420 Magazine Background

The Role Of The Endocannabinoid System In Gametogenesis, Implantation

420 News

New Member
The role of the endocannabinoid system in gametogenesis, implantation and early pregnancy

Abstract

Maternal use of marijuana, in which the exocannabinoid Δ9-tetrahydrocannabinol is the most active psychoactive ingredient, is known to have adverse effects on various aspects of reproduction including ovulation, spermatogenesis, implantation and pregnancy duration. Endogenous cannabinoids of which Anandamide is the prototype are widely distributed in the body especially in the reproductive tract and pregnancy tissues and act through the same receptors as the receptor as Δ9-tetrahydrocannabinol. Anandamide, has been reported to have pleiotropic effects on human reproduction and in experimental animal models. It appears to be the important neuro-cytokine mediator synchronizing the embryo-endometrial development for timed implantation, the development of the embryo into the blastocyst and transport of the embryo across the fallopian tubes. The mechanisms by which it exerts these effects are unclear but could be via direct actions on the various sites within the reproductive system or its differential actions on vascular tone dependent. In this review article we bring together the current knowledge on the role of endoccanabinoids in reproduction and postulate on the potential mechanisms on how these affect reproduction. In addition, we examine its role on the endothelium and vascular smooth muscle as a potential mechanism for adverse pregnancy outcome.
Key words

anandamide
cannabinoid
pregnancy
fetal growth restriction
vascular bed

Previous SectionNext Section
Introduction

Pregnancy complications such as preterm labour, pre-eclampsia and fetal growth restriction (FGR) collectively make a significant contribution to perinatal morbidity and mortality. Although the pathophysiology has not been clearly defined, in most cases, the common phenomenon observed between these diseases is abnormal development and function of the placenta (Salafia, 1997; Pardi et al., 1997; Kim et al., 2002; McMaster et al., 2004).

Normal placental development is dependent upon the differentiation and invasion of the trophoblast, the main cellular component of the placenta that originates from the trophoectoderm of the blastocyst in early pregnancy (Straszewski-Chavez et al., 2005). During this process of development and invasion, trophoblast cells rapidly divide to form the interface between mother and embryo. Other trophoblast subpopulations invade the decidua to remodel the uterine spiral arteries allowing the expansion of extra-embryonic tissues and increase in blood flow to the placenta and developing fetus. Any perturbation of this process, which is tightly regulated and influenced by several factors, may lead to pregnancy complications. Such factors include numerous angiogenic growth factors, cell adhesion molecules, cytokines and growth factors, extracellular matrix metalloproteases, hormones and transcription factors which have been studied extensively (Vuorela et al., 1997; Kayisli et al., 2002; Rajashekhar et al., 2005; Walter and Schonkypl, 2006). Another family of bioactive factors that have not been studied in depth, but thought to be involved in normal placentation is the endocannabinoids.

In the light of recent evidence and increased interest in the role of endocannabinoids in early and late pregnancy problems, this review will re-examine the role of cannabinoids in pregnancy and in the development of the fetoplacental unit with special focus upon the effects of endocannabinoids on the endothelial and vascular smooth muscle cell as pertaining to efficient placental function.
Previous SectionNext Section
The endocannabinoid system
Historical view

Research on the chemistry and pharmacology of cannabinoids was well underway in the 19th century, during a time when cannabis was widely used in medicine (Mechoulam and Hanus, 2000). However, it was more than a century later, that its most psychoactive active component, Δ9-tetrahydrocannabinol (Δ9-THC), was isolated in its pure form and its chemical structure elucidated (Gaoni and Mechoulam, 1964, 1971). Δ9-THC (Fig. 1) is the principal biologically active component of marijuana and is the prototypical cannabinoid family member. This and related molecules (Δ8-THC, Fig. 1) were originally shown to exert their central psychoactive effects via the cannabinoid receptor, CB1, and their peripheral immunoregulatory effects via the CB2 receptor (Matsuda et al., 1990; Munro et al., 1993). Recently, it has been shown that some peripheral tissues contain both receptor isotypes and, in some cases, Δ9-THC may also activate the nociceptive receptor, vanilloid receptor 1 (VR1) (Zygmunt et al., 2000; Zygmunt et al., 2002).
Figure 1:
View larger version:

In this page
In a new window

Download as PowerPoint Slide

Figure 1:

The chemical structures of the main psychoactive ingredient in Cannabis sativa (THC) and the related cannabinoid (CB)-binding exocannabinoid, Δ8-THC

Also shown are the chemical structures of the CB-binding endogenous cannabinoids, AEA and 2-AG
Metabolism–synthesis

Endocannabinoids are generated 'on demand' from long chain polyunsaturated fatty acid precursors derived from arachidonic acid (Habayeb et al., 2002), through enhanced intracellular Ca2+ concentrations, e.g. from cell depolarization, or mobilization of intracellular Ca2+ stores following stimulation of Gq/11 protein-coupled receptors. The enzymes (N-arachidonyol-phosphatidyl ethanolamine selective phospholipase D and sn-1 selective diacylglycerol lipases 1 and 2) that catalyse the last steps in the production of the two most studied endocannabinoids, arachidonyol-ethanolamine (anandamide, AEA, Fig. 1) and 2-arachidonyl-glycerol (2-AG, Fig. 1) are all Ca2+-sensitive. It is widely accepted that AEA is generated in most cell types by the hydrolysis of the membrane phospholipid precursor, N-acylphosphatidylethanolamine (NAPE) by an enzyme that belongs to the phospholipase D family (Di Marzo et al., 1996a; Wang et al., 2006a,b), although very recent evidence suggests that in some cases, AEA can be generated through a phospholipase C-dependent pathway (Liu et al., 2006) or through an α/β-hydrolase 4 enzymatic system (Fig. 2; Simon and Cravatt, 2006).
Figure 2:
View larger version:

In this page
In a new window

Download as PowerPoint Slide

Figure 2:

Synthesis and degradation of AEA

AEA is mainly synthesized from membrane lipids 'on demand' via the actions of TAE and NAPE-PLD

Although the condensation of arachidonic acid and ethanolamine has been proposed, no in vivo evidence for this pathway exists or putative AEA synthase cloned. Degradation occurs through the internalization of AEA-bound receptor and the actions of a cell specific FAAH that resides on the inner surface of the plasma membrane. Additional mechanisms exist for cells that express the lipoxygenases or cyclooxygenase-2 for efficient removal of AEA from local tissues and the circulation. TAE, transacylase; PLC, phospholipase C; PLD, phospholipase D; PTPN22, protein tyrosine phosphatize (Lui et al., 2006); PLA2, phospholipase A2; NAPE-PLD, N-arachidonyol-phosphatidyl ethanolamine selective phospholipase D; NAPE, N-arachidonyol-phosphatidyl ethanolamine; PGE2-Et, Prostaglandin E2-ethanolamine; pAEA, phosphoanandamide; 12S AEA, 12(S)-hydoxy-arachidonylethanolamine. All enzymes are depicted in red and products in boxes. The enzyme marked with an X? is a putative deacetylase (Simon and Cravatt, 2006)

After initial generation within the cell, the endocannabinoids are released into the interstitial space where they either diffuse into the lymph and blood or act in an autocrine or paracrine manner (Piomelli et al., 2000). The mechanism whereby endocannabinoids are released and which cells actually produce the compound is a matter of intense research (Di et al., 2005; Jung et al., 2005; Vogeser et al., 2006). Platelets and endothelial cells are one source of these compounds (Maccarrone et al., 2000a), although the ubiquitous distribution of arachidonic acid and the enzymes that generate NAPE suggest that other cell types including neurons may be the primary source (Liu et al., 2006). However, in the context of reproduction, evidence that estradiol (E2) enhances and progesterone inhibits AEA release from endothelial cells (Maccarrone et al., 2002a) suggests that the endothelial cell could be a prime target for the control of endocannabinoid production in the developing placenta, since the trophoblast progressively produces progesterone which would inhibit AEA release by endothelial cells. By contrast, the denudation of the endothelial layer in maternal spiral arteries that occurs during the second phase of placental development (Redman and Sargent, 2005) is regulated by the invading cytotrophoblast (Cartwright et al., 2002), a process that is under both estrogen and progesterone control. The sudden increase in local AEA concentrations at the invading tips could be a signal for local endothelial cell apoptosis in the decidua and the signal for smooth muscle apoptosis in the myometrium, although more work in this area is required (Thadani et al., 2004). Furthermore, the presence of AEA in tissue macrophages (Di Marzo et al., 1996b) and within many reproductive fluids including semen (Schuel et al., 2002a) suggests that other gonadal steroid target tissues and cells may also be endocannabinoid producers.
Metabolism–transport and degradation

Termination of endocannabinoid signalling at the cannabinoid receptors is thought to occur by transport of the compounds into the cell by a poorly characterized AEA transporter (Di Marzo et al., 2004; Moore et al., 2005; Bari et al., 2006), followed by the rapid degeneration of AEA by fatty acid amide hydrolase (FAAH) found on the internal membranes of AEA target cells (Di Marzo et al., 1994; Cravatt et al., 1996) (Figs. 2 and 3). It has also been suggested that FAAH may act as an AEA transporter and that FAAH not only absorbs AEA from the plasma, but may also export AEA under the appropriate conditions, i.e. estrogen stimulation of loaded endothelial cells (Maccarrone et al., 2002a). The nature of the AEA/FAAH transport molecule in the human has recently been suggested to be an alternative isoform of the original FAAH enzyme (Wei et al., 2006) found on the internal cell surface (Cravatt et al., 1996; Giang and Cravatt., 1997). This novel isoform (type 2) is found on the external surface of the cell (Wei et al., 2006). However, mice appear to express only one isoform of FAAH suggesting that the human and mouse utilize different mechanisms to modulate AEA levels (Wei et al., 2006). There is, however, compelling evidence that AEA is eliminated by transport into and subsequent degradation by intracellular FAAH from human umbilical vein endothelial cell (HUVEC) (Maccarrone et al., 2000a) and human peripheral T lymphocyte studies (Maccarrone et al., 2003a; Maccarrone et al., 2003b). From the HUVEC studies, it is clear that the AEA and FAAH transporters are indeed two independent entities, however, their precise chemical nature is yet to be defined. The currently held view is that the levels of FAAH in T lymphocytes are the sole method of regulating plasma AEA levels despite there being considerable evidence for FAAH expression in sites other than peripheral T lymphocytes (Maccarrone et al., 2003a; Park et al., 2003). The localization of FAAH in human amniotic epithelial cells, chorionic cytotrophoblastic cells, placenta and mouse endometrial epithelial cells (Maccarrone et al., 2002c; Park et al., 2003) and the human uterus (Helliwell et al., 2004) indicates a potentially important role in controlling AEA tone or attenuating local AEA-mediated events. The activity of uterine FAAH is regulated by sex hormones (Maccarrone et al., 2001, 2002c), suggesting that the endocannabinoid system may be involved in the maintenance of human pregnancy. Furthermore, in both in vivo and in vitro studies, the presence of FAAH in maternal lymphocytes has been shown to be integral in pregnancy continuation, as its down-regulation is an early marker for spontaneous abortion (Maccarrone and Finazzi-Agro, 2004). It has also been demonstrated that T-lymphocytes increase their levels of active FAAH approximately two-fold in response to exogenous progesterone (Maccarrone et al., 2001), supporting a primary role for FAAH in regulating AEA plasma levels during the first trimester of pregnancy and possibly local AEA level regulation.
Figure 3:
View larger version:

