Integrated behavioral and biological assessment reveals 5-HT3 receptor-independent nausea/malaise-like responses in...

Cisplatin exhibits anticancer effects but causes serious side effects, including nausea. Considering nausea is a subjective sensation and challenging to evaluate in genetically manipulable animal models (particularly mice), its neural basis remains unclear. Although 5-hydroxytryptamine type 3 receptor (5-HT3R) signaling is a major pathway in chemotherapy-induced vomiting and its antagonists can prevent vomiting, they are less effective against nausea. It has recently been hypothesized that growth differentiation factor 15 (GDF15)-GFRAL pathway may be involved in cisplatin-induced nausea/malaise-like behavior. Furthermore, systemic administration of 5-HT3R antagonists can partially suppress reductions in food intake and body weight caused by exogenous GDF15 administration. However, the functional relationship between the 5-HT3R and GDF15-GFRAL system remains unclear. Herein, we comprehensively evaluated cisplatin-induced nausea/malaise-like states by analyzing reduced food intake, weight loss, decreased spontaneous activity, increased pica behavior, and conditioned taste aversion in cisplatin-administered wild-type (WT) mice. These behavioral changes were observed to a similar extent in 5-HT3R knockout (KO) mice, indicating that 5-HT3R signaling is not essential for cisplatin-induced nausea/malaise-like behavior. Furthermore, the numbers of c-Fos-positive and c-Fos/GFRAL double-positive cells were increased in the area postrema and nucleus tractus solitarius in both WT and 5-HT3R KO mice, accompanied by elevated plasma GDF15 levels persisting for at least 1 day after cisplatin administration. These results suggest that GDF15-GFRAL signaling may be involved in the development of cisplatin-induced malaise-like states via a 5-HT3R-independent pathway. This study contributes to a better understanding of the neural basis of chemotherapy-induced nausea and may help identify new therapeutic targets.