CB₂ receptors in reproduction

Abstract

Cannabinoids have been always identified as harmful drugs because of their negative effects on male and female reproduction. The discovery of the 'endocannabinoid system (ECS)', composed of bioactive lipids (endocannabinoids), their receptors and their metabolic enzymes, and the generation of mouse models missing cannabinoid receptors or other elements of the ECS, has enabled a wealth of information on the significance of endocannabinoid signalling in multiple reproductive events: Sertoli cell survival, spermatogenesis, placentation, fertilization, preimplantation embryo development, implantation and postimplantation embryonic growth. These studies have also opened new perspectives in clinical applications, pointing to the ECS as a new target for correcting infertility and for improving reproductive health in humans. This review will focus on the involvement of type-2 cannabinoid (CB 2 ) receptors in reproductive biology, covering both the male and female sides. It will also discuss the potential relevance of the immunological activity of CB 2 at the maternal/foetal interface, as well as the distinctiveness of CB 2 versus type-1 cannabinoid (CB 1 ) receptors that might be exploited for a receptor subtype-specific regulation of fertility. In this context, the different signalling pathways triggered by CB 1 and CB 2 (especially those controlling the intracellular tone of nitric oxide), the different activation of CB 1 and CB 2 by endogenous agonists (like anandamide and 2-arachidonoylglycerol) and the different localization of CB 1 and CB 2 within membrane subdomains, termed 'lipid rafts', will be discussed. It is hoped that CB 2 -dependent endocannabinoid signalling might become a useful target for correcting infertility, in both men and women.

Histomorphometric evaluation of cannabinoid receptor and anandamide modulating enzyme expression in the human endometrium through the menstrual cycle

“…Increased plasma concentrations of AEA are also associated with 1st trimester miscarriage through mechanisms that might involve its binding to cannabinoid receptors CB1 and CB2 El-Talatini et al 2009a;Habayeb et al 2008b;Maccarrone 2008;Trabucco et al 2009). Thus, the expression and function of AEA and its receptors appear to be critical in providing the correct environment for the establishment and maintenance of a successful pregnancy.…”

The endocannabinoid system and pivotal role of the CB 2 receptor in mouse spermatogenesis

“…The present study, however, was mostly focused on the possible role of CB 2 receptors in spermatogenesis, a possibility that was recently hypothesized (31) but not yet investigated. Our findings clearly show, at both transcriptional and transductional levels, the presence of CB 2 receptors in male germ cells from mitotic SPG to haploid SPT.…”

Comprehensive profiling of the human circulating endocannabinoid metabolome: clinical sampling and sample storage parameters

“…Although it is well accepted that the phytocannabinoid Δ 9 -tetrahydrocannabinol may adversely affect reproductive events in female marijuana users, emerging evidence suggests that programmed changes in endocannabinoid tone help direct uterine and embryonic functions during pregnancy (11,23,24). Endocannabinoid effects on female reproductive status appear temporally and spatially coordinated throughout many stages of pregnancy and childbirth, and perturbations in endocannabinoid ratios/amounts can adversely affect childbearing (12,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33).…”

“…Whether variations in the levels of endocannabinoids other than AEA are determinants of pregnancy outcome remains an intriguing possibility, as does the potential therapeutic impact of endocannabinoid-related drugs on female reproductive problems. For these reasons, clinical application of lipidomics to help define and quantify the impact of diverse endocannabinoids and their dynamics upon female reproductive events has been advocated (11), as well as providing hope that endocannabinoid signaling could be utilized in the correction of infertility (23).…”