Ever since scientists began discovering in the early 1990s that marijuana-like compounds are normally produced in various parts of the body, they have been investigating the function of these compounds. Research has suggested that in the brain, the compounds, called endocannabinoids, inhibit pain perception and help to regulate movement. In the spleen and blood, endocannabinoids seem to be partly involved in suppressing inflammation and other responses of the immune system. Now NIDA-funded researchers have discovered that in the female mouse reproductive tract, one of these endocannabinoids, called anandamide, appears to help regulate the early stages of pregnancy.

Dr. Sudhansu K. Dey and his colleagues at the University of Kansas Medical Center in Kansas City, Kansas, have found that the mouse uterus contains the highest anandamide levels yet discovered in any mammalian tissue. At times, parts of the uterus contain anandamide levels that are more than 100 times higher than those in the brain. The researchers have also found that mouse embryos contain cannabinoid receptors-proteins on the cell surfaces that latch on to endocannabinoids in the vicinity-again, at levels that exceed those of the brain.

To find out why the uterus contains anandamide and the embryo contains cannabinoid receptors, the scientists first examined the effects of anandamide on embryo development. When they placed embryos from mice in cell culture, about 90 percent proceeded to the next stage of embryonic development, the blastocyst, which normally implants into the wall of the uterus and eventually becomes a fetus. With the addition of anandamide, only 36 percent proceeded to the blastocyst stage. However, if these embryos were then placed in cell culture without anandamide, most started developing again.

In addition to inhibiting the growth of embryos prior to implant-ation, anandamide probably also inhibits implantation itself, the researchers found. They determined that administering compounds similar to anandamide prevented blastocysts from implanting in the uterine wall.

Functions of Anandamide

Anandamide may be serving at least three functions before and during implantation, suggests Dr. Dey. First, the compound may be involved in synchronizing the development of the embryo with the preparation of the uterus for receiving it. For example, anandamide secreted into the fluid of the uterine tubes might retard embryo development until the uterus is ready to receive the implanting blastocyst and to sustain it once it has implanted.

Second, anandamide may be involved in embryo selection. "In the mouse, about 15 percent of embryos never implant, and in humans, as many as 60 percent either don't implant or don't survive after implantation," says Dr. Dey. "Perhaps these rejected embryos are inferior in some way, and high anandamide levels in the uterine wall may prevent them from implant-ing or surviving after implantation."

Finally, Dr. Dey suggests, anandamide may prevent a second blastocyst from implanting nearby one that has already implanted. After the first one implants, the anandamide level in the surrounding area increases again, which prevents other blastocysts from implanting at the same site.

Understanding how anandamide acts in the female reproductive tract may lead to an explanation for some cases of infertility in women, if anandamide is found to exist in the human uterus, suggests Dr. Dey. In these infertile women, excessive uterine levels of anandamide may be disrupting embryo development and implantation, says Dr. Dey.

This research may also lead to the development of new contraceptives that can inhibit embryo development and implantation in the same manner as anandamide. Conversely, it could also lead to the development of fertility agents that act in ways opposite to those of anandamide.

Sources

Paria, B.C.; Das, S.K.; and Dey, S.K. The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling. Proceedings of the National Academy of Sciences 92:9460-9464, 1995. [Abstract]

Paria, B.C.; et al. Fatty-acid amide hydrolase is expressed in the mouse uterus and embryo during the periimplantation period. Biology of Reproduction 60:1151-1157, 1999. [Abstract]

Schmid, P.C.; et al. Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation. Proceedings of the National Academy of Sciences 94:4188-4192, 1997. [Abstract and Full Text]

Yang, Z-M; Paria, B.C.; and Dey, S.K. Activation of brain-type cannabinoid receptors interferes with preimplantation mouse embryo development. Biology of Reproduction 55:756- 761, 1996. [Abstract]