Medical Cannabinoids in Chronic Pain: Pharmacological Aspects
Cannabinoids interact with different cannabinoid receptors in the body, sometimes in tandem, sometimes in competition. Each activation gives a response to the damping of painful stimuli and reduces inflammation. This article is dedicated to health specialists.
The inflammatory process is a physiological response to a very large number of harmful stimuli intended to restore homeostasis. Many drugs used in pharmacotherapy are effective in controlling inflammatory responses. However, there is a range of adverse effects attributed to steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs). In this sense, herbal medicines and their derivatives are gaining in popularity because of their efficacy and safety, which shows the importance of medicinal plants, particularly of the genus Cannabis and cannabinoid derivatives.
In the 1940 years, chemistry based on compounds isolated from the plant (Wollner 1942) produced new biologically active molecules (Adams 1948, Ghosh 1940); however, it was only in the 1960 years that the active constituent of marijuana, Δ-tetrahydrocannabinol (THC), a terepenoid molecule, was isolated and characterized (Gaoni and Mechoulam, 1964)
Cannabis is used for centuries in many cultures to treat a wide range of medical conditions. More recently, therapeutic considerations have gone beyond plant extract to explore and produce more pharmacologically refined compounds. CB1 small molecule selective agonists have proven to be therapeutically promising in a wide range of disorders, including pain and inflammation (Cravatt and Lichtman, 2004), multiple sclerosis (Pertwee, 2002, Pryce and Baker, 2015) and neurodegenerative disorders (Fernández-Ruiz 2015).
The first CB1 / inverse agonist selective antagonist, the rimonabant (SR141716, Acomplia [Sanofi-Aventis]) (Rinaldi-Carmona et al., 1994), has been approved by the European Medical Agency as a supplement to diet and exercise to treat obesity (Janero and Makriyannis, 2009). CB1 antagonists have been explored as potential treatments for metabolic disorders related to obesity (Mazier et al., 2015), mental illnesses (Black et al., 2011, Rubino et al., 2015), liver fibrosis (Mallat et al., 2013) and nicotinomania (Schindler et al., 2016). However, rimonabant and other ligands in its class have not been approved in the United States because of concerns about adverse effects, such as increased anxiety, depression, and suicidal ideation.
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Crystalline structure of CB1 and CB2 human cannabinoid receptors
The most known cannabinoid receptors, CB1 and CB2, are proteins that are incorporated into the cell membrane. These surface proteins are then attached to another protein that determines the signaling direction: activation or inhibition. The off signal depends on the molecule (eg, THC that activates) that binds to the receptor. There are, however, many other receptors in the human body that are activated by cannabinoids.
The main difference between the two lies in their distribution throughout the body: CB1 is highly expressed in brain neurons (with the exception of the respiratory center, where it is virtually absent) while CB2 is present in 100 times lower number in the central nervous system and is mainly expressed on immune cells, including those of the brain (called microglia).
The classic effects in the brain of CB1 activation are the reduction of neurotransmitter release. CB2 activation attenuates microglial activation and reduces neurological inflammation, and these are the basic mechanisms for reducing pain (antinociception).
4 types of receivers
A unique feature of CB1 and CB2 receptors is their ability to "associate" with other neuro-receptors, such as dopamine, opioids, orexigen (regulate appetite) and adenosine. This cooperation modifies their neurotransmission.
In the periphery of the body (outside the central nervous system), the reduction of inflammation and neuropathic lesions was mainly attributed to the activation of CB2. CB2 receptors are present in the peripheral nerves, as well as in the inflammatory walls of the joints and the skin. The reduction of colitis in rodents, for example, has been demonstrated using CBX acting CB2, as well as cannabigerol (CBG) acting by CB2.
The cannabinoid 1 receptor (CB1) is the primary target of Δ-tetrahydrocannabinol (THC), a psychoactive chemical of Cannabis sativa with many therapeutic applications and a long history of recreational use. CB1 is activated by endocannabinoids and is a promising therapeutic target for the management of pain, inflammation, obesity and substance use disorders.
Molecular docking predicts CB1 binding modes of THC and cannabinoids
We present here the crystalline structure of 2,8 Å of human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the complex CB1-AM6538 reveals the main characteristics of the receptor and the critical interactions for antagonist binding. Combined with functional studies and molecular modeling, this structure provides a better understanding of the mode of binding of natural CB1 ligands, such as THC and cannabinoids.
