We finally know how endocannabinoids spread in the brain

For three decades, the endocannabinoids, These compounds are similar to certain cannabis molecules, but are produced by the body itself.

A recent study led by Mario van der Stelt, Professor of Molecular Physiology at Leiden University, has revealed that these substances travel through the brain in fat vesicles, rather than in the form of floating molecules like dopamine or serotonin.

This discovery, published in the magazine PNAS, could pave the way for innovative treatments for pain and neurological disorders.

A new form of communication in the brain

The human brain naturally produces endocannabinoids, compounds similar to those found in cannabis. These molecules play an essential role in processes such as memory, anxiety and pain regulation. Among them, two main types stand out: the’anandamide and the 2-AG. The recent study focused on 2-AG, with the aim of understanding its mode of transport between the nerve cells.

Until now, it has been difficult to keep up with the 2-AG movement because of its fat composition, which made it invisible under the microscope. Standard scientific methods did not provide a clear picture, as they often destroyed the cells being examined.

A major breakthrough has been achieved with the development of a sensor technology developed by Chinese researchers. This sensor enabled scientists to observe the movement of 2-AG in real time, by causing the cells to light up when they detected the molecule coming from a neighboring nerve cell.

Fat vesicles: The key to 2-AG transport

Using this innovative sensor, Verena Straub, a PhD researcher in Van der Stelt's team, has confirmed that 2-AG is transported in vesicles.

Through extensive testing, she demonstrated that blocking vesicle formation led to a decrease in 2-AG levels, while stopping 2-AG production led to the formation of vesicles not containing the compound. On average, each vesicle contained around two thousand molecules of 2-AG.

To further validate their results, the researchers collaborated with a US-based research group to analyze the process in intact brain tissue. In addition, in collaboration with the team of Coen van Hasselt, Professor of Pharmacology, they have developed a mathematical model which could only explain the observed signals if 2-AG was effectively transported by the vesicles.

A step towards medical innovation

«This may be a new form of communication between nerve cells in the brain,» explains Van der Stelt.

This discovery not only changes our understanding of the endocannabinoid signaling, but also opens up new avenues for medical applications. Given that 2-AG plays a crucial role in pain management and neurological diseases, understanding its movements could lead to targeted therapies that regulate its function.

The potential of these discoveries extends beyond endocannabinoids. Van der Stelt suggests that other fatty messenger molecules could also use a similar vesicle-based transport system.

As Van der Stelt puts it, «now that we know how it moves, we can look for ways to influence its function».

Thanks to ongoing studies and further validation, this breakthrough could lead to the development of new treatments against chronic pain, epilepsy and neurological disorders.