Cisplatin-evoked induction of c-fos protein in the brainstem of the ferret: the effect of cervical vagotomy and the anti-emetic 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Reynolds
D J
DJ
MRC Unit, Radcliffe Infirmary, Oxford, U.K.
Barber
N A
NA
Grahame-Smith
D G
DG
Leslie
R A
RA
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D001933:Brain Stem / Q000187:drug effects* / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D005260:Female; D005289:Ferrets; D017829:Granisetron; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D009333:Neck / Q000294:innervation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009474:Neurons / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014628:Vagotomy; D014630:Vagus Nerve / Q000502:physiology*
D000932:Antiemetics; D002945:Cisplatin; D017829:Granisetron; D007191:Indazoles; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D012702:Serotonin Antagonists