How cannabinoids kill pain and stop inflammation

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 whole range of side effects attributed to steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs). In this sense, herbal drugs and their derivatives are gaining followers due to their efficacy and safety, which shows the importance of medicinal plants, especially of the genus Cannabis and cannabinoid derivatives.

In the 1940s, chemistry based on compounds isolated from the plant (Wollner 1942) produced new biologically active molecules (Adams 1948, Ghosh 1940); however, it was not until the 1960s that the active constituent of marijuana, Δ-tetrahydrocannabinol (THC), a terpenoid molecule, was isolated and characterized (Gaoni and Mechoulam, 1964)

Cannabis is used for centuries in many cultures to treat a wide variety of medical conditions. More recently, therapeutic considerations have gone beyond the plant extract to explore and produce more pharmacologically refined compounds. CB1 selective small molecule agonists have shown therapeutic promise 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 associated with 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 due to concerns about side effects, such as increased anxiety, depression, and suicidal ideation.

Education : Pharmacology students are expected to acquire a wide range of knowledge including physiology, biochemistry, chemistry, genetics, as well as molecular and clinical pharmacology.

Crystalline structure of CB1 and CB2 human cannabinoid receptors

The most known cannabinoid receptors, CB1 and CB2, are proteins that are incorporated into the membrane of cells. These surface proteins are then attached to another protein that determines the direction of signaling: activation or inhibition. The signal that goes off depends on which molecule (eg THC 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 is their distribution throughout the body: CB1 is strongly expressed in neurons of the brain (except in the respiratory center, where it is practically absent) while CB2 is present in 100 times lower numbers. in the central nervous system and is expressed primarily in immune cells, including those in the brain (called microglia).

The classic effects in the brain of activating CB1 are the reduction in the release of neurotransmitters. CB2 activation attenuates microglial activation and reduces neurological inflammation, and these are the basic mechanisms for reducing pain (antinociception).

The structure of the first cannabinoid receptor revealed

4 types of receivers

A unique characteristic 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 in inflammation and neuropathic damage has been mainly attributed to the activation of CB2. CB2 receptors are found in peripheral nerves, as well as in the inflammatory walls of joints and skin. The reduction of colitis in rodents, for example, has been demonstrated using CBD acting by CB2, as well as cannabigerol (CBG) acting by CB2.

The cannabinoid receptor 1 (CB1) is the primary target of Δ-tetrahydrocannabinol (THC), a psychoactive chemical from 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 abuse 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

Numerous studies have investigated how ligands that bind to CB1 can act as mediators in downstream signaling. Although the variety of compounds with different pharmacological profiles have 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 gap, we determined the crystal structure of CB1 in complex with a tightly bonded antagonist AM6538. In conjunction with molecular docking, the structure has been used to elucidate the binding modes of a diverse set of invisible 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 to facilitate the design of next generation pharmaceuticals to avoid unwanted 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 the stabilizing antagonist CB1 AM6538 for structural studies

One of the main factors facilitating the determination of the structure of CB1 (Figure 1) is the use of the antagonist AM6538, 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. Unlike rimonabant, the substituent of the 5-phenyl ring has been modified to introduce motifs (e.g. alkyne unit) which 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 which has been widely used as a pharmacological standard selective CB1 antagonist, was used as a precursor in the synthetic AM6538 process. 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. 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 serve as a polar group, which can be displaced by an appropriate nucleophile (e.g. thiol) (Pattison and Brown, 1956, Yeates et al. , 1985) at or near the binding domain or bind as an intact group in order to obtain non-covalent, almost irreversible attachment by interaction with hydrogen-binding amino acid residues, as well as residues capable of effecting 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 the relevant cysteine ​​residues.

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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 midbrain. It modulates antinociceptive responses in animals. Activation of GPR55 may be pro- or antinociceptive depending on the type of injury.

For example, co-activation of CB2 and GPR55 increases microglial activity and neuroinflammation, while CB2 alone decreases these responses. The anti-inflammatory and analgesic effects of CBD are explained by the fact that CBD is an inhibitor (antagonist) of GPR55 during activation of CB2.

The effect of THC is a little more unclear as some studies have reported agonist behavior and others 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 its effects.

The PPARg receptor alters the expression of genes that control inflammation

Another unconventional type of cannabinoid receptor is PPARg, which functions in a completely different mode of action than CB1, CB2, and GPR55. It belongs to a family of nuclear hormone receptors which, when activated, cause alterations in gene expression. Unlike classical receptors which are embedded in the cell membrane and exert their action by activating signaling cascades inside the cell, PPARg directly affects the expression of genes involved in inflammation. It has been detected in many types of tissues, including fat, 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 involves CBD acting as a PPARg agonist. Indeed, when CBD activates PPARg, the expression of genes involved in inflammation and oxidative stress decreases, which decreases neuronal cell death and promotes neurogenesis in mouse models of Alzheimer's disease.