This allows us to better understand the molecular basis of physiological functions of CB1 and provides new opportunities for the development of next generation pharmaceutical products targeting CB1.
The crystalline structure of human CB1 in complex with AM6538 is determined
Many studies have investigated how ligands that bind to CB1 can mediate downstream signaling. Although the variety of compounds with different pharmacological profiles has provided clues to CB1 activation, the molecular details defining the binding modes of endogenous and exogenous ligands are still largely unknown. (Guo et al., 1994, Makriyannis, 2014, Picone et al., 2005). In order to fill this understanding deficit, we have determined the crystal structure of CB1 in complex with an AM6538 tight-binding antagonist. In conjunction with molecular docking, the structure was used to elucidate the modes of binding of a diverse set of antagonists / agonists and CB1 agonists. The structural details of the cannabinoid receptor presented here enhance our understanding of how ligands engage to modulate the cannabinoid system and provide a useful model for facilitating the design of next-generation pharmaceuticals to avoid undesirable side effects. The results provide insight into the mechanisms of slow dissociation of antagonists, which can potentially result in long-acting pharmacological effects.
Synthesis of CB1 AM6538 Stabilizing Antagonist for Structural Studies
One of the main factors facilitating the determination of the structure of CB1 (Figure 1) is the use of the AM6538 antagonist, the synthesis of which results from the strategic modification of rimonabant to improve its ability to stabilize the ligand-receptor complex and to promote the formation of CB1 crystals. In contrast to rimonabant, the 5-phenyl ring substituent has been modified to introduce motifs (eg, alkyne unit) that could promote increased affinity for the CB1 receptor. (Tam et al., 2010). The rimonabant analog, AM251, (1, Figure 2A) (Lan et al., 1999), a compound that has been widely used as a pharmacological standard CB1 selective antagonist, has been used as a precursor in the synthetic AM6538 method. The synthesis of AM6538 involves the functionalization of the iodo substituent at the para position of the 5-phenyl ring in AM251 with an acetylenic chain system composed of four carbons and substituted at the omega carbon level. To do this, we first targeted the cysteine residues in CB1 by introducing appropriate electrophilic groups (Janero et al., 2015, Li et al., 2005, Mercier et al., 2010, Picone et al., 2005, Szymanski et al., 2011) to the fourth carbon of the alkyl group, capable of forming a covalent bond with the cysteine thiol group. For AM6538, we introduced at this position a nitrate group (ONO2) whose role was to act as a polar group, which can be displaced by a suitable nucleophile (for example, thiol) (Pattison and Brown, 1956, Yeates et al. , 1985) at or near the binding domain or to bind as an intact group to obtain a non-covalent, almost irreversible binding by interaction with hydrogen-binding amino acid residues, as well as residues capable of performing an interaction π-π In the present study, affinity mass spectrometry analysis suggests that AM6538 reacts with CB1 as an intact molecule without any covalent modification of relevant cysteine residues.
The GPR55 receptor intervenes in the neuroinflammatory response
A more recently discovered unconventional cannabinoid receptor is GPR55. Like CB1 and CB2, it is also attached to a cell membrane and associated with an effector protein inside the cell. GPR55 is localized in the central nervous system, expressed in the hypothalamus, thalamus and the middle brain. It modulates antinociceptive responses in animals. Activation of GPR55 can be pro-antinociceptive depending on the type of injury.
For example, co-activation of CB2 and GPR55 increases microglia activity and neuroinflammation, whereas CB2 alone decreases these responses. The anti-inflammatory and analgesic effects of CBD can be explained by the fact that CBD is an inhibitor (antagonist) of GPR55 during activation of CB2.
The effect of THC is a bit more unclear as some studies have reported agonist behavior and others have no effect on GPR55. Our knowledge of the potential of GPR55 in therapeutic applications is certainly in its infancy and further studies are needed to further explore the effects.
The PPARg receptor alters the expression of genes that control inflammation
Another unconventional type of cannabinoid receptor is PPARg, which operates in a completely different mode of action than CB1, CB2 and GPR55. It belongs to a family of hormonal nuclear receptors that, when activated, cause alterations in gene expression. Unlike conventional receptors that are embedded in the cell membrane and exert their action by activation of signaling cascades inside the cell, PPARg directly affects the expression of genes involved in inflammation. It has been detected in many types of tissue, including adipose, muscle, brain and immune cells. Endocannabinoid anandamide has been shown to interact with PPARg.
