Stockholm Medical Cannabis Conference

High on Relief: Exploring the Role of the Endocannabinoid System in Pain Management

I. Introduction

The endocannabinoid system (ECS) is a complex network of receptors, ligands, and enzymes work together to maintain homeostasis within the body and mind (1). Discovered in the late 1980s and early 1990s, the ECS was originally thought to primarily be involved in the pharmacological effects of plant-derived cannabinoids, such as THC from cannabis. However, it is now clear that the ECS is an important regulatory system involved in a wide range of physiological processes, including pain modulation, appetite regulation, immune function, and mood regulation.

The ECS consists of two primary receptors, CB1 and CB2, which are distributed throughout the central and peripheral nervous systems, as well as other tissues and organs. The endogenous ligands for these receptors are lipid-based molecules called endocannabinoids, which are synthesized on-demand from lipids in the cellular membrane in response to various physiological cues. The best-studied endocannabinoids are anandamide and 2-arachidonoylglycerol (2-AG), with 2-AG generally considered being the major endocannabinoid as it is present in significantly higher quantities in the brain. In recent years, several other less researched endocannabinoids have been identified which have shown to have varying and specific biological activities on different targets within the ECS (2).

Activation of the CB1 receptor is primarily responsible for the psychoactive effects of THC, while activation of the CB2 receptor is thought to mediate some of the anti-inflammatory and immunomodulatory effects of cannabinoids. However, both receptors are involved in a variety of physiological processes, and many other signaling pathways and receptors are also regulated by the ECS.

While much of the scientific understanding of the ECS is still in its infancy, there is growing evidence that targeting the ECS may be a useful therapeutic strategy for a range of conditions. For example, several studies have found that medical cannabis can be effective in treating chronic pain, reducing opioid use, and improving quality of life for patients with various chronic conditions (3,4). Despite this, many medical professionals remain unaware of the therapeutic potential of the ECS and medical cannabis, and more research is needed to fully understand the complex interactions between the ECS and other physiological systems in the body.

II. What is the role of the ECS?

The ECS plays a critical role in maintaining homeostasis in the body, including in the central nervous system (CNS). The ECS regulates neurotransmitter release and modulates synaptic plasticity through retrograde signaling, a unique process in which endocannabinoids are synthesized in the postsynaptic neuron and travel back across the synapse to activate presynaptic cannabinoid receptors. This retrograde signaling allows the ECS to fine-tune neurotransmitter release and maintain a delicate balance of excitation and inhibition in the CNS (5).

Imagine a situation where you are trying to call a friend, but their phone line is constantly busy. You might assume that your friend is talking on the phone with someone else, but in fact, he/she is trying to call you at the same time through a separate line. In the ECS, the postsynaptic neuron can release endocannabinoids that travel backward across the synaptic cleft to bind to presynaptic CB1 receptors. This is what happens in retrograde signaling. Your endocannabinoids binding to the presynaptic cell either reduce or increase the release of neurotransmitters, similar to how your friend might use a separate phone line to call you and ask you to reduce or increase the volume of your voice during the conversation (6).

This process of retrograde signaling plays a critical role in maintaining homeostasis in the CNS, as it allows for fine-tuning of neurotransmitter release and regulation of synaptic activity. It also enables the ECS to modulate a wide range of physiological processes beyond the CNS, including immune function, inflammation, and metabolism (7,8).

Similarly, in the brain, retrograde signaling allows neurons to communicate with each other in a more efficient and balanced way. For example, when there is excessive neurotransmitter release in response to pain, the ECS can activate and send a signal back to the presynaptic neuron to decrease the release of neurotransmitters, reducing pain signals. This process helps to maintain homeostasis in the brain by regulating the activity of neurons and preventing overexcitation.

Overall, retrograde signaling in the CNS through the ECS plays a critical role in maintaining the balance of neurotransmitters and the overall functioning of the brain. Understanding this process is essential for understanding the therapeutic potential of medical cannabis for the management of chronic pain and other conditions.

