Science & Research

Article for Endocannabinoids 7/29/17

This article discusses new pain response signaling systems on the surface of various types of nerve cells that have recently started to be researched. These are like little antennae on the surface of cells that change concentrations- numbers- and thus exert effects on the nerve cell receptor. Let me defer to this articles that make it more precise.

This is basically a review/ commentary/ explanation of this scientific paper, The Endocannabinoid System and Pain By Guindon and Homann in CNS Neurological Disorders and Drug Targets 12/09. There will be some complex ideas, and I will try to explain them in simpler terms along the way. I will quote sections of it, and then re-explain those ideas in a more approachable way so it can be understood by more people. Please mail me with questions and comments. The quotes are from the original paper.

“Cannabis has been used for more than twelve thousand years and for many different purposes (i.e. fiber, medicinal, recreational). However, the endocannabinoid receptor has only recently been the focus of medical research and considered a potential therapeutic target. Endocannabinoids mimic the pharmacological actions of the psychoactive principle of marihuana, the delta-9- tetrahydrocannabinol.” (This should also include the myriad of other analogs of marihuana including CBDs).

“Endocannabinoids are endogenous (naturally occurring) lipid signaling molecules. They are generated in the cell membrane from phospholipid precursors and possess cannabimimetic properties because they bind and activate one or more cannabinoid receptor subtypes”.

This means that these ‘antenna’ are stimulated to act from many different stimuli that are produced in the body, which is what the endocannabiniods are. Some of these become endocannabiniods, and some become receptors of endocannabinoids, this is an important distinction to make as we go through the article. THC and CBD also exert a similar effect on these receptors, which is of course why they are called ‘endocannabinoids’.

“Endocannabinoids are implicated in different physiological and pathological functions (regulation of food intake, immunomodulation, inflammation, analgesia, cancer, addictive behavior, epilepsy and others). The two best-studied endocannabinoids isolated to date are arachidonoylethanolamine (anandamide or AEA) and 2-arachidonoylglycerol (2-AG).”


“Cannabinoids produce their effects through the activation of distinct G protein-coupled receptors identified as CB-1 and CB-2 receptors.”

G protein-coupled means a cascade of actions happens to produce an effect in the cell wall permeability. (It is not necessary to know for this article, but this is specifically how G-proteins coupled work. These receptors are by far the largest in number, and the alpha subunit can bind GTP and GDP. The binding of the first messenger to the receptor changes the conformation of the receptor. This activated receptor increases the affinity of the alpha subunit for the G protein for GTP. When bound to GTP, the alpha subunit dissociates from the beta and gamma subunits of the trimeric G protein. This dissociation allows the activated alpha subunit to link up with still another plasma membrane protein, either an ion channel or an enzyme. These ion channels and enzymes are termed plasma membrane effector proteins because they mediate the next steps in the sequence of events leading to the cells response.) In essence then, these receptors are known as ‘G-protein-coupled receptors’. Protein serves as a switch to couple a receptor to an ion channel or to an enzyme in the plasma membrane. The G protein may cause the ion channel to open, with a resulting change in electrical signal. In the case of Ca+2 channels, changes in the cytosolic Ca+2 concentration occur. This is a basic primer on how the G protein works.

“Cannabinoid CB-1 receptors are found mainly in the CNS (Central Nervous System) and to a lesser extent, in certain peripheral tissues (adrenal gland, adipose tissue, heart, lung and presynaptic nerve terminals). Within the brain, they are found in the cerebral cortex, hippocampus, amygdala, basal ganglia, etc. (More significantly, for the purposes of this paper, they are found at the central and peripheral levels of the pain pathways.) The distribution of the cannabinoid receptors provides an anatomical basis for the analgesic effects of the cannabinoids. Activation of CB-1 receptors in different brain regions inhibits the release of neurotransmitters by decreasing calcium conductance and increasing potassium conductance.”

This means that these CB-1 cannabinoid receptors can accept calcium and potassium through the cell wall thus altering the electrical gradient inside versus the outside of the cell wall. This process will inhibit inflammatory and other molecules involved in the pain response from being released.