Multiple in vivo studies have shown that CBD reduces neuroinflammation in diseases such as dementia and Alzheimer's disease, and it has been suggested that the mechanism of action implies that CBD acts as a PPARg agonist. Indeed, when CBD activates PPARg, the expression of the genes involved in inflammation and oxidative stress decreases, which decreases neuronal cell death and promotes neurogenesis in mouse models of Alzheimer's disease.
In addition, a recent study has shown that the acidic form of THC, tetrahydrocannabinolic acid (THCa) present in the raw plant, has a similar effect on PPARg. It has been shown that THCa activates PPARg with more potency than its decarboxylated counterpart, THC, which was neuroprotective in mice. THCa also improved motor deficits, prevented neurotoxicity and reduced neuroinflammation.
TPRV1 can be activated to produce analgesic effects
Cannabinoids also exert their action on the TRPV1 ion channel. This ion channel is different from the cannabinoid receptors in that it allows the passage of specific ions (sodium and calcium), which trigger a painful burning sensation. Known activators of TRPV1 include a temperature greater than 430 ° C (which is a protective mechanism that will prompt us to look for strategies to cool ourselves), acidic conditions (such as when we eat a hot pepper), or eating a compound in wasabi.
In addition, it has been shown that CB1 is present at the same time as TRPV1. The TRPV1 ion channels are known to have desensitization potential, which explains the possibility of developing a tolerance for increasingly spicy foods. An interesting application of the interaction between cannabis, TRPV1 and capsacin (the compound that makes hot peppers) is the cannabinoid hyperemesis syndrome, which is a clinical disorder characterized by severe nausea and vomiting.
Topical capsaicin is primarily used for the treatment of neuropathic pain, but has also been used successfully in cases of cannabinoid hyperemesis syndrome. It appears that capsacin competes with THC and produces analgesia for desensitization, which leads to symptomatic relief.
The complete characterization of the interaction between TRPV1, capsacin and hyperalgesia is not yet complete, but it would nevertheless be useful, as capsacin relief can prevent patients from unnecessary laboratory tests and tests and the potentially harmful use of drugs. opioids.
One day, we hope to have enough information about the action of cannabinoid receptors and the interaction between cannabinoids, to be able to control more specifically pain and inflammation with the help of cannabis.
Why use cannabis to relieve pain?
Cannabis for medical purposes is becoming one of the most popular alternative treatments for the treatment of chronic pain. This can range from pain caused by conditions such as migraine or arthritis to pain caused by an injury.
The two main treatments currently available for pain relief include nonsteroidal anti-inflammatory drugs (NSAIDs) and prescription opioid medications. These painkillers are not as safe as the cannabis.
Opioid drugs are the most addictive drugs on the market and their use can be fatal if they are abused: in the United States, sixty people die each day from after an overdose of opioids.
What about nonsteroidal anti-inflammatory drugs?
While NSAIDs are generally effective in reducing the pain caused by inflammation, prolonged use is accompanied by many dangerous side effects. These include increased risk of heart attacks and strokes .
Cannabis has fewer side effects and no risk of non-tolerance or overdose. Cannabis sativa and its components have been shown to be safe and effective for pain management.
As the legality of marijuana is widespread in the United States and other countries, many people are now being offered the opportunity to switch from dangerous and addictive drugs to a safer, natural alternative.
Whether you have chronic nerve or body pain, or short-term pain caused by muscle tension, headaches, toothache, or simply sore muscles, cannabis offers an option safer and perhaps more effective than what is generally used today for ease the pain.
Yet for these patients as well as for practitioners and clinicians, the question is: What is the best marijuana to treat pain?
Should patients turn to singular compounds in the plant or turn to the plant itself? If you use the whole plant, which marijuana varieties are best for pain relief?
Surrounding effect: Full spectrum?
When you compare Western medicine to traditional medicine around the world, one of the most striking differences is the need in the West to determine a specific molecule responsible for treating a disease or a symptom. This view runs counter to the idea of holistic medicine, that you are taking something in its entirety for medicinal purposes.
The "entourage" effect is a new term coined to describe the idea that all compounds in the cannabis plant work synergistically, providing more benefits than the individual compounds alone would provide.
The plant of c is one of today's greatest examples of this fierce battle between Western medicine and traditional medicine.