III. Endocannabinoid Receptors

The ECS exerts its effects by interacting with two primary G protein-coupled receptors, CB1 and CB2, which are found throughout the body (9). CB1 receptors are primarily expressed in the brain and central nervous system, although they can also be found in peripheral tissues such as adipose tissue, liver, and muscle (10,11,12). Activation of CB1 receptors in the CNS can lead to a range of effects, including reduced neurotransmitter release, decreased inflammation, modulation of pain perception and change in mood (9).

CB2 receptors, on the other hand, are primarily expressed in immune cells and tissues involved in immune function, such as the spleen, thymus, and tonsils (9). Activation of CB2 receptors can modulate immune function and reduce inflammation and has been implicated in a range of immune-related conditions such as rheumatoid arthritis and multiple sclerosis (9,13).

Beyond CB1 and CB2 receptors, recent research has revealed the existence of additional endocannabinoid receptors, including GPR55 and GPR119, which may play important roles in regulating metabolic function and insulin release (14,15). Additionally, the so called expanded endocannabinoidome includes a range of other lipid mediators that can interact with cannabinoid receptors and other receptors in the body, including N-acylethanolamines, monoacylglycerols and 2-arachidonoylglycerol esters (16). These novel endocannabinoids and their receptors are currently the subject of ongoing research and may represent promising targets for the development of new therapeutics for a range of conditions.

In summary, the ECS is a complex signaling system that involves a range of receptors and endogenous ligands. While CB1 and CB2 receptors are the best-studied components of the ECS, recent research has revealed the existence of additional receptors and endocannabinoids, suggesting that the full extent of the system’s physiological effects is far from being fully elucidated.

IV. Endocannabinoids

The endocannabinoids are a class of lipids that are produced on-demand and act as retrograde signaling molecules in the ECS. The two best-studied endocannabinoids are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). AEA is synthesized on-demand from N-arachidonoyl-phosphatidylethanolamine (NAPE) by the action of the enzyme N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD). 2-AG is produced on-demand from diacylglycerol (DAG) by the action of diacylglycerol lipase alpha (DAGLα) or beta (DAGLβ) enzymes. Both AEA and 2-AG are broken down by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively (15).

In addition to AEA and 2-AG, several other endocannabinoids have been identified, including N-arachidonoyl-dopamine (NADA), virodhamine, and N-arachidonoyl-glycine (NAGly) (16). These endocannabinoids have been shown to activate CB1 and/or CB2 receptors and may also have non-CB1/CB2 receptor targets (16).

Endocannabinoids are involved in a variety of physiological processes, including pain modulation, appetite regulation, mood and behavior, and immune function (17). Dysregulation of the ECS and endocannabinoid signaling has been implicated in several pathological conditions, including pain disorders, anxiety and depression, neurodegenerative diseases, and inflammatory disorders (18).

Understanding the roles of endocannabinoids in these processes has led to the development of novel therapeutic strategies targeting the ECS. For example, inhibition of FAAH to increase levels of AEA has been proposed as a potential treatment for pain and anxiety disorders (19). This is one of the defined mechanisms of action of CBD, which blocks the transport protein FABP from shuttling AEA to the intracellularly located FAAH, thus increasing its levels (2). Similarly, modulation of the levels of 2-AG by targeting DAGLα has been suggested as a potential therapy for neurodegenerative diseases (20).

Overall, endocannabinoids play crucial roles in maintaining physiological homeostasis and are promising targets for the development of new therapeutic interventions.

V. Phytocannabinoids

Phytocannabinoids such as THC and CBD have been shown to exert their effects through various mechanisms of action. THC is known to induce psychotropic effects through the CB1 receptor, while CBD is an allosteric modulator at both CB1 and CB2, as well as an agonist for 5HT1a and TRPV1, and several other receptors (21,22). The pharmacological effects of phytocannabinoids are not limited to THC and CBD, as the plant contains over 100 different cannabinoids, each with its own unique effects. CBG is an example of a non-psychoactive cannabinoid that is being explored for its potential as an anti-inflammatory and anti-cancer agent (23). Another fascinating minor cannabinoid with medical potential is THCV, which has been shown to decrease appetite in rodent models and is currently being explored in clinical trials as a potential weight loss drug (24).