In this page
In a new window

Download as PowerPoint Slide

Figure 3:

Proposed mechanism for the control of plasma AEA concentrations by the T-lymphocyte

Plasma AEA is transported into the T-lymphocyte via a membrane-bound transporter protein complex that 'flips' in the membrane to release AEA to the fatty acid amide hydrolase FAAH enzyme that degrades it. Alternatively, the presence of a second FAAH isoform isolated on external surface of the cell suggests that one isoform of FAAH 'transports' AEA from the outside of the cell to the other intracellular FAAH isoform for degradation i.e. either localized to the internal surface of the plasma membrane or the external surface of the mitochondrial membrane (Wei et al., 2006). The intracellular levels of FAAH are regulated by progesterone, through the induction of the transcription factor, Ikaros, that binds to and trans-activates the FAAH promoter. Any and all of these factors may be therapeutic targets for regulation of plasma AEA levels (Bari et al., 2005)
Endocannabinoid receptors
Cannabinoid receptors

Two cannabinoid receptors (CB1 and CB2) have been identified and cloned from several species (Pertwee, 1997; Chataigneau et al., 1998), and a third (CB3) has been proposed, but has yet to be cloned (Fride et al., 2003). In most species, the major receptor, CB1, is primarily expressed in the cerebrum (Matsuda et al., 1990) and cerebellum (Kishimoto and Kano, 2006) but has also been demonstrated in peripheral tissues such as the eye, placenta, the fetal membranes and myometrium (Straiker et al., 1999; Park et al., 2003; Dennedy et al., 2004). The CB2 receptor, on the other hand, is mainly expressed by cells of the immune system (Munro et al., 1993), although transcripts for this gene have been identified in the placenta and trophoblastic cells (Buckley, et al., 1998). Distinction between these receptors is based on differences in their amino acid sequence (Matsuda et al., 1990; Munro et al., 1993), signalling mechanisms (Felder et al., 1995), tissue distribution (Matsuda et al., 1990; Munro et al., 1993; Shire et al., 1995), sensitivity to certain agonists such as WIN 55212-2 (a pravadoline derivative of the aminoalkylindole group) (Martin et al., 1991; Pertwee 1997), 1-propyl-2-methyl-3(1-naphthoyl)indole and 2-methylarachidonyl-(2′-fluoroethyl)amide (Huffman et al., 1996; Showalter et al., 1996) and antagonists that show receptor selectivity such as SR141716A and LY320135 (Compton et al., 1996; Felder et al., 1998). CB1 receptors have been shown to be involved in the relaxant and vasodilator actions of AEA via the antagonistic action of the CB1 receptor antagonist, SR141716A (Randall et al., 1996; Zygmunt et al., 1997). However, adding to the complexity of cannabinoid action, other studies have demonstrated that the vasodilatory response to AEA (in rat mesenteric arteries) may involve two other receptors: a non-CB1 endothelial receptor that is also sensitive to the effects of SR141716A and another vascular smooth muscle receptor i.e. resistant to SR141716A (Wagner et al., 1999). The relative contribution of these two components to the net response to AEA is thought to depend on the species and tissue used and on the condition of the endothelium, which may explain why conflicting studies have demonstrated both the ability and the inability of SR141716A to inhibit the vasorelaxant effect of AEA (Randall et al., 1996; Wagner et al., 1999). Furthermore, in rat mesenteric arteries, SR141716A was shown to inhibit vascular responses to the endothelium-dependent vasorelaxants, carbachol and the calcium ionophore, A23187 (Randall et al., 1996; White and Hiley 1997), whereas other studies have failed to demonstrate similar responses in guinea-pig carotid, rat mesenteric, porcine coronary and bovine coronary arteries (Plane et al., 1997; Pratt et al., 1998).

Finally, although many studies have demonstrated the action of AEA via cannabinoid receptors, a putative endothelial non-CB1 non-CB2 receptor has also been suggested by studies demonstrating a persistence in AEA-induced vasodilatation in mice deficient in both CB1 and CB2 receptors (Jarai et al., 1999). This has led to the idea that a third CB receptor may exist, and, indeed, the in silico analysis of CB gene structure indicates that GPR55 may be considered a strong candidate for the CB3 receptor (Baker et al., 2006).
Vanilloid receptors

Structural similarities between AEA and ligands of the capsaicin-sensitive vanilloid receptors (VR1) that signal and control nociception indicate that AEA may produce some of its effects through a low-affinity interaction with vanilloid receptors (VR1) (Di Marzo et al., 1998; Zygmunt et al., 1999). However, such (in vitro) effects have been shown to require supra-physiological concentrations of AEA, suggesting that AEA may act in concert with VR1-stimulating activity, leading to the idea of endovanilloids (Ross, 2003; Van Der Stelt and Di Marzo, 2004). These findings reinforce the complexity of AEA activity, because in addition to the involvement of CB1 receptors in some blood vessels, it has an SR141716A-sensitive component mediated by an as yet unidentified endothelial receptor and an endothelium-independent, SR141716A-resistant component likely mediated by vanilloid receptors (Jarai et al., 1999).
Previous SectionNext Section
Role of cannabinoids in reproduction
Folliculogenesis

To the best of our knowledge, there have been very few published studies on the effects of AEA on folliculogenesis. Most of the published studies have examined the effects of the active components of marijuana, namely, Δ9-THC, on oocyte development. [It is worth noting that older papers refer to Δ1-THC, which is in fact the same molecule as Δ9-THC.]

Δ9-THC has been shown to inhibit ovulation by suppressing plasma follicle-stimulating hormone (FSH) and the pre-ovulatory surge of LH when administered to rats on the day of proestrus (Nir et al., 1973; Ayalon et al., 1977). Reich et al. (1982) suggested that this may be primarily due to the hypothalamic inhibition of GnRH secretion. Furthermore, the inhibition of ovarian prostaglandin synthesis by Δ1-THC has also been demonstrated in granulosa cells, suggesting a direct suppressive effect of the drug on the ovary (Lewysohn et al., 1984). Furthermore, Δ9-THC has also been shown to cause a dose-dependent inhibition of the FSH-stimulated accumulation of progesterone and estrogen in ovarian granulosa cells (Lewysohn et al., 1984).

Although there is a paucity of data concerning the actions of endocannabinoids on the oocyte, AEA and its congeners, N-palmitoylethanolamine and N-oleoylethanolamine have been quantified in follicular fluid retained following oocyte aspiration from women undergoing IVF treatment (Schuel et al., 2002a). These endocannabinoids are thought to be produced by the granulosa cells in ovarian follicles and in granulosa cells surrounding ovulated oocytes. However, the mechanism controlling their production and release are currently unknown but are presumably under hormonal control. Additionally, cannabinoid receptors have been demonstrated to be present in the ovary (Galiegue et al., 1995), suggesting a local paracrine action of endocannabinoids. Ovulation is dependent upon cAMP accumulation, an effect that is inhibited by Δ9-THC in cultured rat granulosa cells (Treinen et al., 1993), suggesting that endocannabinoid signalling may help regulate follicle maturation and development (Schuel et al., 2002b). It may be this mechanism that accounts for the reported adverse effects of marijuana on ovulation (Abel, 1981; Powell and Fuller, 1983; Mueller et al., 1990; Schuel et al., 2002a). These data suggest that endocannabinoids exert both a direct and an indirect effect on ovulation.

Another possible additional mechanism for an indirect effect of endocannabinoids on folliculogenesis is via modulation of nutritional status. There is some evidence linking obesity, leptin production and reproduction (Clarke and Henry, 1999; Messinis and Milingos, 1999; Goumenou et al., 2003; Bajari et al., 2004; Linne, 2004) with obesity having an adverse effect on reproductive potential, and weight loss prior to assisted reproduction treatment having a beneficial effect on pregnancy outcomes (Fedorcsak et al., 2004). Recently, Di Marzo et al. (2001) elegantly linked the process of food intake, leptin production and endocannabinoids in the homozygous and heterozygous CB1-knockout mouse models, whereby defective leptin signalling leads to an increased hypothalamic cannabinoid level and action. In this way, it was proposed that an inhibitory action on pituitary gonadotrophin release is produced which has an adverse effect on ovulation. However, although the inverse relationship between AEA and leptin is clearly demonstrated in those studies as far as appetite and feeding is concerned, a direct link between these two molecules in the control of reproduction has not yet been found (Mechoulam and Fride, 2001).

Additional evidence in the control of appetite and obesity has come from clinical trials with the CB1 antagonist, SR141716 (Rimonabant), with several reports of successful regulation of body weight (Van Gaal et al., 2005; Cleland et al., 2004) and significant reductions in body mass in type 2 diabetics (Hollander, 2007). Although these results are encouraging as regards appetite suppression and body mass control, the use of CB1 antagonists in this way must be treated with caution since the precipitation of multiple sclerosis in pre-disposed individuals from the use of this drug may occur (van Oosten et al., 2004). Additionally, there are no data from these trials about reproductive function and whether the use of Rimonabant prior to assisted reproduction procedures would have any beneficial or adverse effects. Indeed, obesity control through the regulation of the endocannabinoid system requires much more research.
Spermatogenesis

Although it is well known that chronic marijuana use transiently decreases male fertility in animal models and humans (Murphy et al., 1994), there are relatively few published studies on Δ9-THC and human spermatogenesis. The mechanism involved in marijuana-induced infertility remains unclear, although several studies have implicated reduced testosterone secretion (Wenger et al., 2001; Kolodny et al., 1974), sperm production (Nahas et al., 2002; Dalterio et al., 1977; Patra and Wadsworth, 1990), sperm motility (Zimmerman et al., 1979; Ambrosini et al., 2003; Schuel and Burkman, 2005) and sperm viability (Schuel and Burkman, 2002b) as possible culprits. Additionally, chronic marijuana use is associated with reduced LH production both centrally and within the testes, suggestive of both central and local endocannabinoid effects, as is the case in the female. The local effect of cannabinoids appears to be mediated through a CB2-dependent mechanism that involves modulation of Sertoli cell FAAH expression and regulation of AEA levels (Maccarrone et al., 2003c), with the suggestion that the pro-apoptotic nature of AEA (Maccarrone et al., 2000c; Maccarone and Finazzi-Agro, 2003) is responsible for aged Sertoli cell eradication. However, this is only part of the story, since AEA action on Sertoli cells is age-dependent and in nascent cells is probably not mediated via the CB2 receptor, because binding of AEA to the CB2 receptors on these cells has an anti-apoptotic effect (Maccarrone et al., 2003c). In spite of this, there is increasing Sertoli cell survival in spermatogenesis which may be due to the FSH-dependent increase in Sertoli cell FAAH activity that further degrades local AEA levels, thereby preventing Sertoli cell apoptosis (Maccarrone et al., 2003c). This suggests that endocrine regulation of FAAH activity in the Sertoli cell and the subsequent hydrolysis of AEA is a major check-point in human male fertility and that relative activities of the CB receptors during early spermatogenesis are controlling factors.

