Suppression of Cisplatin-Induced Vomiting by Cannabis sativa in Pigeons: Neurochemical Evidences

Abstract

Cannabis sativa (CS, family Cannabinaceae) has been reported for its anti-emetic activity against cancer chemotherapy-induced emesis in animal models and in clinics. The current study was designed to investigate CS for potential effectiveness to attenuate cisplatin-induced vomiting in healthy pigeons and to study the impact on neurotransmitters involved centrally and peripherally in the act of vomiting. High-performance liquid chromatography system coupled with electrochemical detector was used for the quantification of neurotransmitters 5-hydroxytryptamine (5HT), dopamine (DA) and their metabolites; Di-hydroxy Phenyl Acetic acid (Dopac), Homovanillic acid (HVA), and 5-hydroxy indole acetic acid (5HIAA) centrally in specific brain areas (area postrema and brain stem) while, peripherally in small intestine. Cisplatin (7 mg/kg i.v.) induce emesis without lethality across the 24 h observation period. CS hexane fraction (CS-HexFr; 10 mg/kg) attenuated cisplatin-induced emesis ∼ 65.85% (P < 0.05); the reference anti-emetic drug, metoclopramide (MCP; 30 mg/kg), produced ∼43.90% reduction (P < 0.05). At acute time point (3^rd h), CS-HexFr decreased (P < 0.001) the concentration of 5HT and 5HIAA in the area postrema, brain stem and intestine, while at 18^th h (delayed time point) CS-HexFr attenuated (P < 0.001) the upsurge of 5HT caused by cisplatin in the brain stem and intestine and dopamine in the area postrema. CS-HexFr treatment alone did not alter the basal neurotransmitters and their metabolites in the brain areas and intestine except 5HIAA and HVA, which were decreased significantly. In conclusion the anti-emetic effect of CS-HexFr is mediated by anti-serotonergic and anti-dopaminergic components in a blended manner at the two different time points, i.e., 3^rd and 18^th h in pigeons.

Keywords: Cannabis sativa; cisplatin; emesis; neurotransmitters; pigeon.

FIGURE 1

Extraction scheme for Cannabis sativa to get n-hexane fraction (Ullah, 2013). The plant material was macerated twice with n-hexane. The extract was filtered and concentrated under reduced pressure using rotary evaporator to get CS-HexFr.

FIGURE 2

Sketch of cisplatin-induced emesis in pigeons and the effect of treatments (A–F) on cisplatin induced emesis profile during a 24 h observation period. (A) Cisplatin control, (B) Metoclopramide treatment, (C) Cannabis sativa hexane fraction 5 mg treatment, (D) Cannabis sativa hexane fraction 10 mg treatment, (E) Cannabis sativa hexane fraction 10 mg BD treatment; the arrow indicates second dose administration, and (F) Cannabis sativa hexane fraction 15 mg treatment. Data represents the mean ± SEM of the total numbers of retches + vomits occurring during 1 h intervals (n = 7–8).

FIGURE 3

Percent protection observed by either once daily dose of Cannabis sativa hexane fraction (OD; 5, 10, and 15 mg/kg) or twice daily (BD; 10 mg/kg) 30 min before cisplatin challenge. The values represent mean ± SEM of 5–8 determinations.

FIGURE 4

The vomiting suppression time profile in pigeons of standard metoclopramide (MCP; 30 mg/kg) or Cannabis sativa hexane fraction (CS-HexFr; 5, 10, and 15 mg/kg) against cisplatin-induced vomiting during a 24 h observation period; each bar represents the mean ± SEM of vomiting episodes occurring during 4 h periods (n = 5–8). Values significantly different from cisplatin control are denoted as ^∗P < 0.05, 2^∗P < 0.01, 3^∗P < 0.001 (ANOVA followed by Tukey’s post hoc test).