Cannabinoids go retro
If you’ve ever taken an introductory neuroscience class, one of the first things you learned was how neurons (brain cells) communicate with one another. Using both electrical and chemical signaling, messages jump from cell to cell along different circuits throughout the brain. This transmission ensures the coordination of various behaviors, from as simple as tying your shoe to as complex as solving a mathematical proof.
But, let’s talk more about the chemical messengers involved in this process, which are called neurotransmitters. GABA, for example, is a neurotransmitter that regulates inhibitory activity in the brain; those who enjoy alcoholic beverages are familiar with the results of increasing its effects.
At the synapse (connection point between neurons, kind of like an airport), neurotransmitters are released from one neuron (called pre-synaptic) to another neuron (called post-synaptic).  This is the standard way messages flow from one cell to the next in the brain.
Endocannabinoids like anandamide and 2-arachidonoylglycerol (2-AG) are indeed chemical messengers but are not technically considered neurotransmitters.  Why?
Well, for one, endocannabinoids are lipophilic, or fat loving. This makes living in the watery environment that neurons are bathed in quite challenging. And endocannabinoids are quite the rebels when it comes to influencing neuronal activity—they actually work against the usual traffic and travel backward from the post-synaptic neuron to the pre-synaptic neuron.  What?
Endocannabinoids, specifically 2-AG, possess quite an interesting mechanism of action, which is known as retrograde signaling. [3,4] The reason why they break the mold is not because they are chemical renegades but is rather due to their origin of creation. Endocannabinoids are made in the post-synaptic neuron and therefore must travel backwards to bind to cannabinoid receptors in the pre-synaptic neuron to take effect.  For these reasons, they are referred to as neuromodulators versus neurotransmitters.
How does this mechanism affect their influence on the brain?
In the pre-synaptic neuron, endocannabinoids can regulate the release of neurotransmitters, thus allowing a postsynaptic cell to affect how many and which neurotransmitters are released.  Pretty retro, man, from one neuron to another.
Understanding of retrograde signaling and how endocannabinoids (and by proxy, exocannabinoids like THC and CBD) affects neuron functioning at the level of the synapse explains a lot about how these chemicals affect the brain. Unfortunately, just like the chemicals themselves, these effects can be a bit messy, and presents a challenge when trying to pry apart the influence of, say, just one cannabinoid on one behavior.
It’s important to note that cannabinoids affect more than just cannabinoid receptors, and how they influence those receptors occurs in different ways. In fact, there is evidence that anandamide works through a mechanism called long-term depression, where connections between neurons are made weaker.  Although this sounds like a bad thing, it actually represents a very important aspect of plasticity, or the ability of the brain to change over time.
Even though retrograde signaling was identified as a mechanism of action many years ago, there is still much more to learn. And if scientists obtain greater access to cannabis, as well as much needed grant funding, we will continue to uncover essential aspects about how these important neuromodulators contribute to vital functions and how they can be used for therapeutic purposes.
- Alger, B.E., “Getting High on the Endocannabinoid System.” Cerebrum, Nov-Dec 2013, pp. 1-14. (impact factor: N/A; cited by: 11)
- Kano, M., “Control of Synaptic Function by Endocannabinoid-mediated Retrograde Signaling.” Proc Jpn Acad Ser B Phys Biol Sci. vol.90, no.7, 2014, pp. 235-250. (impact factor: 1.833; cited by: 41)
- Zou S. & Kumar U. “Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System.” Int J Mol Sci. vol.19, no.3, 2018, pp. 1-23. (impact factor: 4.183; cited by: 33)
- Ohno-Shosaku, T., et al., “Endogenous Cannabinoids Mediate Retrograde Signals from Depolarized Postsynaptic Neurons to Presynaptic Terminals.” Neuron, vol.29, no.3, 2001, pp.729-738. (impact factor: 14.403; cited by: 686)