This article explores the synaptic mechanisms of cannabinoids and how they work with the endocannabinoid system to engage in retrosynaptic signaling, a backward version of traditional synaptic signalling of classic neurotransmitters (e.g. serotonin, dopamine, endorphins, etc.)
To start our paper on the synaptic elements of cannabinoids, we start with the broad neurosynaptic basics. Here we have a diagram showing how animal behavior works: with 4 key parts.
1st is the sensory neurons. These are your eyes, ears, nose, tongue, and nerve endings in your skin, for a total of 5 (thus the expression 6th sense).
2nd we have the interneurons. This stimulation from sensors gets passed to the central nervous system (CNS) where they act as the spine and brain.
3rd we have the motor neurons, which for lack of a better term are the function of the ganglia exiting the CNS. These neurons tell which muscle to contract and when.
4th we have the muscle cells themselves.
Many don’t realize it, but the only thing a nervous system can do is decide which muscle fiber to contract, and when. The rest, including muscle “extension” is actually an illusion. (i.e. extensor muscle groups are simply counter-balancing contraction groups to the flexors).
For the second part of our paper we examine how anterosynaptic signaling works, or forward direction signaling in a neural circuit. A simplified version of the diagram of post 1 is shown at the head of this image to help illustrate the dynamics of a neural circuit, including the soma-axon anatomy of individual neurons.
What we examine here is the classical anterosynaptic signaling, essentially a vesicle of neurotransmitters being released into the synapse by an incoming action potential (from the previous cell in the circuit). These releases then diffuse across the synapse to bind to receptors on the down-circuit neuron (i.e. post-synaptic). This, when it reaches the appropriate critical mass of activation, sends a new action potential downstream to the next neuron in the circuit.
For the third part of our paper, we examine how retrosynaptic signaling works, or backward direction signaling in a neural circuit. This system is an add-on from the anterosynaptic signaling covered in the previous post in this series (No. 2). The signal that comes across the synapse not only stimulates propagation of the signal down the greater circuit, but also minimizes waste and inefficiency in the synapse by inhibiting further neurotransmitter release. This is efficient because the down-circuit neuron has incorporated the signal and needs no further stimulation. We will see in the following posts how this affects cannabinoid neurology more specifically.
Here we see a simple model of the cannabinoid synapse dynamics illustrating the retrosynaptic concept from the previous post (No. 3). The essential elements that apply to endocannabinoids such as anandamide (AEA), tetrahydrocannabinol (THC), and cannabidiol (CBD) are illustrated. Additionally the enzyme that is responsible for breaking down retrosynaptic neurotransmitters is shown, named fatty acid amid hydrolase (FAAH). This lives in the synapse and metabolizes any active retrosynaptic neurotransmitters from the endocannabinoid system (ECS), such as AEA. THC is shown to be an agonist of the CB1 receptor just like AEA. But CBD is shown to both inhibit THC’s agonism of the CB1 as well as inhibit the FAAH’s ability to down-regulate natural AEA. These are opposite effects at the CB1 receptor which are dependent on whether the CB1 receptor agonism is natural from human brain chemistry or from outside the body. This, among many other very complex mechanisms, may explain CBD’s ability to selectively regulate side-effects of phytocannabinoids (coming from plant, i.e. outside of the body) without interfering with the core function within the human animal physiology.
In the final image of our neuro-synaptic cannabinoid series, we see a more comprehensive diagram of the model. In red we see anterosynaptic signaling leaving the vesicles in the pre-synaptic neuron but binding to receptors in the post-synaptic neuron. This is reversed in green for retrosynaptic signaling, stimulated by agonism of receptors on the post-synaptic side and releasing neurotransmitters that agonize the receptors on the pre-synaptic neuron that inhibit further neurotransmitter release. The presence of anandamide (AEA), THC, CBD, and FAAH are indicated. For review: tetrahydrocannabinol (THC), cannabidiol (CBD), fatty acid amide hydrolase (FAAH), and cannabinoid receptor 1 (CB1) are the acronyms used here.
To “walkthrough” the diagram, we start with a neurotransmitter in red being released out of its vesicle on the left from the pre-synaptic side. This diffuses across to its red receptor on the right post-synaptic side. This stimulates the release of anandamide which travels back to the pre-synaptic (right) side and stimulates the cannabinoid receptor, which inhibits the further release of the original red neurotransmitter. This process slows down transmission at the synapse. THC can interact with the same cannabinoid receptor in place of anandamide and slow down synaptic transmission. CBD can do the same but by inhibiting FAAH which in turn inhibits anandamide, leading to more anandamide and reduction of synaptic transmission as well. Though from one way of thinking anandamide, THC and CBD have the same effect, the differences in their mechanism of action underlie their pharmacological differences.
CITATION
Mackie, Ken. "Cannabinoid receptors: where they are and what they do." Journal of neuroendocrinology 20 (2008): 10-14.
Pertwee, Roger Guy. "The pharmacology of cannabinoid receptors and their ligands: an overview." International journal of obesity 30.1 (2006): S13-S18.
Comments