The ideal opioid, or How to get rid of the Sword of Damocles

Article for the “bio/mol/text” competition: In order to get rid of pain, modern people have a wide selection of medications. Surely, the idea of using morphine to relieve a headache has never occurred to you. But there are categories of sick people for whom opioid analgesics, although they cause a number of side effects, are not just the drugs of choice, but a vital necessity. What scientists did for these patients, turning the historical basis of opioids at the molecular level, will be discussed in this article.

"Bio/mol/text"-2016

This work was published in the “Free Topic” category of the “bio/mol/text” competition 2016.

The general sponsor of the competition, according to our crowdfunding, was entrepreneur Konstantin Sinyushin, for which he has great human respect!

The audience award was sponsored by.

What philosopher endured toothache calmly! But they wrote with immortal eloquence against fate and suffering. William Shakespeare. Much ado about nothing

Side effects from pharmaceutical drugs

Even one-time use of pharmaceutical drugs in greatly increased dosages can lead to the following consequences:

the appearance of nausea and vomiting;
convulsions;
loss of consciousness, in extreme cases coma;
disruption of the heart and blood vessels, arrhythmia, tachycardia;
sudden surges in pressure;
sweating, chills, fever;
panic attacks, anxiety, aggression;
the appearance of visual and auditory hallucinations;
severe headaches;
loss of orientation in time and space, memory gaps;
terrible pain in the abdomen and sternum.

Wonderful or terrible?

The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage” [1]. Regardless of the severity of the pain, it always requires a response, the sooner the better. But the pain is chronic, intolerable, like in cancer patients, and does not respond to taking “standard” non-narcotic analgesics or drugs from “grandmother’s medicine cabinet.” Such patients are forced to take drugs that are stronger in their analgesic effect, most often opioids.

Medicines that reduce or relieve pain are called analgesics. The modern classification of analgesics involves dividing them into four main groups [2]:

narcotic (opioid) analgesics;
non-narcotic (non-opioid) analgesics;
analgesics of mixed action;
drugs of other pharmacological groups that have an analgesic effect.

Everyone has heard something about opioids, but most people probably have associations with the abuse of these substances. But we are not interested in the recreational effect of the alkaloid Papaver somniferum, but in its medical use.

Perhaps everyone knows the “global star” among the group of narcotic analgesics. Meet morphine. His father can be considered without a twinge of conscience as the pharmacist Friedrich Wilhelm Sertürner, a twenty-year-old young man at that time (Fig. 1). In the laboratory of his father, who was fond, as was fashionable at that time, of the art of alchemy, young Serturner received all the skills for his subsequent discovery. After his father's death, he begins experimenting with various substances in the court pharmacy in Paderborn. Since opium was covered with an aura of mystery, then, of course, Serturner did not ignore it. The isolated powder was boldly tested on all the dogs running past the pharmacy. The dogs did not object and after a treat mixed with magic powder they fell into a deep sleep without feeling Serturner’s pinch [3]. The young scientist immediately realized that a substance with similar properties could become of great importance for humanity. After performing a series of experiments on himself, Serturner named it morphine in honor of the Greek god of sleep. This happened in 1804. You know the rest of the story. From centuries of use and admiration to legislation to curb opioid use and the emergence of black markets.

Figure 1. Friedrich Wilhelm Serturner was a German pharmacist who discovered morphine in 1804.

"Wikipedia"

Basics of treatment with narcotic analgesics

All narcotic analgesics are strictly controlled drugs. These drugs are prescribed exclusively by a doctor.

Typically, narcotic analgesics are prescribed once or in short courses (up to 7-10 days). In rare cases, if the cause of the pain cannot be eliminated - for example, in the last stages of cancer, narcotic analgesics are used continuously if necessary.

The effect of narcotic analgesics can be enhanced if they are used simultaneously with non-narcotic analgesics (for example, paracetamol).

Double-Edged Sword: Positive and Negative Effects of Opioids

Figure 2. Dimeric structure of the opioid μ receptor.

www.painresearchforum.org

The easiest way to understand the mechanism of action of opioids is to know that an opioid is a substrate that excites specific receptors. Opioid receptors in modern pharmacology are divided into five types, the most studied of which are μ, δ, κ. All opioids interact to varying degrees with different types of opioid receptors, but for each type of opioid receptor there are most typical agonists and antagonists. There are a lot of effects realized through these receptors, they are all very interesting and affect a person, if not at the organismal level, then certainly at a multi-organ level (from the central nervous system to the urinary system). The pronounced activity of opium manifests itself more through its effect on μ-receptors (Fig. 2).

μ receptors are divided into subtypes. There are three of them in total, and different effects are realized through exposure to a specific subtype. The effect of the ligand on the μ1 receptor will lead to an analgesic effect. At the same time, physical tolerance to opium drugs develops through this receptor subtype. When the ligand interacts with the μ2 receptor subtype, side effects occur: respiratory depression up to apnea, decreased motility in the gastrointestinal tract, physical and mental dependence. In addition, effects such as depression of the cardiovascular center in the medulla oblongata, oligo- or anuria, nausea, vomiting, constipation and many other very undesirable things may occur [2], [4]. The function of the μ3 receptor is not yet known.

