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

• Published in: Neurogastroenterology and motility Vol. 29; no. 3; pp. np - n/a
• Main Authors: Abalo, R., Uranga, J. A., Pérez‐García, I., Andrés, R., Girón, R., Vera, G., López‐Pérez, A. E., Martín‐Fontelles, M. I.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-03-2017
• Subjects: 5‐fluorouracil; Animals; Antineoplastic Agents - toxicity; cannabinoids; Cannabinoids - pharmacology; Cannabinoids - therapeutic use; chemotherapy‐induced adverse effects; diarrhea; Diarrhea - chemically induced; Diarrhea - pathology; Diarrhea - prevention & control; Fluorouracil - toxicity; gastrointestinal motility; Gastrointestinal Motility - drug effects; Gastrointestinal Motility - physiology; Intestinal Mucosa - drug effects; Intestinal Mucosa - pathology; Male; Mucositis - chemically induced; Mucositis - diagnostic imaging; Mucositis - prevention & control; Rats; Rats, Wistar; 5-fluorouracil; chemotherapy-induced adverse effects; gastrointestinal motility; cannabinoids; diarrhea
• ISSN: 1350-1925; 1365-2982
• DOI: 10.1111/nmo.12952

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.
In this article, we have characterized the effects of the antineoplastic drug 5‐fluorouracil using X‐rays and conventional histology in the rat, and have evaluated whether cannabinoids might be useful for treating 5‐FU‐induced diarrhea. A low dose of the non‐selective cannabinoid agonist WIN partially prevented the development of diarrhea, probably through actions on motility, but did not prevent 5‐FU‐induced mucositis. This is the first experimental study on the effects of cannbinoids on chemotherapy‐induced diarrhea.