If you live in a state where marijuana is legal, you may have noticed that the advertised products are "isolates" or "whole plant extracts". Proponents of the isolationist theories of Western medicine would advocate isolates, which are simply products containing only tetrahydrocannabinol (THC). or simply cannabidiol (CBD), or much less commonly, none of the other individual phytocannabinoids.
CBD is the second best known cannabinoid in cannabis and, like most other phytocannabinoids, is non-psychotropic.
They are the two most abundant and best studied cannabinoids. Many published studies have shown that these two properties had analgesic and relieving properties in humans. Although they may be the most abundant, THC and CBD are certainly not the only compounds present in cannabis that are known to have positive effects on human health.
In each cannabis plant, there is a unique blend of hundreds of plant compounds, consisting of phytocannabinoids, terpenes and flavonoids. The research suggests that these compounds also have an influence on our neurochemistry. Together they can work in synergy, producing better improvements in pain relief than anyone would do on their own.
This research supports the idea that it is best to use all the cannabis plant, CBD, THC and the natural mixture of additional compounds. This harmony between the various plant chemicals found in marijuana is commonly referred to as the surrounding effect.
How CBD and THC influence the surrounding effect?
THC and CBD proved to work differently together than when they were separated.
It has been proved that the joint use of these two compounds to mitigate side effects and improve efficiency, CBD plus THC showing more benefits for certain conditions than THC alone.
Studies confirmed that the CBD helps combat some of the sedative effects, thrills, anxiety and fast heartbeats associated with THC consumption. It was also found that the extension of the half-life THC could be helpful, which may help prolong the benefits of pain relief. This allowed the use of higher doses of THC in clinical trials for the treatment of pain caused by multiple sclerosis, peripheral neuropathic pain, refractory cancer pain, and rheumatoid arthritis. Greater effectiveness in treating these types of pain has been observed.
You may be wondering what is the ideal ratio between CBD and THC?
Each strain you can buy at a clinic will have a label with THC and CBD content, which can be helpful in choosing which strain to choose for pain relief.
Advantages of high CBD strains for the treatment of pain
CBD has been found to have improvements in the treatment of pain whether used alone or in combination with THC. When used alone, CBD is largely preferable to inflammatory pain, such as that caused by arthritis or injuries.
An animal study of arthritis pain showed that topical application of CBD resulted in reduced inflammation and pain. Another animal study has shown that CBD helps reduce neuropathic pain by suppressing chronic inflammation.
CBD does not bind directly to the receptors present in the endocannabinoid system, but acts rather to modulate the effects of endocannabinoids (the cannabinoids found naturally in our body), as well as acting as a CB1 receptor antagonist.
The main mechanism by which CBD is thought to help mitigate pain is to reduce inflammation, mainly by blocking inflammatory mediators. It is also believed to potentiate glycine receptors, which help to regulate pain at the level of the spine. This removes neuropathic pain and inflammatory.
Advantages of high THC strains for the treatment of pain
THC is used clinically for pain treatment and studies have shown that it helps relieve central and neuropathic pain. It is also used to help reduce pain in patients with cancer, AIDS, and fibromyalgia , for which resistance to other pain treatments has been found.
Le mode of action THC is a partial agonist of CB1 receptors, which means that it will bind to these receptors, but not completely, resulting in variability of the documented effects when THC is present with other agonists, antagonists, or both. It has been found to have an impact on the serotonergic, dopaminergic and glutamatergic systems - an action that could contribute to its pain-relieving benefits. In addition, THC has been shown to act as that anti-inflammatory agent .
Un survey conducted Chronic non-cancer pain patients in Canada found that 35% of respondents reported using cannabis to relieve pain.
Another study a revealed that, on nearly 3 000 patients consuming cannabis for medical purposes, 97% indicated that they were able to reduce their use of opioids when they also used marijuana for medical purposes, most of them indicating that the relief they received was comparable to that of other pain medications. .
Anecdotal studies and reports have shown that cannabis is good for pain. Whether you like to smoke grass or not, there are many products that you can use if you live in a state where this plant is legal.
Some products can help you if you want something other than the flower:
- Lotions or creams
- Dyes (dropper bottles with infused oils)
- Capsules or pills
- Edibles (chocolates, sweets, teas or other infused foods)
When considering these products, it is important to choose the one that is a complete plant extract (Full Spectrum). This allows you to access the full potential of the wide range of healthy and anti-inflammatory compounds found in the plant.