Abstract
Background: In different models of paralytic ileus, cannabinoid receptors are overexpressed and endogenous cannabinoids are massively released, contributing to gastrointestinal dysmotility. The antitumoral drug vincristine depresses gastrointestinal motility and a similar mechanism could participate in this effect. Therefore, our aim was to determine, using CB1 and CB2 antagonists, whether an increased endocannabinoid tone is involved in vincristine-induced gastrointestinal ileus.Methods: First, we confirmed the effects of vincristine on the gut mucosa, by conventional histological techniques, and characterized its effects on motility, by radiographic means. Conscious male Wistar rats received an intraperitoneal injection of vincristine (0.1–0.5 mg/kg), and barium sulfate (2.5 ml; 2 g/ml) was intragastrically administered 0, 24, or 48 h later. Serial X-rays were obtained at different time-points (0–8 h) after contrast. X-rays were used to build motility curves for each gastrointestinal region and determine the size of stomach and caecum. Tissue samples were taken for histology 48 h after saline or vincristine (0.5 mg/kg). Second, AM251 (a CB1 receptor antagonist) and AM630 (a CB2 receptor antagonist) were used to determine if CB1 and/or CB2 receptors are involved in vincristine-induced gastrointestinal dysmotility.Key results: Vincristine induced damage to the mucosa of ileum and colon and reduced gastrointestinal motor function at 0.5 mg/kg. The effect on motor function was particularly evident when the study started 24 h after administration. AM251, but not AM630, significantly prevented vincristine effect, particularly in the small intestine, when administered thrice. AM251 alone did not significantly alter gastrointestinal motility.Conclusions: The fact that AM251, but not AM630, is capable of reducing the effect of vincristine suggests that, like in other experimental models of paralytic ileus, an increased cannabinoid tone develops and is at least partially responsible for the alterations induced by the antitumoral drug on gastrointestinal motor function. Thus, CB1 antagonists might be useful to prevent/treat ileus induced by vincristine.
Highlights
Vincristine is a vinca alkaloid widely used in the treatment of hematological malignancies and solid tumors since the 1960’s (Johnson et al, 1960; Bohannon et al, 1963)
We showed that the nonselective cannabinoid agonist WIN 55, 212-2 was not capable of improving cisplatin-induced gastrointestinal dysmotility, and even worsened it (Abalo et al, 2013), whereas at a nonpsychoactive dose, it tended to reduce diarrhea associated to 5fluorouracil treatment (Abalo et al, 2016)
(2) To determine whether the motor alterations induced by vincristine might be prevented by the CB1-selective cannabinoid antagonist AM251 and by the CB2-selective cannabinoid antagonist AM630
Summary
Vincristine is a vinca alkaloid widely used in the treatment of hematological malignancies and solid tumors since the 1960’s (Johnson et al, 1960; Bohannon et al, 1963). It is a cell cycle specific agent which blocks mitosis with metaphase arrest through disruption of the mitotic apparatus and it may affect several body systems (Rosenthal and Kaufman, 1974). Gastrointestinal complications may be present in up to 30–40% of patients receiving vincristine and the earliest symptoms may include colicky abdominal pain, constipation, and adynamic or paralytic ileus as the major manifestations. Our aim was to determine, using CB1 and CB2 antagonists, whether an increased endocannabinoid tone is involved in vincristine-induced gastrointestinal ileus
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