The normal mature human sperm has been shown to respond to AEA via the CB receptors with a resultant reduced motility (Suarez and Ho, 2003; Rossato et al., 2005), reduced capacitation ability (Rossato et al., 2005) and reduced binding to the zona pellucida. In addition, there is a reduction in the hydrolysis of the oocyte membranes (Rossato et al., 2005), suggesting that excess AEA production in the female reproductive tract reduces the success of fertilization. Using the boar sperm as a model system, Maccarrone et al. (2005) have demonstrated that the acrosomal reaction of sperm requires a small amount of AEA that acts through first the CB1 and then the VR1 receptor for full activity, and it has been postulated that during sperm capacitation, a dual stage-dependent endocannabinoid effect is in operation where AEA in seminal plasma and uterine fluids prevents capacitation in freshly ejaculated sperm, whereas sperm that have travelled through the uterus and into the Fallopian tube are exposed to gradually reduced AEA concentrations that release the molecular 'brake' of CB1 inhibition so that capacitation occurs (Schuel et al., 2002b). These data suggest that a full understanding and subsequent treatment of male infertility requires better appreciation of the involvement of the endocannabinoid system in both the male and female reproductive tracts.
Fertilization and oviductal transport

During early pregnancy, the development of the pre-implantation embryo and their timely oviductal transport into the uterus occurs simultaneously. Both endogenous and exogenous cannabinoids have been demonstrated to inhibit embryo development at the 2-cell stage through a CB1-dependent mechanism (Paria et al., 1995, 1998). Although early embryos are reported to express CB2 transcripts (Sharov et al., 2003), the role and function of CB2 is currently unknown with the implication that CB2 is confined to the inner cell mass that develops into the fetus and the CB1 receptor expressed in the developing trophoblast (Wang et al., 2006a,b). Although the authors suggest that the CB1 receptor is the functional receptor for normal embryo growth and development and that the CB2 receptor is responsible for controlling stem cell populations (Sharov et al., 2003; Wang et al., 2006a,b), these data need further clarification.

Embryos reaching the early blastocyst stage will have developed and differentiated to the point of having gained implantation potential. It is now clear that the endocannabinoid system is also involved in embryo transport, with clear evidence from CB1 and CB2 knockout studies that oviductal transport is a CB1-dependent mechanism in mice (Paria et al., 2001; Wang et al., 2004). CB1 knockout mothers retain their embryos in the oviduct with about 40% of CB1 knockout mothers failing to implant their embryos through this mechanism (Paria et al., 2001). This suggests that CB1 receptor deficiencies in some women may have a role to play in tubal pregnancy or female infertility. Interestingly, mice treated with either the non-hydrolysable AEA analogue, methanandamide or Δ9-THC showed pregnancy loss with embryos retained in the oviduct (Wang et al., 2004), suggesting that either inhibited or enhanced cannabinoid signalling impairs embryo transport. From these data it is clear that appropriate CB1 expression and function in the Fallopian tube is a limiting factor in oviductal transport and pregnancy success.
Implantation

The highest concentration of AEA found in any species thus far studied was in the non-implantation site of the pregnant mouse uterus, suggesting an important role in mammalian reproduction (Schmid et al., 1997). Indeed, these data have been confirmed and extended to indicate that the spatial and temporal expression of the N-arachidonylphosphatidylethanolamine-hydrolysing phospholipase D (NAPE-PLD) enzyme in the mouse uterus is the main determinant of local AEA concentrations (Guo et al., 2005) and that AEA in concentrations above a critical level is toxic to the implanting blastocyst (Wang et al., 1999).

Wang et al. (1999) also suggested that site-specific levels of AEA in the uterus may regulate implantation by promoting trophoblast differentiation at the sites of blastocyst implantation, while at the same time limiting invasion beyond those sites. Furthermore, levels of AEA in the implantation sites have been found to be lower compared with those at the inter-implantation sites, suggesting that the implanting blastocyst may influence the local levels of AEA within the mouse uterus (Schmid et al., 1997; Paria et al., 1999).

Through studies like these it is now clear that AEA may be considered to be involved in the regulation of the 'window' of implantation whereby embryonic development is synchronized with the preparation of the uterus for implantation (Schmid et al., 1997). The finding that higher levels of AEA in non-implantation sites and lower levels within implantation sites (Paria and Dey, 2000) suggests that high levels of AEA may be responsible for inhibition of trophoblastic proliferation, whereas low levels are required for trophoblastic proliferation (Paria and Dey, 2000). Furthermore, endocannabinoids also appear to play a major role in regulating the development of the blastocyst to guarantee successful implantation in the endometrium (Wang et al., 2003).
Fetal development

Several groups have investigated the role of AEA and FAAH as important signals in early fetal development in both human and animal models (Wang et al., 1999, 2000; Maccarrone and Finazzi-Agro, 2004). It has been reported that AEA is synthesized within the reproductive tract of the female mouse, with uterine AEA and blastocyst CB1 receptor levels significantly higher than those in the (mouse) brain, highlighting the importance of AEA in the early stages of pregnancy (Yang et al., 1996). AEA has also been shown to act on cannabinoid receptors expressed on the embryonic cell surface to regulate the development of the preimplantation embryo in mice (Paria et al. 1996).

Other studies in mice have demonstrated that exposure of early embryos to high levels of cannabinoids inhibits blastocyst formation, zonal hatching and trophoblastic growth and that these effects are mediated via CB1 receptors (Paria et al., 1995; Yang et al., 1996; Schmid et al., 1997; Wang et al., 1999, 2003). The developmental arrest that occurs in mouse blastocysts in a non-receptive uterine environment associates well with its higher levels of AEA (Paria et al., 1996; Schmid et al., 1997). However, these effects appear to vary depending on the concentration of AEA and the developmental stage of the embryo. At lower doses of AEA, blastocyst formation is inhibited while trophoblastic outgrowth is accelerated in vitro. In stark contrast, when exposed to higher doses of AEA, trophoblastic outgrowth within the blastocyst was significantly inhibited (Wang et al., 1999). As uterine AEA levels vary depending on the stages of uterine receptivity and non-receptivity, these observations suggest that the effects of AEA are biphasic, and differentially executed depending on the embryonic stage and the cannabinoid levels to which the fetus is exposed (Wang et al., 1999; Paria et al., 2002).

In several animal studies, Δ9-THC has been shown to adversely affect the course and outcome of pregnancy by retarding embryo development, resulting in fetal abnormalities and teratological malformations in the newborn (Paria and Dey, 2000). Although gross teratological malformations are unknown in women subjected to chronic marijuana use, an association between chronic marijuana smoking and spontaneous abortion has been demonstrated (Lockwood, 2000; Nygren and Andersen, 2001). Furthermore, a decrease in both the birthweight and birthlength of the newborn associated with a symmetrical pattern of FGR has also been reported in marijuana users (Frank et al., 1990). The symmetrical nature of the FGR suggests an early onset, most likely from the time of implantation or during placental development. It is thought that 'isolated' FGR may be a consequence of abnormal placental vascular adaptation to pregnancy, resulting in a high pressure, low volume flow system (Takagi et al., 2004; Thaete et al., 2004). The precise mechanisms for maintaining low vascular reactivity within both the maternal and placental vascular beds during healthy pregnancies are unknown, although, sex steroids and locally produced vasoactive factors are thought to be implicated (Jaffe 1983; Gangula et al., 1997; Lockitch, 1997; Sladek et al., 1997). Vasoactive substances can induce either vasodilation or vasoconstriction by acting directly on vascular smooth muscle or indirectly via the vascular endothelium (Ang et al., 2002). Additionally, our demonstration that plasma AEA levels decline during normal pregnancy indicates that endocannabinoids may also be involved in the regulation of on-going pregnancy (Habayeb et al., 2004), but there is no epidemiological evidence in the literature that AEA or Δ9-THC adversely affect in utero fetal development, although there is evidence that marijuana use during pregnancy affects postnatal infant behaviour and learning difficulties (Woods, 1996).
Placental development

The development of the human placenta occurs in three waves–the first at ∼9—12 weeks, the second at ∼16 weeks and the third at ∼32 week gestation (Castellucci et al., 1990). It is, however, the first wave of trophoblastic invasion of the spiral arteries that appears to be the major physiological transition in placental development (Burton et al., 1999). Levels of FAAH in both the human placenta and the maternal circulation increase towards the end of the first trimester of pregnancy, before declining by the early second trimester (Maccarrone et al., 2000b; Helliwell et al., 2004). Furthermore, high levels of FAAH have been observed in the villous cytotrophoblast. Its expression in the syncytiotrophoblast suggest that FAAH in these cells help prevent the transfer of AEA from maternal blood (Helliwell et al., 2004), which, to some degree, has been suggested as a protective mechanism for the developing fetus (Helliwell et al., 2004). Previous studies have suggested that circulating FAAH and AEA levels may be critical to the outcome of early pregnancy (Maccarrone et al., 2000d, 2002b). It has been shown that decreased expression and activity of FAAH in peripheral blood lymphocytes is an early marker of early spontaneous abortion (Maccarrone et al., 2000d, 2002b). The importance of FAAH in early placental development has been supported by a recent study that demonstrated the expression of FAAH and CB2 (rather than CB1) receptors in the human first trimester placenta. This study also provides evidence that the endocannabinoid regulation within placental tissue is independent of the maternal immune system (Helliwell et al., 2004).