Additionally, the concept of an entourage effect has been proposed, which suggests that the therapeutic benefits of phytocannabinoids, terpenes and other molecules are enhanced and act in synergy when used together in their natural ratios. This is markedly different from how most other modern medicines work but not that uncommon among medical plants (25,26). One study from 2018 found that a full-spectrum cannabis extract provided greater pain relief than isolated THC or CBD alone (27). Another study from the same year found that cannabis extracts containing a variety of cannabinoids and terpenes showed greater anti-inflammatory effects than extracts containing only THC or CBD (28). Dr Ethan Russo has conducted several studies supporting the existence of an entourage effect and has proposed that the interactions between different cannabinoids, terpenes, and other compounds in cannabis can result in greater therapeutic effects than any single compound alone (18,21).

Although research on phytocannabinoids is still in its early stages, clinical studies have validated the efficacy and safety of using of cannabis-based medicines in multiple conditions, including chronic pain (29,30), multiple sclerosis (29,30,31) and epilepsy (32,33).

Overall, the pharmacodynamics of phytocannabinoids are complex and multi-faceted, and their potential therapeutic benefits are vast. As research continues to explore the many mechanisms of action of these compounds, it is likely that their potential applications will continue to expand.

VI. ECS and Pain

The ECS plays a critical role in regulating pain at multiple levels (9). At the peripheral level, the ECS modulates the release of neurotransmitters and neuropeptides from nociceptors, or pain-sensing nerve endings, in response to injury or inflammation (34). The activation of cannabinoid receptors on these nerve endings can inhibit the release of pro-inflammatory mediators and enhance the release of anti-inflammatory mediators, thereby reducing pain and inflammation (35).

In addition, the ECS also regulates pain at the central level, where it modulates the perception and processing of pain signals in the brain and spinal cord. The activation of cannabinoid receptors in the spinal cord can inhibit the transmission of pain signals to higher brain centers, while the activation of cannabinoid receptors in the brain can alter the perception of pain by modulating emotional and cognitive responses to pain (36).

Moreover, the ECS can also regulate pain through its effects on the efferent nerve fibers that control muscle tone and movement. The activation of cannabinoid receptors on these fibers can reduce muscle spasms and cramping, which are often associated with chronic pain conditions (37,38).

Overall, the ECS is a complex system that modulates pain at multiple levels, and its dysregulation has been implicated in the development of chronic pain syndromes. Understanding the role of the ECS in pain regulation may provide new therapeutic targets for the treatment of chronic pain.

A recent systematic reviews of clinical trials found that medical cannabis and cannabinoids can be a highly effective for the treatment of chronic pain for some patients (39). These findings suggest that the modulation of the ECS constitutes a promising approach for the treatment of chronic pain.

VII. Conclusion

After diving deep into the research on the endocannabinoid system (ECS) and its role in regulating pain, it is evident that this complex system plays a crucial role in the modulation of pain and inflammation throughout the body. The ECS has been shown to regulate pain at multiple levels, including the peripheral, central, and motor levels, demonstrating its ability to affect the entire pain pathway (9). The activation of cannabinoid receptors at these different levels can lead to the inhibition of pro-inflammatory mediators and the enhancement of anti-inflammatory mediators, ultimately resulting in a reduction of pain and inflammation (40). Futhermore, activation of central CB1 receptors seems to change the perception and emotional response of pain (41).

Furthermore, research on the therapeutic potential of medical cannabis in managing various conditions such as chronic pain, multiple sclerosis, and epilepsy has also demonstrated the importance of the ECS in treating these conditions. The treatment of these indications with medical cannabis is supported by clinical evidence from several positive clinical trials (42,43,44), however they are also accompanied by a growing number of very large Real World Evidence-studies which have validated their beneficial effects in the real world (45,46,47). Overall, the study of the endocannabinoid system and its effects on pain and inflammation is a rapidly evolving field that warrants further research. The importance of the ECS cannot be understated and the future holds an incredible potential for medical cannabis as therapeutic agents in treating a wide range of medical conditions in addition to pain.

Stefan Broselid, Ph.D.
Molecular Pharmacology
Editor-In-Chief, Aurea Care Medical Science Journal

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