How Cannabinoids Interact With Pain Circuits

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Often times when we think about how cannabis is affecting the brain, we consider its effects on the dopaminergic tracts in the central nervous system. And why not, that is the primary region of the brain that produces our experience with cannabis. But there is far more to the biochemical propensity of exogenous cannabinoids and the receptors they act on. Researchers are now looking into cannabinoids for pain, and in the midst of our nation’s opioid crisis, cannabinoids for pain management is a hot topic.

I have known from personal experience that cannabis can help dull pain when the going gets tough, but I have often wondered, “Is there actually a reduction in pain or is my perception of it diminished?” Questions about cannabinoids for pain management like these were explored in an extensive review article by the German scientist, Jörn Lötsch, in the European Journal of Pain. I have done my best to untangle a small portion of this vast review, so that the general public may better understand cannabis’ role in modern health and society.

Our nervous system can be broken up into two primary components: the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS is composed of our brain and spinal cord; whereas, the PNS consists of every other nerve in our body that receives a stimulus to transmit to the brain. Cannabinoid receptors (CB-1, and CB-2) are expressed everywhere in our body; however, different regions have a higher concentration of one over the other.

While we often associate all of our cannabinoid interactions with CB-1, the neuronal process of pain is one that requires both receptors. There are many different sub-systems in our brain, made up of different types of cells. The neuronal circuit that is implicated in pain is known as nocioreceptors. These are the neurons responsible for relaying information on pain to the brain. They exist in both the CNS, as well as the PNS.

While pain is a complex process in our bodies, we can attempt to break it down to the relative activity of nocioreceptor neurons. When they are active, we call that the sensation of pain; thus, their activity (number of synapses per second) is directly proportional to the amount of pain we feel. If we can modulate their activity, we can modulate pain.

Cannabinoid-mediated activation of CB-1 leads to the inhibition of the neuron that they are bound to, but this can sometimes lead to a net result of activation down the stream of information. In the case of nocioreceptors, which are often glutamatergic (excitatory, glutamate-expressing) neurons, the activation of CB-1 will inhibit their activity.

The resulting conclusion from an article published in the esteemed journal Science was that activation of CB-1 in glutamatergic nocioreceptors, and the subsequent inhibition of the receptors, is the primary mechanism for pain reduction.

This is but one theory for the direct reduction in pain due to inhibition of pain receptors, yet there is another way to look at this issue.

If pain is something we feel/perceive, then it is directly related to the structure and function of our brains. Thusly, the two components of pain are the pain signal (us getting hurt) and the perception of the pain itself.

Remember how I said that CB-1 may activate another circuit downstream as a result of inhibition of its parent neuron? Well, that is exactly what is happening in our hippocampus, known generally as the part of the brain responsible for memory formation. While glutamate is an excitatory signal, gamma-aminobutyric acid (GABA) is an inhibitory signal. Cannabinoid-mediated inhibition of GABAergic neurons in the hippocampus leads to changes in our memory of aversive stimuli, as described by Jimok Kim, and Bradley Alger in the journal Nature Neuroscience.

This may lead to what another group of scientists (Marsiacano et al., Nature, 2002) proposed; a net activation of inhibitory networks may lead to cannabinoid activated loss of aversive memories and fear. Now we already knew that cannabis may have some effects on our short-term memory, but I had no idea that bad memories were specifically targeted. Good guy cannabis, helping you forget the bad stuff!

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