The mechanism whereby the main psychoactive ingredient of marijuana, Δ9-THC, causes FGR has been postulated to occur through four mechanisms. First, Δ9-THC crosses the placenta to a greater extent during the early proliferative growth phase compared with the hypertrophic growth phase of late pregnancy to affect the fetus (Vardaris et al., 1976). Secondly, the extended half-life of Δ9-THC in the maternal circulation results in prolonged fetal exposure (Hutchings et al., 1989). Thirdly, the indirect exposure of the fetus and the trophoblast to increased levels of carbon monoxide from smoking marijuana is directly toxic (Clapp et al., 1987), and fourthly, marijuana has a tendency to increase maternal heart rate and blood pressure (Sidney, 2002), inducing uterine vasoconstriction and thereby reducing feto-placental perfusion (Zuckerman et al., 1989). Recent evidence from our group demonstrating that Δ9-THC acts directly on the human cytotrophoblast cell to inhibit cell growth and the transcription of genes involved in growth and apoptosis (Khare et al., 2006), via the relatively unstudied CB2 receptor (Taylor et al., 2007) suggest that endocannabinoids may similarly inhibit trophoblast growth and development.
Previous SectionNext Section
Vascular effects: potential mechanism for reproductive failure

One possible factor, which has been shown to have direct effects on the vasculature and could be a contributing factor to the disruption of a low pressure, high volume flow placental system so necessary in normal pregnancy, is AEA. This speculation is based on ex vivo studies showing that AEA produces complex and variable vascular effects (Plane et al., 1997; Randall and Kendall, 1998), depending on the species and vascular bed studied (Pratt et al., 1998; Chaytor et al., 1999), with both endothelium-dependent and endothelium-independent vasorelaxation that may involve several different mechanisms (Fig. 4) (Randall et al., 1996; Chaytor et al., 1999; Wagner et al., 1999; Zygmunt et al., 1999).
Figure 4:
View larger version:

In this page
In a new window

Download as PowerPoint Slide

Figure 4:

A schematic representation of the possible mechanisms regulating the vasorelaxation induced by cannabinoids

Vasorelaxation is dependent upon the binding of cannabinoids to cannabinoid receptors CB1 or the putative CB3 or other isoforms of the cannabinoid receptor, but not the CB2 receptor or through binding to the putative AEA mediated transporter system. (1) Binding of ligand to receptor increases nitric oxide (NO) production, which is released into the interstitial space and alters cyclic guanosine monophosphate (cGMP) levels in the vascular smooth muscle cell by decreasing intracellular Ca2+ levels. (2) Endothelium-derived hyperpolarising factor EDHF is either induced by intracellular AEA concentrations or by signalling through a non-CB1-dependent pathway and causes membrane depolarization at Ca2+-dependent K+-channels on the membrane surface of smooth muscle cells lining the vasculature to cause reduced intracellular K+ and Ca2+ levels. By either direct activation of the K+-channel or direct inhibition of Ca2+levels in mitochondria. (3) Cannabinoids may act through a CB1-dependent pathway by increasing intracellular cGMP or cAMP in the vascular smooth muscle cell, which inhibit L-type Ca2+ channels in vascular smooth muscle cells to reduce intracellular Ca2+ levels or inhibit the production of contractile proteins, respectively. Any or all of these mechanisms may be involved in cannabinoid-induced vasorelaxation [adapted from Ribuot et al. (2005)]

AEA has been shown to have pleiotropic effects on the cardiovascular system in vivo. In anaesthetized rats, AEA causes a brief pressor and more prolonged depressor effect (Varga et al., 1995). In humans, both marijuana smoking and the intravenous administration of Δ9-THC have resulted in peripheral vasodilation and tachycardia (Dewey, 1986). These effects manifest themselves as a fall in peripheral resistance and hence blood pressure. The control of resistance within the vasculature is important because it ultimately affects blood flow and tissue/organ perfusion, and this has major implications for normal placental development and trophoblast survival (Battaglia and Regnault, 2001; Haggarty, 2002; Illsley, 2002).
Endothelium-dependent responses

Several groups have reported a vasodilatory effect of AEA through the release of various endothelium-derived releasing factors (Randall and Kendall, 1998; Harris et al., 2002). Using the rat model, Deutsch et al. (1992) showed that exposing cultured renal endothelial cells to AEA stimulated the release of nitric oxide, while the presence of the nitric oxide synthase inhibitor, L-nitroarginine methyl ester (L-NAME), abolished this response.

Another endothelium-dependent vasodilator, the putative endothelium-derived hyperpolarizing factor (EDHF; Fig. 4), has been suggested as one of the mechanisms of AEA-induced vasorelaxation (Randall and Kendall, 1998; Harris et al., 1999; Jarai et al., 1999), whereas others have demonstrated that AEA induces membrane hyperpolarization via another unknown intermediate (Zygmunt et al., 1997). It has also been suggested that in rabbit mesenteric arteries, the endothelial component of AEA-induced vascular relaxation is secondary to gap junction communication and not to a specific vasoactive factor (Chaytor et al., 1999). Therefore, the role of EDHF in AEA-induced relaxation may vary according to the tissue species and vascular bed studied.

Endothelial (HUVEC) cells also express the CB1 receptor and the presence of these receptors are postulated to confer an anti-apoptotic effect via an AEA-dependent mechanism (Maccarrone et al., 2000c; Yamaji et al., 2003). These receptors have been localized by immunohistochemistry in the endothelium and trophoblast cells of human term placenta and gestational membranes (Park et al., 2003), which these authors suggest could be involved in the development of FGR, whereby the placental expression of CB1 receptors may be modified, leading to varying degrees of apoptosis and FGR. Importantly, the presence of CB1 receptors in the placenta and fetal membranes at term may be related to parturition, although these data require further proof.
Endothelium-independent responses

AEA has also been shown to exert some of its effects directly on vascular smooth muscle via the CB1 receptor, independent of the endothelium (Gebremedhin et al., 1999). The contribution of direct effects on smooth muscle to the vasodilatory effects of cannabinoids varies among vascular beds, as does the mechanism of action (Hillard, 2000). For example, AEA has been shown to inhibit the opening of L-type calcium channels (Gebremedhin et al., 1999), thereby modulating calcium influx (Ho and Hiley 2003a), release (Fimiani et al., 1999) and sensitivity. Other studies have demonstrated AEA-induced inhibition of smooth muscle intracellular calcium stores (Zygmunt et al., 1997), as well as modulating calcium entry through voltage-gated calcium channels (Gebremedhin et al., 1999; Ho and Hiley, 2003b).

Other endothelium-independent mechanisms responsible for the vasodilatory effects of AEA include the release of calcitonin gene-related peptide (CGRP), a vasodilator released from perivascular sensory nerves, and activation of CGRP receptors on vascular smooth muscle by interacting with VR1 receptors on rat and guinea pig perivascular sensory nerve endings (Zygmunt et al., 1999; Mukhopadhyay et al., 2002). Vasorelaxation induced by CGRP has been proposed to be mediated by two pharmacological actions, one being the stimulation of smooth muscle cell adenylate cyclase with the subsequent accumulation of intracellular cyclic adenosine monophosphate (cAMP) (Edwards et al., 1991), and the other, the activation of potassium channels within the vascular smooth muscle (Brayden et al., 1991), which is known to cause smooth muscle cell relaxation and inhibition of agonist-induced contractions (Wray et al., 2003).

It is possible, therefore, that arterial and venule endothelial cells which may have different receptors, different signalling pathways and different phenotypes will exhibit differential responses to AEA.
Hormonal regulation of AEA-induced vasorelaxation

At physiological concentrations, estrogen stimulates the release, rather than the uptake of AEA from endothelial cells, leading to a rapid elevation of intracellular calcium and nitric oxide release (Maccarrone et al., 2000a). In addition, 17 β-E2 has also been shown to increase vascular sensitivity to CGRP (Gangula et al., 1999), suggesting that estrogen modulates the vascular effects of AEA. However, other studies have found no sex-linked difference in the vasorelaxant effects of AEA (McCulloch and Randall 1998). There appears to be little else published on the effect of gonadal or adrenal steroids on vascular smooth muscle cell and cannabinoid interactions.
Previous SectionNext Section
Conclusions

The detrimental effects of AEA on the embryo, the oviduct and the blastocyst are prevented by the presence of an efficient system for its removal which is under hormonal control, showing an interplay between endocannabinoids and gonadal steroid hormones in regulating fertility in mammals (Maccarrone et al., 2000b).

The expression of CB1 receptors in the pre-implantation embryo, oviduct, uterus and sperm and the synthesis of AEA in the pregnant uterus and sperm suggest that cannabinoids may be involved in the regulation of all aspects of reproduction including fertilization, pre-implantation embryo development, implantation and placental development. These data have led to the hypothesis that a major imbalance in FAAH or AEA levels at any stage of reproduction may lead to reproductive failure. Indeed, as the placenta develops at the implantation site, the amount of AEA required must be tightly regulated or implantation does not occur. Later imbalances in AEA or FAAH levels lead to spontaneous abortion, and thus it is possible that when the disruptions are not severe enough to result in spontaneous abortion, trophoblast development and interaction with endothelial cells becomes unstable, ultimately impairing placental function. Even transient impairment could be sufficient to result in placental dysfunction. All these data implicate cannabinoid signalling in normal vascular or trophoblast responses that lead to normal pregnancy, and any minor disruption may result in complications of pregnancy related to placental dysfunction such as FGR and pre-eclampsia to FGR, with any major disruption leading to spontaneous abortion. Table 1 provides some supporting evidence for the effects of cannabinoids on reproductive outcomes in the human and some areas where they are speculated to have an action. The table also points to areas of future research, where the effects of these compounds are currently unknown and where further work is required in order to validate these hypotheses in the human.
View this table:

In this window
In a new window

Table 1:

Effects of endocannabinoids and exocannabinoids on reproductive function before, during and after pregnancy

A.H. Taylor,
C. Ang,
S.C. Bell and
J.C. Konje1

+ Author Affiliations

Endocannabinoid Research Group (ERG) Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, Robert Kilpatrick Clinical Sciences Building, University of Leicester, Leicester Royal Infirmary, PO Box 65, Leicester, Leicestershire LE2 7LX, UK

1Correspondence address. Tel: +44-116-252-5826; Fax: +44-116-252-5846; E-mail: jck4@le.ac.uk

Received January 22, 2007.
Revision received April 24, 2007.
Accepted May 15, 2007.

