caused by cisplatin and markedly reduced the cisplatin-evoked FLI in the nucleus of the solitary tract; treatment with this drug had no significant effect on cisplatin-evoked FLI in the area postrema. The results suggest that cisplatin induces c-fos gene expression in the nucleus of the solitary tract by an action involving vagal afferent pathways and also by a vagally independent, direct action on the area postrema. The anti-emetic 5-HT3 antagonist drug granisetron mimicked the effect of vagotomy on c-fos protein induction suggesting that it may act via 5-HT3 receptors known to be associated with vagal afferent terminals. The FLI seen in the area postrema was neither vagally dependent nor was it abolished by granisectron. FLI in the area postrema may reflect some vagus nerve activity but also a direct action of cisplatin on the 'chemoreceptor trigger zone for vomiting' which is considered to be in the area postrema, and may represent a central site of action for cisplatin-induced nausea and vomiting. On the other hand, the observation that ependymal cells also show FLI following cisplatin administration raises the possibility that some c-fos protein induction in the area postrema arises from an action of cisplatin, such as DNA damage, which may not be directly associated with its emetic properties.