Additionally, a recent study has shown that the acidic form of THC, tetrahydrocannabinolic acid (THCa), found in the raw plant, has a similar effect on PPARg. THCa has been shown to activate PPARg more potently 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 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 temperature above 430 ° C (which is a protective mechanism that will cause us to look for strategies to cool off), acidic conditions (such as when we eat a hot pepper), or when eating a compound. in wasabi.

In addition, CB1 has been shown to be present at the same time as TRPV1. TRPV1 ion channels are known to have desensitizing 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 chili peppers hot) is 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 it has also been used successfully in cases of cannabinoid hyperemesis syndrome. It appears that capsacin competes with THC and produces desensitizing analgesia, resulting in symptom relief.

The full characterization of the interaction between TRPV1, capsacin and hyperalgesia is not yet complete, but it would nonetheless be useful, as relief with capsacin can save patients unnecessary laboratory examinations and tests and the potentially harmful use of drugs. opioids.

One day, we hope to have enough information on the action of cannabinoid receptors and the interaction between cannabinoids, to be able to more specifically control pain and inflammation with the help of cannabis.

Why use cannabis to relieve pain?

Cannabis for medical purposes is emerging as 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 injury.

The two main treatments currently available for pain relief include nonsteroidal anti-inflammatory drugs (NSAIDs) and prescription opioid drugs. These pain relievers are not as safe as 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 pain caused by inflammation, prolonged use comes with many dangerous side effects. These include an increased risk of heart attacks and strokes .

Cannabis has fewer side effects and no risk of tolerance or overdose. Cannabis sativa and its components have been shown to safe and effective for pain management. 

With the legality of marijuana spreading in the United States and other countries, many people are now being offered the opportunity to switch from dangerous and addictive drugs to a natural and safer alternative.

Whether you suffer from chronic pain in your nerves or body, or experience short-term pain caused by muscle tension, headaches, toothaches or just sore muscles, cannabis offers an option. safer and perhaps more effective than what is generally used today for ease the pain

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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 the singular compounds present in the plant or turn to the plant itself? If you are using the whole plant, which marijuana varieties are best for pain relief?

The entourage 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 symptom. This view goes against the idea of ​​holistic medicine, where you take something in its entirety for medicinal purposes.

The "entourage" effect is a new term coined to describe the idea that all of the compounds found in the cannabis plant work synergistically, together providing more benefits than the individual compounds on their own.

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.

THC is a phytocannabinoïde psychotropic which owes its gratitude to the fact that users produce an "intoxicating" effect when they smoke. It was found that the user had various health benefits.

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. While they may be the most abundant, THC and CBD are certainly not the only compounds found 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's best to use the entire cannabis plant, CBD, THC, and the natural blend of additional compounds. This harmony between the various plant chemicals found in marijuana is commonly referred to as the entourage effect.

How do CBD and THC influence the entourage effect?

THC and CBD have been shown 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, with 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 rapid 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 pain relief benefits. This has enabled 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 efficacy 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 show improvements in the treatment of pain, whether used alone or in combination with THC. When used alone, CBD is much preferable to inflammatory pain, such as that caused by arthritis or injuries. 

An animal study on 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 receptors found in the endocannabinoid system, but rather works to modulate the effects of endocannabinoids (the cannabinoids that are found naturally in our body), as well as to act as a CB1 receptor antagonist. 

The main mechanism by which CBD is thought to help mitigate pain is to reduce inflammation, primarily 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 the 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 , in which resistance to other pain treatments has been observed. 

Le mode of action THC is a partial agonist of the CB1 receptors, meaning that it will bind to these receptors, but not completely, resulting in variability in the effects documented when THC is present with other agonists, antagonists, or both. It was found to impact the serotonergic, dopaminergic, and glutamatergic systems - an action that may contribute to its pain-relieving benefits. Additionally, THC has been shown to act as as an anti-inflammatory agent . 

Anecdotal evidence

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 of the nearly 3 patients who used cannabis for medical purposes, 000% indicated that they were able to reduce their use of opioids when they also used medical marijuana, most of them 'between them indicating that the relief they received was comparable to that of other pain medications. .

Studies and anecdotal reports have shown cannabis to be good for pain. Whether you like to smoke weed or not, there are many products you can use if you live in a state where the herb 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 array of healthy, anti-inflammatory compounds found in the plant. 

Tags : Pain killerAnti-inflammatoryChronic PainMedicalResearch
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