© The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Previous Section

References


Abel EL
. Marihuana and sex: a critical survey. Drug Alcohol Depend 1981;8:1-22.
CrossRefMedlineWeb of Science
Ambrosini A,
Zolese G,
Ambrosi S,
Bertoli E,
Mantero F,
Boscano M,
Balercoia G
. Idiopathic infertility: effect of palmitoylethanolamide (a homologue of anandamide) on hyperactivated sperm cell motility and Ca2+ influx. J Androl 2005;26:429-436.
Abstract/FREE Full Text

Ang C,
Hillier C,
Johnston F,
Cameron A,
Greer I,
Lumsden MA
. Endothelial function is preserved in pregnant women with well-controlled type 1 diabetes. Br J Obstet Gynaecol 2002;109:699-707.

Ayalon D,
Nir I,
Cordova T,
Bauminger S,
Puder M,
Naor Z,
Kashi R,
Zor U,
Harell A,
Lindner HR
. Acute effect of delta 1-tetrahydrocannabinol on the hypothalamo-pituitary-ovarian axis in the rat. Neuroendocrinology 1977;23:31-42.
MedlineWeb of Science

Bajari TM,
Nimpf J,
Schneider WJ
. Role of leptin reproduction. Curr Opin Lipidol 2004;15:315-319.
CrossRefMedlineWeb of Science

Baker D,
Pryce G,
Davies WL,
Hiley CR
. In silico patent searching reveals a new cannabinoid receptor. Trends Pharm Sci 2006;27:1-4.
CrossRefMedline

Bari M,
Battista N,
Fezza F,
Gasperi V,
Maccarrone M
. New insights into endocannabinoid degradation and its therapeutic potential. Mini Rev Med Chem 2006;6:257-268.
CrossRefMedlineWeb of Science

Battaglia FC,
Regnault TR
. Placental transport and metabolism of amino acids. Placenta 2001;22:145-161.
CrossRefMedlineWeb of Science

Brayden JE,
Quayle JM,
Standen NB,
Nelson MT
. Role of potassium channels in the vascular response to endogenous and pharmacological dilators. Blood Vessels 1991;29:147-153.
Buckley NE,
Hansson S,
Harta G,
Mezey E
. Expression of the CB1 and CB2 receptor messenger RNAs during embryonic development in the rat. Neuroscience 1998;82:1131-1149.
CrossRefMedlineWeb of Science

Burton GJ,
Jauniaux E,
Watson AL
. Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy: the Boyd collection revisited. Am J Obstet Gynecol 1999;181:718-772.
CrossRefMedlineWeb of Science

Cartwright JE,
Kenny JC,
Dash PR,
Crocker IP,
Aplin JD,
Baker PN,
Whitley GS
. Trophoblast invasion of spiral arteries: a novel in vitro model. Placenta 2002;23:232-235.
CrossRefMedlineWeb of Science

Castellucci M,
Scheper M,
Scheffen I,
Celona A,
Kaufmann P
. The development of the human placental villous tree. Anat Embryol 1990;181:117-128.
Medline

Chataigneau T,
Feletou M,
Thollon C,
Villeneuve N,
Vilaine JP,
Duhault J,
Vanhoutte PM
. Cannabinoid CB1 receptor and endothelium-dependent hyperpolarization in guinea-pig carotid, rat mesenteric and porcine coronary arteries. Br J Pharmacol 1998;123:968-974.
CrossRefMedlineWeb of Science

Chaytor AT,
Martin PEM,
Evans WH,
Randall MD,
Griffith TM
. The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication. J Physiol 1999;520:539-550.
Abstract/FREE Full Text

Clapp JF,
Wesle M,
Cooke R,
Pekala R,
Holstein C
. The effects of marijuana smoke on gas exchange in ovine pregnancy. Alcohol Drug Res 1987;7:85-92.
MedlineWeb of Science

Clarke IJ,
Henry BA
. Leptin and reproduction. Rev Reprod 1999;4:48-55.
Abstract

Cleland JG,
Ghosj J,
Freemantle N,
Kaye GC,
Nasir M,
Clark AL,
Colletta AP
. Clinical trials update and cumulative meta-analyses from the American College of Cardiology: WATCH, SCD-HeFT, DINAMIT, CASINO, INSPIRE, STRATUS-US, RIO-Lipids and cardiac resynchronisation therapy in heart failure. Eur J Heart Fail 2004;6:501-518.
Abstract/FREE Full Text

Compton DR,
Aceto MD,
Lowe J,
Martin BR
. In vivo characterisation of a specific cannabinoid receptor antagonist (SR141716A): inhibition of Delta9-tetrahydrocannabinol-induced responses and apparent agonist activity. J Pharmacol Exp Ther 1996;277:586-594.
Abstract/FREE Full Text

Cravatt BF,
Giang DK,
Mayfield SP,
Boger DL,
Lerner RA,
Gilula NB
. Molecular characterisation of an enzyme that degrades neuromodulatory fatty-acide amides. Nature 1996;384:83-87.
CrossRefMedline

Dalterio S,
Bartke A,
Burstein S
. Cannabinoids inhibit testosterone secretion by mouse testis in vitro. Science 1977;196:1472-1473.
Abstract/FREE Full Text

Dennedy MC,
Friel AM,
Houlihan DD,
Broderick VM,
Smith T,
Morrison JJ
. Cannabinoids and the human uterus during pregnancy. Am J Obstet Gynecol 2004;190:2-9.
CrossRefMedlineWeb of Science
Deutsch DG,
Goligorsky MS,
Schmid PC,
Krebsbach RJ,
Schmid HH,
Das SK,
Devane WA,
Hanus L,
Breuer A,
Pertwee R,
et al
. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992;258:1946-1949.
Abstract/FREE Full Text

Dewey WL
. Cannabinoid pharmacology. Pharmacol Rev 1986;38:151-178.
Abstract

Di S,
Boudaba C,
Popescu IR,
Weng FJ,
Harris C,
Marcheselli VL,
Bazan NG,
Tasker JG
. Activity-dependent release and actions of endocannabinoids in the rat hypothalamic supraoptic nucleus. J Physiol 2005;569:751-760.
Abstract/FREE Full Text

Di Marzo V,
Fontana A,
Cadas H,
Schinelli S,
Cimino G,
Schwartz JC,
Piomelli D
. Formation and inactivation of cannabinoid anandamide in central neurons. Nature 1994;372:686-691.
CrossRefMedline

Di Marzo V,
De Petrocellis L,
Sepe N,
Buono A
. Biosynthesis of anandamide and related acylethanolamides in mouse J774 macrophages and N18 neuroblastoma cells. Biochem J 1996a;316:977-984.
MedlineWeb of Science

Di Marzo V,
De Petrocellis L,
Sugiura T,
Waku K
. Potential biosynthetic connections between the two cannabimimetic eicosanoids, anandamide and 2-arachidonoyl-glycerol, in mouse neuroblastoma cells. Biochem Biophys Res Commun 1996b;227:281-288.
CrossRefMedlineWeb of Science

Di Marzo V,
Bisogno T,
Melck D,
Ross R,
Brockie H,
Stevenson L,
Pertwee R,
De Petrocellis L
. Interactions between synthetic vanilloids and the endogenous cannabinoid system. FEBS Letts 1998;436:449-454.
CrossRefMedlineWeb of Science
Di Marzo V,
Goparju SK,
Wang L,
Lui J,
Batkal S,
Jaral Z,
Fezza F,
Miura GI,
Palmiter RD,
Sugiura T,
et al
. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001;410:822-825.
CrossRefMedline

Di Marzo V,
Ligresti A,
Morera E,
Nalli M,
Ortar G
. The anandamide membrane transporter. Structure-activity relationships of anandamide and oleoylethanolamine analogs with phenyl rings in the polar head group region. Bioorg Med Chem 2004;12:5161-5169.
CrossRefMedline

Edwards RM,
Stack EJ,
Trizna W
. Calcitonin gene-related peptide stimulayes adenylate cyclase and relaxes intracerebral arterioles. J Pharmacol Exp Ther 1991;257:1020-1024.
Abstract/FREE Full Text
Fedorscak P,
Dale PO,
Storeng R,
Ertzeid G,
Bjercke S,
Oldereid N,
Omland AK,
Abyholm T,
Tanbo T
. Impact of overweight and underweight on assisted reproduction treatment. Hum Reprod 2004;11:2523-2528.

Felder CC,
Joyce KE,
Briley EM,
Mansouri J,
Mackie K,
Blond O,
Lai Y,
Ma AL,
Mitchell RL
. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol 1995;8:443-450.

Felder CC,
Joyce KE,
Briley EM,
Glass M,
Mackie KP,
Fahey KJ,
Cullinan GJ,
Hunden DC,
Johnson DW,
Chaney MO,
et al
. LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation. J Pharmacol Exp Ther 1998;284:291-297.
Abstract/FREE Full Text

Fimiani C,
Mattocks D,
Cavani F,
Salzet M,
Deutsch DG,
Pryor S,
Bilfinger TV,
Stefano GB
. Morphine and anandamide stimulate intracellular calcium transients in human arterial endothelial cells: coupling to nitric oxide release. Cell Signal 1999;11:189-193.
CrossRefMedlineWeb of Science

Frank DA,
Bauchner H,
Parker S,
Huber AM,
Kyei-Aboagye K,
Cabral H,
Zuckerman B
. Neonatal body proportionality and body composition after in utero exposure to cocaine and marijuana. J Pediatr 1990;117:622-626.
CrossRefMedlineWeb of Science
Fried PA,
Buckingham M,
Von Kulmiz P
. Marijuana use during pregnancy and perineatl risk factors. Am J Obstet Gynecol 1983;146:992-994.
MedlineWeb of Science
Fried PA,
Watkinson B,
Willan A
. Marijuana use during pregnancy and decreased length of gestation. Am J Obstet Gynecol 1984;150:23-37.
MedlineWeb of Science

Fride E,
Foox A,
Rosenberg E,
Faigenboim M,
Cohen V,
Barda L,
Blau H,
Mechoulam R
. Milk intake and survival in newborn cannabinoid CB1 receptor knockout mice: evidence for a "CB3" receptor. Eur J Pharmacol 2003;461:27-34.
CrossRefMedlineWeb of Science

Galiegue S,
Mary S,
Marchand J,
Dussossoy D,
Carriere D,
Carayon P,
Bouaboula M,
Shire D,
Le Fur G,
Casellas P
. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 1995;232:54-61.
MedlineWeb of Science

Gangula PRR,
Wimalawansa S,
Yallampalli C
. Progesterone up-regulates vasodilator effects of calcitonin gene-related peptide in NG-nitro-L-arginine methyl ester-induced hypertension. Am J Obstet Gynecol 1997;176:894-900.
CrossRefMedlineWeb of Science

Gangula PRR,
Zhao H,
Supowit S,
Wimalawansa S,
DiPette D,
Yallampalli C
. Pregnancy and steroid hormones enhance the vasodilation responses to CGRP in rats. Am J Phys Heart Circ Physiol 1999;276:H284-H288.
Abstract/FREE Full Text

Gaoni Y,
Mechoulam R
. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 1964;86:1646-1647.
CrossRefWeb of Science
Gaoni Y,
Mechoulam R
. The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish. J Am Chem Soc 1971;93:217-224.
CrossRefMedlineWeb of Science

Gebremedhin D,
Lange AR,
Campbell WB,
Hillard CJ,
Harder DR
. Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current. Am J Physiol Heat Circ Physiol 1999;276:H2085-H2093.
Giang DK,
Cravatt BF
. Molecular characterization of human and mouse fatty acid amide hydrolases. Proc Natl Acad Sci USA 1997;94:2238-2242.
Abstract/FREE Full Text
Gibson GT,
Baghurst PA,
Colley DP
. Maternal alcohol, tobacco and cannabis consumption and the outcome of pregnancy. Aust NZ J Obstet Gynaecol 1983;23:15-19.
MedlineWeb of Science

Goumenou AG,
Matalliotakis IM,
Koumantakis GE,
Panidi DK
. The role of leptin in fertility. Eur J Obstet Gynecol 2003;106:118-124.
CrossRefWeb of Science
Greenland S,
Staisch KJ,
Brown N,
Gross SJ
. The effects of marijuana use during pregnancy. I. Am J Obstet Gynecol 1982;143:408-413.

