Investigation of the mechanisms and modulation of irinotecan‐induced emesis in Suncus murinus

BACKGROUND AND PURPOSE: Irinotecan is a widely used chemotherapeutic agent that frequently causes nausea and emesis. Its emetic mechanism of action is poorly understood and the choice of drugs to reduce nausea and emesis is largely empirical. EXPERIMENTAL APPROACH: Using Suncus murinus, we examined (i) the dose-response and temporal profile of irinotecan-induced emesis; (ii) emetic potential of its active metabolite, SN-38; (iii) involvement of vagal and central pathways; (iv) efficacies of classical antiemetics administered alone, or in combinations. Behavioural, respiratory, metabolic and c-Fos immunohistochemical analyses were used to delineate mechanisms involved in emesis control. A microelectrode array (MEA) system assessed the effects of irinotecan and SN-38 on gastrointestinal slow-wave activity. KEY RESULTS: Irinotecan induced dose-dependent emesis within 24 h, whereas SN-38 was inactive. Neither compound altered respiration. Bilateral abdominal vagotomy attenuated early-phase (0-4 h) of irinotecan-induced emesis. Palonosetron suppressed emesis and was the most effective monotherapy; olanzapine alone also showed antiemetic efficacy. Notably, olanzapine-containing combinations with palonosetron and aprepitant or dexamethasone provided superior protection compared with monotherapies. Irinotecan increased c-Fos expression in the brainstem, and hypothalamic and limbic regions; palonosetron selectively reduced brainstem activation. Serum metabolomics revealed reduced tyramine levels and associations between emetic episodes and 5-HT-related pathways. MEA recordings showed that irinotecan, but not SN-38, produced selective disruptions of upper-gut rhythmic activity. CONCLUSION AND IMPLICATIONS: Irinotecan-induced emesis is mediated predominantly through 5-HT₃-dependent vagal-brainstem pathways with additional activation of hypothalamic and limbic regions. Altered intestinal pacemaker activity and 5-HT metabolism may contribute to gastrointestinal adverse effects.