May cannabinoids prevent the development of chemotherapy‐induced diarrhea and intestinal mucositis? Experimental study in the rat

Background The antineoplastic drug 5‐fluoruracil (5‐FU) is a pirimidine analog, which frequently induces potentially fatal diarrhea and mucositis. Cannabinoids reduce gastrointestinal motility and secretion and might prevent 5‐FU‐induced gut adverse effects. Here, we asked whether cannabinoids may prevent diarrhea and mucositis induced by 5‐FU in the rat. Methods Male Wistar rats received vehicle or the non‐selective cannabinoid agonist WIN 55,212‐2 (WIN; 0.5 mg kg−1 injection−1, 1 injection day−1, 4 consecutive days) by intraperitoneal (ip) route; on the first 2 days, animals received also saline or 5‐FU (150 mg kg−1 injection−1, cumulative dose of 300 mg kg−1). Gastrointestinal motor function was radiographically studied after barium contrast intragastric administration on experimental days 1 and 4. Structural alterations of the stomach, small intestine and colon were histologically studied on day 4. PAS staining and immunohistochemistry for Ki67, chromogranin A and CD163 were used to detect secretory, proliferating, and endocrine cells, and activated macrophages respectively. Key Results As shown radiographically, 5‐FU induced significant gastric emptying delay (on days 1 and 4) and diarrhea (on day 4). WIN did not significantly alter the motility curves obtained for either control or 5‐FU‐treated animals but tended to reduce the severity of 5‐FU‐induced diarrhea and increased permanence of barium from day 1 to the beginning of day 4 in 5‐FU‐treated animals. 5‐FU‐induced mucositis was severe and not counteracted by WIN. Conclusions and Inferences 5‐FU‐induced diarrhea, but not mucositis, was partly prevented by WIN at a low dose. Cannabinoids might be useful to prevent chemotherapy‐induced diarrhea.