6-Gingerol, a major ingredient of ginger, attenuated cisplatin-induced pica in rats via regulating 5-HT3R/Ca2+/CaMKII/ERK1/2 signaling pathway

6-gingerol, the representative single ingredient in ginger, was demonstrated antiemetic properties against CINV via blocking the 5-hydroxytryptamine 3 receptors (5-HT3Rs), however, its underlying mechanism has not been fully clarified. Emerging evidence suggested that the 5-HT3R-mediated activation of calcium/calmodulin-dependent protein kinase II/extracellular signal-regulated kinase 1/2 (Ca2+/CaMKII/ERK1/2) signaling pathway may contribute to the occurrence of CINV. We first verified the antiemetic action of 6-gingerol via a cisplatin-induced pica model of rats, and found that 6-gingerol significantly reduced the kaolin intake. Further, 6-gingerol markedly down-regulated the expression of 5-HT3Rs and the levels of calmodulin, CaMKII, p-CaMKII, ERK1/2, p-ERK1/2, and β-arrestin2. Additionally, we demonstrated that 6-gingerol significantly decreased the level of intracellular Ca2+ in NG108-15 cells, and inhibited the Ca2+/CaMKII/ERK1/2 signaling pathway mediated by 5-HT3Rs. Taken together, 6-gingerol has an antiemetic effect against CINV, and the underlying mechanism may be related to the inhibition of the 5-HT3R-mediated Ca2+/CaMKII/ERK1/2 signaling pathway.