Guo Y,
Wang H,
Okamoto Y,
Ueda N,
Kingsley PJ,
Marnett LJ,
Schmid HH,
Das SK,
Dey SK
. N-acylphosphatidylethanolamine-hydrolyzing phospholipase D is an important determinant of uterine anandamide levels during implantation. J Biol Chem 2005;280:23429-23432.
Abstract/FREE Full Text

Habayeb OMH,
Bell SC,
Konje JC
. Endogenous cannabinoids: Metabolism and their role in reproduction. Life Sci 2002;70:1963-1977.
CrossRefMedlineWeb of Science

Habayeb OM,
Taylor AH,
Evans MD,
Cooke MS,
Taylor DJ,
Bell SC,
Konje JC
. Plasma levels of the endocannabinoid, anandamide, in women — a potential role in pregnancy maintenance and labour? J Clin Endocrinol Metab 2004;89:5482-5487.
Abstract/FREE Full Text

Haggarty P
. Placental regulation of fatty acid delivery and its effects on fetal growth — a review. Placenta 2002;23:S28-S38.
CrossRefMedlineWeb of Science

Harris D,
Kendall DA,
Randall MD
. Characterisation of cannabinoid receptors coupled to vasorelaxation by endothelium-derived hyperpolarising factor. N-S Arch Pharmacol 1999;359:48-52.
CrossRef

Harris D,
McCulloch AI,
Kendall DA,
Randall MD
. Characterisation of vasorelaxant responses to anandamide in the rat mesenteric arterial bed. J Physiol 2002;539:893-902.
Abstract/FREE Full Text

Helliwell RJ,
Chamley LW,
Blake-Palmer K,
Mitchell MD,
Wu J,
Kearn CS,
Glass M
. Characterization of the endocannabinoid system in early human pregnancy. J Clin Endocrinol Metab 2004;89:5168-5174.
Abstract/FREE Full Text

Hillard CJ
. Endocannabinoids and vascular function. J Pharmacol Exp Ther 2000;294:27-32.
Abstract/FREE Full Text

Ho WS,
Hiley CR
. Endothelium-independent relaxation to cannabinoids in rat-isolated mesenteric artery and role of Ca2+ influx. Br J Pharmacol 2003a;139:585-597.
CrossRefMedlineWeb of Science

Ho WS,
Hiley CR
. Vasodilator actions of abnormal cannabidiol in rat isolated small mesenteric artery. Br J Pharmacol 2003b;138:1320-1332.
CrossRefMedlineWeb of Science

Hollander P
. Endocannabinoid blockade for improving glycemic control and lipids in patients with Type 2 diabetes mellitus. Am J Med 2007;120:S18-S28.
CrossRefMedlineWeb of Science

Huffman JW,
Yu S,
Showalter VM,
Abood ME,
Wiley JL,
Compton DR,
Martin BR,
Bramblett RD,
Reggio PH
. Synthesis and pharmacology of a very potent cannabinoid lacking a phenolic hydroxyl with high affinity for the CB2 receptor. J Med Chem 1996;39:3875-3877.
CrossRefMedlineWeb of Science

Hutchings DE,
Martin BR,
Gamagaris Z,
Miller N,
Fico T
. Plasma concentrations of delta-9-tetrahydrocannabinol in dams and fetuses following acute or multiple prenatal dosing in rats. Life Sci 1989;44:697-701.
CrossRefMedlineWeb of Science

Illsley NP
. Glucose transporters in the human placenta. Placenta 2002;21:14-22.
CrossRef

Jaffe RB
. Fetoplacental endocrine and metabolic physiology. Clin Perinatol 1983;10:669-693.
MedlineWeb of Science

Jarai Z,
Wagner JA,
Varga K,
Lake KD,
Compton DR,
Martin BR,
Zimmer AM,
Bonner TI,
Buckley NE,
Mezey E,
et al
. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci USA 1999;96:14136-14141.
Abstract/FREE Full Text

Jung KM,
Mangieri R,
Stapleton C,
Kim J,
Fegley D,
Wallace M,
Mackie K,
Piomelli D
. Stimulation of endocannabinoid formation in brain slice cultures through activation of group I metabotropic glutamate receptors. Mol Pharmacol 2005;68:1196-1202.
Abstract/FREE Full Text

Kayisli UA,
Demir R,
Erguler G,
Arici A
. Vasodilator-stimulated phosphoprotein expression and its cytokine-mediated regulation in vasculogenesis during human placental development. Mol Hum Reprod 2002;8:1023-1030.
Abstract/FREE Full Text

Khare M,
Taylor AH,
Konje JC,
Bell SC
. Δ9-Tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod 2006;12:321-333.
Abstract/FREE Full Text

Kim YM,
Chaiworapongsa T,
Gomez R,
Bujold E,
Yoon BH,
Rotmensch S,
Thaler HT,
Romero R
. Failure of physiologic transformation of the spiral arteries in the placental bed in preterm premature rupture of membranes. Am J Obstet Gynecol 2002;187:1137-1142.
CrossRefMedlineWeb of Science

Kishimoto Y,
Kano M
. Endogenous cannabinoid signaling through the CB1 receptor is essential for cerebellum-dependent discrete motor learning. J Neuroscience 2006;26:8829-8837.
Abstract/FREE Full Text

Kolodny RC,
Masters WH,
Kolodner RM,
Toro G
. Depression of plasma testosterone levels after chronic intensive marijuana use. N Engl J Med 1974;290:872-874.
MedlineWeb of Science

Lewysohn O,
Cordova T,
Nimrod A,
Ayalon D
. The suppressive effect of delta 1-tetrahydrocannabinol on the steroidogenic activity of rat granulosa cells in culture. Horm Res 1984;19:43-51.
MedlineWeb of Science

Linne Y
. Effects of obesity on women's reproduction and complications during pregnancy. Obes Rev 2004;5:137-143.
CrossRefMedline

Liu J,
Wang L,
Harvey-White J,
Osei-Hyiaman D,
Razdan R,
Gong Q,
Chan AC,
Zhou Z,
Huang BX,
Kim H-Y,
et al
. A biosynthetic pathway for anandamide. Proc Natl Acad Sci USA 2006;103:13345-13350.
Abstract/FREE Full Text

Lockitch G
. Clinical biochemistry of pregnancy. Crit Rev Clin Lab Sci 1997;34:67-139.
MedlineWeb of Science

Lockwood CJ
. Prediction of pregnancy loss. Lancet 2000;355:1292-1293.
CrossRefMedlineWeb of Science

Maccarrone M,
Bari M,
Lorenzon T,
Bisogno T,
Di Marzo V,
Finazzi-Agro A
. Anandamide uptake by human endothelial cells and its regulation by nitric oxide. J Biol Chem 2000a;275:13484-13492.
Abstract/FREE Full Text
Maccarrone M,
Finazzi-Agro A
. The endocannabinoid system, anandamide and the regulation of mammalian cell apoptosis. Cell Death Differ 2003;10:946-955.
CrossRefMedlineWeb of Science

Maccarrone M,
Finazzi-Agro A
. Anandamide hydrolase: a guardian angel of human reproduction? Trends Pharmacol Sci 2004;25:353-357.
CrossRefMedline

Maccarrone M,
De Felici M,
Bari M,
Klinger FG,
Siracusa G,
Finazzi-Agro A
. Down-regulation of anandamide hydrolase in mouse uterus by sex hormones. Eur J Biochem 2000b;267:2991-2997.
MedlineWeb of Science

Maccarrone M,
Lorenzon T,
Bari M,
Melino G,
Finazzi-Agro A
. Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors. J Biol Chem 2000c;275:31938-31945.
Abstract/FREE Full Text

Maccarrone M,
Valensise H,
Bari M,
Lazzarin N,
Romanini C,
Finazzi-Agro A
. Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet 2000d;355:1326-1329.
CrossRefMedlineWeb of Science

Maccarrone M,
Valensise H,
Bari M,
Lazzarin N,
Romanini C,
Finazzi-Agro A
. Progesterone up-regulates anandamide hydrolase in human lymphocytes: role of cytokines and implications for fertility. J Immunol 2001;166:7183-7189.
Abstract/FREE Full Text

Maccarrone M,
Bari M,
Battista N,
Finazzi-Agro A
. Estrogen stimulates arachidonoylethanolamide release from human endothelial cells and platelet activation. Blood. 2002a;100:4040-4048.
Abstract/FREE Full Text
Maccarrone M,
Bisogno T,
Valensise H,
Lazzarin N,
Fezza F,
Manna C,
Di Marzo V,
Finazzi-Agro A
. Low fatty acid amide hydrolase and high anandamide levels are associated with failure to achieve an ongoing pregnancy after IVF and embryo transfer. Mol Hum Reprod 2002b;8:188-195.
Abstract/FREE Full Text

Maccarrone M,
Falciglia K,
Di Rienzo M,
Finazzi-Agro A
. Endocannabinoids, hormone-cytokine networks and human fertility. Prostaglandins Leukot. Essent. Fatty Acids. 2002c;66:309-317.
CrossRef

