Differential effects on gastrointestinal and hepatic vagal afferent fibers in the rat by the anti-cancer agent cisplatin

Abstract

Cisplatin, a cancer chemotherapy agent, like many toxins, produces emesis and nausea. Abdominal vagotomy, or treatment with 5-HT 3 receptor antagonists, blocks cisplatin-induced emesis, which suggests that it produces (albeit indirectly) activation of 5-HT 3 receptors on vagal afferent fibers. Cisplatin induces a large release of intestinal 5-hydroxytryptamine (5-HT) that enters the hepatic portal vein, which may activate vagal afferent fibers in the portal vein or liver to induce emesis or other side effects of treatment (e.g., reduced food intake). This study was conducted to assess the effects of cisplatin on gastrointestinal and portal vein/liver vagal afferent fibers by recording the neurophysiological responses of the common hepatic branch (CHB) of the vagus in the rat. The CHB contains vagal afferent fibers that innervate the gastrointestinal (GI) tract, portal vein, and liver. Cisplatin (10 mg/kg; jugular vein, j.v.) produced an increase in multi-unit CHB activity and this effect was blocked by a 5-HT 3-receptor antagonist (Y-25130, 0.8 mg, j.v.). Cutting the gastroduodenal branch (GDB), a sub-branch of the CHB that contains GI afferent fibers, resulted in a complete suppression of the multi-unit CHB discharge produced by cisplatin treatment. Single units that were cisplatin sensitive had their activity reduced by either 5-HT 3 receptor antagonist treatment or cutting the GDB. Conversely, cisplatin insensitive units were not affected by 5-HT 3-antagonism or GDB ablation. The present results indicate that cisplatin activates GI vagal afferent fibers via 5-HT 3 receptors but does not affect portal vein/liver vagal afferent fibers, which indicates that intestinal but not hepatic afferent fibers are involved in the toxic effects of cisplatin.