Ginger and its pungent constituents non-competitively inhibit activation of human recombinant and native 5-HT₃ receptors of enteric neurons

Background: Beneficial effects of ginger in the treatment of gastrointestinal (GI) problems and chemotherapy-induced nausea and vomiting are well accepted. In rodents, the action of ginger seems to be mediated by the inhibition of 5-HT₃ receptors, which are established targets to combat emesis and irritable bowel syndrome. Methods: Heterologously expressed human 5-HT₃A or 5-HT₃AB receptors were characterized by means of Ca²⁺influx studies using HEK293 cells. Complementing Ca²⁺ measurements in Fluo-4-AM-stained whole-mount preparations of the human submucous plexus were carried out. Furthermore, [3H]GR65630 binding assays were performed to reveal the mode of action of ginger and its pungent compounds. Key Results: We show for the first time that ginger extracts and its pungent arylalkane constituents concentration-dependently inhibit activation of human 5-HT₃ receptors. Ginger extracts inhibited both receptors with increasing content of pungent compounds, confirming that these are part of ginger's active principle. Inhibition potencies of the arylalkanes 6-gingerol and 6-shogaol on both receptors were in the low micromolar range. A lipophilic ginger extract and 6-gingerol had no influence on 5-HT potency, but reduced the 5-HT maximum effect, indicating non-competitive inhibition. The non-competitive action was confirmed by [³H]GR65630 binding, showing that the ginger extract did not displace the radioligand from 5-HT₃A and 5-HT₃AB receptors. The potential relevance of the inhibitory action of ginger on native 5-HT₃ receptors in the gut was confirmed in whole-mount preparations of the human submucous plexus. While a general neurotoxic effect of 6-gingerol was ruled out, it inhibited the 2-methyl-5-HT-mediated activation of 5-HT₃ receptors residing on enteric neurons. Conclusions & Inferences: Our findings may encourage the use of ginger extracts to alleviate nausea in cancer patients receiving chemotherapy and to treat functional GI disorders.