Role of the endocannabinoid system in the control of mouse myometrium contractility during the menstrual cycle.

Cannabis and cannabinoids are known to affect female reproduction. However, the role of the endocannabinoid system in mouse uterine contractility in the dioestrus and oestrus phases has not been previously investigated. The present study aimed at filling this gap. Endocannabinoid (anandamide and 2-arachidonoylglycerol) levels were measured in mouse uterus at dioestrus and oestrus phases by liquid chromatography-mass spectrometry; quantitative reverse transcription-PCR and western blot were used to measured the expression of cannabinoid receptors and enzymes involved in the metabolism of endocannabinoids. Contractility was evaluated in vitro either on the spontaneous contractions or by stimulating the isolated uterus with exogenous spasmogens. The tissue concentrations of anandamide and 2-AG were reduced in the oestrus phase, compared to dioestrus. Uteri obtained in the dioestrus, but not oestrus, phase showed spontaneous phasic prostaglandin-mediated contractions that were reduced by ACEA (CB1 receptor agonist) and to a lower extent by JWH133 (CB2 receptor agonist). These inhibitory effects were counteracted by the corresponding selective antagonists. Neither ACEA nor JWH133 did affect the contractions induced by exogenous PGE2 in the uterus from the oestrus phase. The FAAH inhibitor JNJ1661010 and, to a lower extent, the MAGL inhibitor JZL184 also reduced spontaneous contractions. It is concluded that the endocannabinoid system undergoes to adaptive changes between the oestrus and dioestrus phases. CB1 and, to a lower extent, CB2 receptor activation results in selective inhibition of myometrial contractility, without un-specific relaxing effects on the smooth muscle. These results might be of interest for female marijuana smokers as well as for the design of novel tocolytic agents.

An Orally Active Cannabis Extract with High Content in Cannabidiol attenuates Chemically-induced Intestinal Inflammation and Hypermotility in the Mouse.

Anecdotal and scientific evidence suggests that Cannabis use may be beneficial in inflammatory bowel disease (IBD) patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD), here named CBD BDS for "CBD botanical drug substance," on mucosal inflammation and hypermotility in mouse models of intestinal inflammation. Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Motility was evaluated in the experimental model of intestinal hypermotility induced by irritant croton oil. CBD BDS or pure CBD were given - either intraperitoneally or by oral gavage - after the inflammatory insult (curative protocol). The amounts of CBD in the colon, brain, and liver after the oral treatments were measured by high-performance liquid chromatography coupled to ion trap-time of flight mass spectrometry. CBD BDS, both when given intraperitoneally and by oral gavage, decreased the extent of the damage (as revealed by the decrease in the colon weight/length ratio and myeloperoxidase activity) in the DNBS model of colitis. It also reduced intestinal hypermotility (at doses lower than those required to affect transit in healthy mice) in the croton oil model of intestinal hypermotility. Under the same experimental conditions, pure CBD did not ameliorate colitis while it normalized croton oil-induced hypermotility when given intraperitoneally (in a dose-related fashion) or orally (only at one dose). In conclusion, CBD BDS, given after the inflammatory insult, attenuates injury and motility in intestinal models of inflammation. These findings sustain the rationale of combining CBD with other minor Cannabis constituents and support the clinical development of CBD BDS for IBD treatment.