Marijuana exerts its effects in the brain and peripheral organs through two cannabinoid receptors, CB1 and CB2. Lipid molecules made by the body, called “endocannabinoids,” activate these receptors, and are involved in several important physiological functions, including memory, pain and appetite.
In the 1990s, while at the University of Kansas Medical Center in Kansas City, Dey and his colleagues found that the mouse pre-implantation embryo, or blastocyst, had much higher levels of the CB1 receptor than did the brain. They also found that the uterus produced one of the activating molecules, called anandamide.
After moving to Vanderbilt two years ago, the researchers found that anandamide regulates implantation of the mouse embryo in the wall of the uterus. At low concentrations, it synchronizes embryo development with uterine receptivity so that successful implantation occurs. At higher levels, however, implantation is blocked. Elevated levels of anandamide also have been shown to cause spontaneous pregnancy loss in women.
“I feel that it has a fundamental physiological function in reproduction,” said Dey, who directs the division of Reproductive and Developmental Biology at Vanderbilt.
The current study began with the observation that mice commonly used in genetic experiments often fail to deliver pups, even though they become pregnant. Upon flushing the oviducts, the researchers found the embryos, which for some reason were unable to reach the uterus.
This strain of mouse lacks the gene for the CB1 receptor. When the researchers gave a drug that blocked CB1 in normal mice, they observed the same phenomenon – in most of the mice the embryos failed to reach the uterus. The same thing happened when the mice were given an amandamide-like drug to over-stimulate the receptor.
In a search to unravel this mystery, Haibin Wang, Ph.D., research assistant professor of Pediatrics, found that the CB1 receptor is located near two other receptors (adrenergic receptors) that – through the action of noradrenaline, a neurotransmitter – regulate muscle contraction. Wang, who led the study, has received two Lalor Foundation fellowships supporting research in reproductive biology.
Subsequent experiments supported a new concept: the CB1 receptor modulates the release of noradrenaline, which in turn stimulates waves of muscle contraction and relaxation in the oviduct, nudging the embryo toward the uterus. Too much or too little of this “endocannabinoid tone” can result in pregnancy failure.
In support of this hypothesis, abnormal muscular contraction that prevents human embryos from reaching the uterus is one known cause of ectopic pregnancy, Dey said.
Polymorphisms (different forms) of the CB1 gene have been associated with drug dependency in humans. Dey and his colleagues plan to study whether certain polymorphisms also may reflect an increased risk for ectopic pregnancy. “That will be the ultimate test” for proving the receptor’s role in ectopic pregnancy in humans, he says.