Maccarrone M,
Bari M,
Di Rienzo M,
Finazzi-Agro A,
Rossi A
. Progesterone activates fatty acid amide hydrolase (FAAH) promoter in human T lymphocytes through the transcription factor Ikaros. Evidence for a synergistic effect of leptin. J Biol Chem 2003a;278:32726-32732.
Abstract/FREE Full Text

Maccarrone M,
Di Rienzo M,
Finazzi-Agro A,
Rossi A
. Leptin activates the anandamide hydrolase promoter in human T lymphocytes through STAT3. J Biol Chem 2003b;278:13318-13324.
Abstract/FREE Full Text

Maccarrone M,
Cecconi S,
Rossi G,
Battista N,
Pauselli R,
Finazzi-Agro A
. Anandamide activity and degradation are regulated by early postnatal aging and follicle-stimulating hormone in mouse Sertoli cells. Endocrinology 2003c;144:20-28.
Abstract/FREE Full Text
Maccarone M,
Barboni B,
Paradisi A,
Bernabo N,
Gasperi V,
Pistilli MG,
Fezza F,
Lucidi P,
Mattioli M
. Characterization of the endocannabinoid system in boar spermatozoa and implications for sperm capacitation and acrosome reaction. J Cell Sci 2005;118:4393-4404.
Abstract/FREE Full Text

Martin BR,
Compton DR,
Thomas BF,
Prescott WR,
Little PJ,
Razdan RK,
Johnson MR,
Melvin LS,
Mechoulam R,
Ward SJ
. Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs. Pharmacol Biochem Behav 1991;40:471-478.
CrossRefMedlineWeb of Science

Matsuda LA,
Lolait SJ,
Brownstein MJ,
Young AC,
Bonner TI
. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561-564.
CrossRefMedline

McCulloch AI,
Randall MD
. Sex differences in the relative contributions of nitric oxide and EDHF to agonist-stimulated endothelium-dependent relaxations in the rat isolated mesenteric arterial bed. Br J Pharmacol 1998;123:1700-1706.
CrossRefMedlineWeb of Science

McMaster MT,
Zhou Y,
Fisher SJ
. Abnormal placentation and the syndrome of pre-eclampsia. Semin Nephrol 2004;24:540-547.
MedlineWeb of Science

Mechoulam R,
Hanus L
. A historical overview of chemical research on cannabinoids. Chem Phys Lipids 2000;108:1-13.
CrossRefMedlineWeb of Science

Mechoulam R,
Fride E
. A hunger for cannabinoids. Nature 2001;410:783-785.

Messinis IE,
Milingos SD
. Leptin in human reproduction. Hum Reprod Update 1999;5:52-63.
Abstract/FREE Full Text
Moore C,
Negrusz A,
Lewis D
. Determination of drugs of abuse in meconium. J Chromatogr B 1998;713:137-146.
CrossRef

Moore SA,
Nomikos GG,
Dickason-Chesterfield AK,
Schober DA,
Schaus JM,
Ying BP,
Xu YC,
Phebus L,
Simmons RM,
Li D,
et al
. Identification of a high-affinity binding site involved in the transport of endocannabinoids. Proc Natl Acad Sci USA 2005;102:17852-17857.
Abstract/FREE Full Text

Mueller BA,
Daling JR,
Weiss N S,
Moore DE
. Recreational drug use and the risk of primary infertility. Epidemiology 1990;1:195-200.
Medline

Mukhopadhyay S,
Chapnick BM,
Howlett AC
. Anandamide-induced vasorelaxation in rabbit aortic rings has two components: G protein dependent and independent. Am J Phys Heart Circ Physiol 2002;282:H2046-H2054.
Abstract/FREE Full Text

Munro S,
Thomas KL,
Abu-Shaar M
. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365:61-65.
CrossRefMedline

Murphy LL,
Gher J,
Steger RW,
Bartke A
. Effects of Δ9-tetrahydrocannabinol on copulatory behaviour and neuroendocrine responses of male rats to female rat conspecifics. Pharmacol Biochem Behav 1994;48:1011-1017.
CrossRefMedlineWeb of Science

Nahas GG,
Frick HC,
Lattimer JK,
Latour C,
Harvey D
. Pharmacokinetics of THC in brain and testis, male gametotoxicity and premature apoptosis of spermatozoa. Hum Psychopharmacol 2002;17:103-113.
CrossRefMedlineWeb of Science

Nir I,
Ayalon D,
Tsafriri A,
Cordova T,
Lindner HR
. Suppression of the cyclic surge of LH and of ovulation in the rat by Delta 1-tetrahydrocannabinol. Nature 1973;234:470-471.

Nygren KG,
Andersen AN
. Assisted reproductive technology in Europe, 1998. Results generated from European registers by ESHRE. Hum Reprod 2001;16:2459-2471.
Abstract/FREE Full Text

Pardi GAM,
Marconi AM,
Cetin I
. Pathophysiology of intrauterine growth retardation: role of the placenta. Acta Paediatr Suppl 1997;423:170-172.
Medline

Paria BC,
Dey SK
. Ligand-receptor signalling with endocannabinoids in preimplantation embryo development and implantation. Chem Phys Lipids 2000;108:211-220.
CrossRefMedlineWeb of Science

Paria BC,
Das SK,
Dey SK
. The preimplantation mouse embryo is a target for endocannabinoid ligand-receptor signalling. Proc Natl Acad Sci USA 1995;92:9460-9464.
Abstract/FREE Full Text

Paria BC,
Deutsch DD,
Dey SK
. The uterus is a potential site for anandamide synthesis and hydrolysis: differential profiles of anandamide synthase and hydrolase activities in mouse uterus during the preimplantation period. Mol Reprod Dev 1996;45:183-192.
CrossRefMedlineWeb of Science
Paria BC,
Ma W,
Andrenyak DM,
Schmid PC,
Schmid HH,
Moody DE,
Deng H,
Makriyannis A,
Dey SK
. Effects of cannabinoids on preimplantation mouse embryo development and implantation are mediated by brain-type cannabinoid receptors. Biol Reprod 1998;58:1490-1495.
Abstract/FREE Full Text

Paria BC,
Zhao X,
Wang J,
Das SK,
Dey SK
. Fatty acid amide hydrolase is expressed in the mouse uterus and embryo during the periimplantation period. Biol Reprod 1999;60:1151-1157.
Abstract/FREE Full Text

Paria BC,
Song H,
Wang X,
Schmid PC,
Krebsbach RJ,
Schmid HH,
Bonner TJ,
Zimmer A,
Dey SK
. Dysregulated cannabinoid sgnaling disrupts uterine receptivity for embryo implantation. J Biol Chem 2001;276:20523-20528.
Abstract/FREE Full Text

Paria BC,
Wang H,
Dey SK
. Endocannabinoid signalling in synchronizing embryo development and uterine receptivity for implantation. Chem Phys Lipids 2002;121:201-210.
CrossRefMedlineWeb of Science

Park B,
Gibbons HM,
Mitchell MD,
Glass M
. Identification of the CB1 cannabinoid receptor and fatty acid amide hydrolase (FAAH) in the human placenta. Placenta 2003;24:473-478.
CrossRefMedlineWeb of Science
Patra PB,
Wadworth RM
. Effect of synthetic cannabinoid nabalone on spermatogenesis in mice. Experimentia 1990;46:852-854.
CrossRefMedlineWeb of Science

Pertwee R
. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 1997;74:129-180.
CrossRefMedlineWeb of Science

Piomelli D,
Giuffrida A,
Calignano A,
Rodriguez de Fonseca F
. The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol Sci 2000;21:218-224.
CrossRefMedline

Plane F,
Holland M,
Waldron GJ,
Garland CJ,
Boyle JP
. Evidence that anandamide and EDHF act via different mechanisms in rat isolated mesenteric arteries. Br J Pharmacol 1997;121:1509-1511.
CrossRefMedlineWeb of Science

Powell DJ,
Fuller RW
. Marijuana and sex: strange bedpartners. J Psychoactive Drugs 1983;15:269-280.
MedlineWeb of Science

Pratt PF,
Hillard CJ,
Edgemond WS,
Campbell WB
. N-arachidonylethanolamide relaxation of bovine coronary artery is not mediated by CB1 cannabinoid receptor. Am J Phys 1998;274:H375-H381.

Rajashekhar G,
Loganath A,
Roy AC,
Chong SS,
Wong YC
. Hypoxia up-regulated angiogenin and down-regulated vascular cell adhesion molecule-1 expression and secretion in human placental trophoblasts. J Soc Gynecol Invest 2005;12:310-319.
Abstract/FREE Full Text

Randall MD,
Kendall DA
. Anandamide and endothelium-drived hyperpolarising factor act via a common vasorelaxant mechanism in rat mesentery. Eur J Pharmacol 1998;346:51-53.
CrossRefMedlineWeb of Science

Randall MD,
Alexander SP,
Bennet T,
Boyd EA,
Fry JR,
Gardiner SM,
Kemp PA,
McCulloch AI,
Kendall DA
. An endogenous cannabinoid as an endothelium-derived vasorelaxant. Biochem Biophys Res Comm 1996;229:114-120.
CrossRefMedlineWeb of Science

Redman CW,
Sargent IL
. Latest advances in understanding preeclampsia. Science 2005;308:1592-1594.
Abstract/FREE Full Text
Reich R,
Laufer N,
Lewysohn O,
Cordova T,
Ayalon D,
Tsafriri A
. In vitro effects of cannabinoids on follicular function in the rat. Biol Reprod 1982;27:223-231.
Abstract

Ross R
. Anandamide and vanilloid TRPV1 receptors. Br J Pharmacol 2003;140:790-801.
CrossRefMedlineWeb of Science

Rossato M,
Ion Popa F,
Ferigo M,
Clarim G,
Foresta C
. Human sperm express cannabinoid receptor CB1, the activation of which inhibits motility, acrosome reaction, and mitochondrial function. J Clin Endocrinol Metab 2005;90:984-991.
Abstract/FREE Full Text

Salafia CM
. Placental pathology of fetal growth restriction. Clin Obstet Gynecol 1997;40:740-749.
CrossRefMedlineWeb of Science

Schmid PC,
Paria BC,
Krebsbach RJ,
Schmid HH,
Dey SK
. Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation. Proc Natl Acad Sci USA 1997;94:4188-4192.
Abstract/FREE Full Text

Schuel HL,
Burkman LJ
. A tale of two cells: endocannabinoid-signaling regulates functions of neurons and sperm. Biol Reprod. 2005;73:1078-1086.
FREE Full Text