“Since endocannabinoids are produced on demand and can be released immediately from cells, they can regulate synaptic transmission, both excitatory and inhibitory. In the CNS, endocannabinoids act as neurotransmitters. Endocannabinoids are released from depolarized postsynaptic neurons and travel to presynaptic terminals where they activate CB1 receptors through a retrograde signaling mechanism.”

This means that these endocannabinoids – AEA and 2-AG- are released from neurons and make effects in the following way. The retrograde signaling mechanism basically means one part of a cell is controlled by the feedback from another part of the cell, or where one cell sends reciprocal messages back to another cell that regulates it. In this case, the AEA is released from a neuron, and travels “backwards” to bind to it’s own presynaptic terminal. This process continues the down regulation of inflammatory and pain stimulating components.

(Brain regions of cannabinoid action.)

“Direct support for supraspinal sites of cannabinoid analgesic action was derived from studies injecting synthetic cannabinoid agonists intraventricularly and locally into various brain regions.” Some of the more significant areas were- “periaqueductal gray (PAG), the thalamus, and rostral ventromedial medulla (RVM). These studies have permitted the identification of brain regions responsible for the antinociceptive properties of cannabinoids. Activation of these sites by endocannabinoids (and external cannabinoids) may therefore produce antinociception” (decrease in pain from trauma).
“Endocannabioid levels are altered following nerve injury in specific brain regions implicated in cannabinoid antinociceptive mechanisms. For example, injury of the sciatic nerve increases AEA and 2-AG levels in the PAG and RVM.”

This means that various brain regions are involved in the analgesic action, but also do not alter the activity of purely non- nociceptive neurons. (I must define the terms “nociception” and “antinociception, nociceptors are nerve cells that are activated from thermal, mechanical, and chemical deviations- or injuries; and antinociception is the lack of this action- a calming response.)


“Intrathecal administration (injection into the spinal cord) of cannabinoids produces antinocipection and suppresses nociceptive neuronal activity. These studies initially documented the existence of spinal sites of cannabinoid antinociceptive actions. Indeed behavioral, electrophysiological, and neurochemical studies have demonstrated that cannabinoids act at the spinal level to modulate pain.”
“Upregulation of cannabinoid receptors is also observed in the spinal cord following nerve injury, suggesting that both endocannabinoids, and their receptors are regulated under conditions of injury.”

These are the cranial nerves, spinal nerves, and their roots and branches. These conduct information to and from the CNS (central nervous system).

“Cannabinoid receptors are synthesized in dorsal root ganglia (DRG) cells, which are the source of primary afferent input to the spinal cord. Thereby enabling communication between the periphery and specific areas of the CNS that contribute to pain perception. Following the induction of neuropathy (by spinal ligation), cannabinoid receptors and their endogenous ligands (AEA and 2-AG) are increased in the DRG on the ipsilateral (situated on the same side of the body) side of the injury.”

I think this paragraph is self-explanatory. This paper goes on to discuss acute and chronic pain and neuropathic pain. They look at different tests using exogenous endocannabinoids and the resulting response from CB1 and CB2 receptors. These tests just confirm and show how pervasive the endocannabinoid system is to mediate the pain response in the body at all levels.

“Endocannabinoids modulate pain under physiological conditions. Pharmacological approaches that enhance the levels of endocannabinoids by inhibiting enzymes, controlling endocannabinoid deactivation or by blocking their reuptake may exhibit therapeutic potential.”

Or increasing the external cannabinoids applied to the area!

“Adjunctive approaches show strong promise for improving the efficacy of existing pharmacotherapies for pain and limiting unwanted side-effects.”

To me this shows other ways of using this natural pain modulation system may be employed with some good effect- maybe.

This is a fascinating discovery to me that there is a whole system of modulating pain in the nervous system. It’s amazing that these receptors are affected by cell-induced processes, and that cannabinoids affects these receptors in the same way! That is not a random coincidence. Be that as it may, I am very encouraged by the possibilities.

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