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

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. 

To address this, Osaka Metropolitan University researchers 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.

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