Schuel H,
Burkman LJ,
Lippes J,
Crickard K,
Forester E,
Piomelli D,
Giuffrida A
. N-Acylethanolamines in human reproductive fluids. Chem Phys Lipids 2002a;121:211-227.
CrossRefMedlineWeb of Science

Schuel H,
Burkman LJ,
Lippes J,
Crickard K,
Mahony MC,
Giuffrida A,
Picone RP,
Makriyannis A
. Evidence that anandamide signaling regulates human sperm functions required for fertilization. Mol Reprod Dev 2002b;63:376-387.
CrossRefMedlineWeb of Science

Sharov AA,
Piao Y,
Matoba R,
Dudekula DB,
Qian Y,
Van Buren V,
Falco G,
Martin PR,
Stagg CA,
Bassey UC,
et al
. Transcriptome analysis of mouse stem cells and early embryos. PLoS Biol 2003;1:E74.
Medline

Shire D,
Carillon C,
Kaghad M,
Calandra B,
Rinaldi-Carmona M,
Le Fur G,
Caput D,
Ferrara P
. An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing. J Biol Chem 1995;270:3726-3731.
Abstract/FREE Full Text

Showalter VM,
Compton DR,
Martin BR,
Bood ME
. Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands. J Pharmacol 1996;278:989-999.
Web of Science

Sidney S
. Cardiovascular consequences of marijuana use. J Clin Pharmacol 2002;42:64S-70S.
Abstract/FREE Full Text

Simon GM,
Cravatt BF
. Endocannabinoid biosynthesis proceeding through glycerophospho-N-acyl ethanolamine and a role for α/β-hydrolase 4 in this pathway. J Biol Chem 2006;281:26465-26472.
Abstract/FREE Full Text

Sladek SM,
Magness RR,
Conrad KP
. Nitric oxide and pregnancy. Am J Phys 1997;272:R441-R463.

Straiker AJ,
Maguire G,
Mackie K,
Lindsey J
. Localisation of cannabinoid CB1 receptors in the human anterior eye and retina. Invest Ophthalmol Vis Sci 1999;40:2442-2448.
Abstract/FREE Full Text
Straszewski-Cavez SL,
Abrahams VM,
Mor G
. The role of apoptosis in the regulation of trophoblast survival and differentiation during pregnancy. Endocr Rev 2005;26:877-897.
Abstract/FREE Full Text

Suarez SS,
Ho HC
. Hyperactivated motility in sperm. Reprod Domest Anim 2003;38:119-124.
CrossRefMedlineWeb of Science

Takagi Y,
Nikaido T,
Toki T,
Kita N,
Kanai M,
Ashida T,
Ohira S,
Konishi I
. Levels of oxidative stress and redox-related molecules in the placenta in preeclampsia and fetal growth restriction. Vir Arch 2004;444:49-55.
CrossRef

Taylor AH,
Abbas MS,
Bell SC,
Konje JC
. The inhibitory effect of Δ9-tetrahydrocannabinol on trophoblast cell proliferation and transcription is mediated via the CB-2 receptor. Br J Obstet Gynecol 2007.

Thadani PV,
Strauss JF III,
Dey SK,
Anderson VM,
Audus KL,
Coats KS,
Cross JC,
Erlebacher A,
Ganapathy V,
Linzer DI
. National Institute on Drug Abuse Conference report on placental proteins, drug transport, and fetal development. Amer J Obstet Gynecol 2004;191:1858-1862.
CrossRefMedlineWeb of Science

Thaete LG,
Dewey ER,
Neerhof MG
. Endothelin and the regulation of uterine and placental perfusion in hypoxia-induced fetal growth restriction. J Soc Gynecol Invest 2004;11:16-21.
Abstract/FREE Full Text

Treinen KA,
Sneeden JL,
Heindel JJ
. Specific inhibition of FSH-stimulated cAMP accumulation by delta 9-tetrahydrocannabinol in cultured rat granulosa cells. Toxicol Appl Pharmacol 1993;118:53-57.
CrossRefMedlineWeb of Science

Van Der Stelt M,
Di Marzo V
. Endovanilloids. Putative endogenous ligands of transient receptor potential vanilloid 1 channels. Eur J Biochem 2004;271:1827-1834.
MedlineWeb of Science

Van Gaal LF,
Rissanen A,
Scheen A,
Ziegler AM,
Rossner S
. Effect of rimonabant on weight reduction and cardiovascular risk. Lancet 2005;366:369-370.
MedlineWeb of Science

Van Oosten BW,
Killestein J,
Mathus-Vliegen EMH,
Polman CH
. Multiple sclerosis following treatment with a cannabinoid receptor-1 antagonist. Mult Scler 2004;10:330-331.
Abstract/FREE Full Text

Vardaris RM,
Weisz DJ,
Fazel A,
Rawitch AB
. Chronic administration of delta-9-tetrahydrocannabinol to pregnant rats: studies of pup behavior and placental transfer. Pharmacol Biochem Behav 1976;4:249-254.
CrossRefMedlineWeb of Science

Varga K,
Lake KD,
Kunos G
. Novel antagonist implicates the CB1 cannabinoid receptor in the hypotensive action of anandamide. Eur J Pharmacol 1995;278:279-283.
CrossRefMedlineWeb of Science

Vogeser M,
Hauer D,
Christina Azad S,
Huber E,
Storr M,
Schelling G
. Release of anandamide from blood cells. Clin Chem Lab Med 2006;44:488-491.
CrossRefMedlineWeb of Science

Vuorela P,
Hatva E,
Lymboussaki A,
Kaipainen A,
Joukov V,
Persico MG,
Alitalo K,
Halmesmaki E
. Expression of vascular endothelial growth factor and placenta growth factor in human placenta. Biol Reprod 1997;56:489-494.
Abstract

Wagner JA,
Varga K,
Jarai Z,
Kunos G
. Mesenteric vasodilation mediated by endothelial anandamide receptors. Hypertension 1999;33:429-434.
Abstract/FREE Full Text

Walter I,
Schonkypl S
. Extracellular matrix components and matrix degrading enzymes in the feline placenta during gestation. Placenta 2006;27:291-306.
CrossRefMedlineWeb of Science

Wang J,
Paria BC,
Dey SK,
Armant DR
. Stage-specific excitation of cannabinoid receptor exhibits differential effects on mouse embryonic development. Biol Reprod 1999;60:839-844.
Abstract/FREE Full Text

Wang H,
Matsumoto H,
Guo Y,
Paria BC,
Roberts RL,
Dey SK
. Differential G protein-coupled cannabinoid receptor signaling by anandamide directs balstocyst activation for implantation. Proc Natl Acad Sci 2003;100:14914-14919.
Abstract/FREE Full Text

Wang H,
Guo Y,
Wang D,
Kingsley PJ,
Marnett L,
Das SK,
DuBois RN,
Dey SK
. Aberrant cannabinoid signaling impairs oviductal transport of embryos. Nat Med 2004;10:1074-1080.
CrossRefMedlineWeb of Science

Wang H,
Dey SK,
Maccarrone M
. Jekyll and Hyde: Two faces of cannabinoid signaling in male and female fertility. Endocr Rev 2006a;27:427-448.
Abstract/FREE Full Text
Wang J,
Okamoto Y,
Morishita J,
Tsuboi K,
Miyatake A,
Ueda N
. Functional analysis of the purified anandamide-generating phospholipase D as a member of the metallo-β-lactamase family. J Biol Chem 2006b;281:12353-12335.

Wei BQ,
Mikkelsen TS,
McKinney MK,
Lander ES,
Cravatt BF
. A second fatty acid amide hydrolase with variable distribution among placental mammals. J Biol Chem 2006;281:36569-36578.
Abstract/FREE Full Text

Wenger T,
Ledent C,
Csernus V,
Gerendai I
. The central cannabinoid receptor inactivation suppresses endocrine reproductive function. Biochem Biophys Res Commun 2001;284:363-368.
CrossRefMedlineWeb of Science

White R,
Hiley CR
. A comparison of EDHF-mediated and anandamide-induced relaxations in the rat isolated mesenteric artery. Br J Pharmacol 1997;122:1573-1584.
CrossRefMedlineWeb of Science

Woods JR Jr
. Adverse consequences of prenatal illicit drug exposure. Curr Opin Obstet Gynecol 1996;8:403-411.
MedlineWeb of Science

Wray S,
Jones K,
Kupittayanant S,
Li Y,
Matthew A,
Monir-Bishty E,
Noble K,
Pierce SJ,
Quenby S,
Shmygol AV
. Calcium signaling and uterine contractility. J Soc Gynecol Invest 2003;10:252-264.
Abstract/FREE Full Text

Yamaji K,
Sarker KP,
Kawahara K,
Iino S,
Yamakuchi M,
Abeyama K,
Hashiguchi T,
Maruyama I
. Anandamide induces apoptosis in human endothelial cells: its regulation system and clinical implications. Thromb Haemost 2003;89:875-884.
MedlineWeb of Science

Yang ZM,
Paria BC,
Dey SK
. Activation of brain-type cannabinoid receptors interferes with preimplantation mouse embryo development. Biol Reprod 1996;55:756-761.
Abstract

Zimmerman AM,
Bruce WR,
Zimmerman S
. Effects of cannabinoids on sperm morphology. Pharmacology 1979;18:143-148.
MedlineWeb of Science

Zuckerman B,
Frank DA,
Hingson R,
Amaro H,
Levenson SM,
Kayne H,
Parker S,
Vinci R,
Aboagye K,
Fried LE,
et al
. Effects of maternal marijuana and cocaine use on fetal growth. New Engl J Med 1989;320:762-768.
MedlineWeb of Science

Zygmunt PM,
Hogestatt ED,
Waldeck K,
Edwards G,
Kirkup AJ,
Weston AH
. Studies on the effects of anandamide in rat hepatic artery. Br J Pharmacol 1997;122:1679-1686.
CrossRefMedlineWeb of Science

Zygmunt PM,
Petersson J,
Andersson DA,
Chuang H,
Sorgard M,
Di Marzo V,
Julius D,
Hogestatt ED
. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 1999;400:452-457.
CrossRefMedline

Zygmunt PM,
Hogestatt ED,
Julius D,
Di Marzo V
. Anandamide - the other side of the coin. Trends Pharmacol Sci 2000;21:43-44.
CrossRefMedline

Zygmunt PM,
Andersson DA,
Hogestatt ED
. Delta -9-tetrahydrocannabinol and cannabinol activate capsaicin-sensitive sensory nerves via a CB1 and CB2 cannabinoid receptor-independent mechanism. J Neurosci 2002;22:4720-4727.


Source: The role of the endocannabinoid system in gametogenesis, implantation and early pregnancy
 
Top Bottom