The main effect of interest to us - analgesic - is realized through inhibition of the activity of the structures of the central nervous system. These structures are located at different levels and perform a controlling (limiting) function in relation to painful stimuli. They can be divided into 3 levels [5]:

subcortical structures - periductal gray matter, reticular formation, raphe nuclei;
hypothalamus;
cerebral cortex.

Also, the analgesic effect occurs through a decrease in the excitability of the emotional and autonomic centers of the hypothalamus , limbic system and cerebral cortex, which leads to a weakening of the negative emotional and mental assessment of pain [2].

List of pharmaceutical drugs 2021 and their consequences

Lyrics, tramad
Nurofen plus
Terpincode
Tropicamide
Tramadol
Antidepressants: Coaxil, Zoloft, Prozac, Aurorix
Codeine-containing drugs
Baksolan

Lyrics, tramad

The use of Lyrica leads to the following consequences:

chronic fatigue syndrome,
apathy;
suicidal tendencies,
impotence and infertility,
headaches, memory problems,
fainting, convulsions,
sweating, skin rash.

Nurofen plus

This drug contains codeine. To achieve the effect, drug addicts accept several standards at once. Persistent dependence occurs after 2-3 packs of medication.

This drug is much more destructive than cocaine. Death can occur within a couple of months, most often due to sudden cessation of breathing.

Terpincode

This is an antitussive drug that contains codeine. Drug addicts take several packs at once, or extract codeine from tablets and inject it intravenously.

The following problems arise when using Terpincode:

vision goes down,
heart diseases,
constant headaches,
epilepsy attacks,
skin decay,
death of brain cells, dementia,
mental illness,
suicidal tendencies.

Tropicamide

These eye drops are used to examine the fundus of the eye and in the treatment of inflammatory diseases. Drug addicts take tropicamide in large doses to induce hallucinations.

Addiction occurs within a month of use and leads to many serious consequences:

visual impairment,
cardiovascular diseases,
neurological disorders,
mental illness,
purulent inflammations,
liver and kidney diseases.

An overdose leads to paralysis of the respiratory center in the brain, coma and death.

Tramadol

This strong analgesic is addictive after 2-3 doses, when taken as a drug.

Persistent addiction leads to the following problems:

headaches and muscle pain,
seizures, epilepsy,
heart diseases,
dementia, panic attacks, hysteria, depression, psychosis and other mental disorders.

Antidepressants: Coaxil, Zoloft, Prozac, Aurorix

After stopping antidepressants, patients experience:

apathy,
headache,
lethargy,
tachycardia,
intestinal obstruction,
panic attacks,
insomnia.

An overdose of antidepressants often leads to cardiac arrest or lethargy, which can be fatal.

Codeine-containing drugs

Codeine is found in some cough suppressants and pain relievers. To achieve a narcotic effect, they are drunk in packs or used to prepare surfactants in artisanal conditions. One of the most striking examples of such experiments is the drug krokodil, known for its destructive effects, which kills thousands of people every year.

Baksolan

When the therapeutic dosage is increased several times, the following symptoms appear:

mood improves;
relaxation appears;
vivid hallucinations appear;
convulsions occur;
blood pressure decreases;
coordination is impaired.

Endogenous opioids

As for the analgesic effect, opioids are simply excellent and have surpassed many! It's always interesting to discover the secrets of those who are great at something. The secret of opioids was revealed at the end of the last century. First, receptors in the brain were discovered that responded to the effects of opiates. Then came one of the outstanding achievements in neuroscience - the discovery of the neural mechanism of action of opiates [6]. These studies led to the discovery of a class of brain chemicals called enkephalins and later to the discovery of endorphins. All of these are morphine-like endogenous substances ( endogenous opioids ). Endorphins have a rather long path of formation: it all starts with proopiomelanocortin (POMC), which is produced in the anterior and intermediate lobes of the pituitary gland and in some other tissues (intestines, placenta). After the magical transformation of POMC into adrenocorticotropic hormone (ACTH) and β-lipotropin, in different cells a different set of peptides is formed from these precursors, including endorphins (Fig. 3).

Figure 3. Endorphins are morphine-like endogenous substances.

www.compoundchem.com

Imagine! Each of us has our own excellent system of protection from any pain, any experiences, any negative phenomena. After all, endogenous opioids, like exogenous ones, bind to opioid receptors and exert an analgesic effect. That's all true, but not quite.

After the discovery of endorphins, attempts were indeed made to produce synthetic analogues, since it now became clear that opioids are not such an evil, but, as is usually the case with drugs, a double-edged sword. Such compounds were supposed to be powerful painkillers, free of the adverse effects associated with the use of narcotic drugs: after all, they are the human body's own product. Unfortunately, the search was not crowned with success. The analgesic effect of the resulting substances was weaker than that of morphine. And if scientists tried to make the effect comparable in terms of pain relief to exogenous opiates, they ended up with serious side effects [7].

Why did this happen? Let's remember that our body has a system for ensuring homeostasis. Everyone from school remembers what it is. You can even say it in chorus: the body’s ability to maintain a constant internal environment. So, in a normal physiological state, there is a balance between synthesis, release, binding to the receptor and reuptake of the neurotransmitter, which results in a feeling of internal comfort. What is important is that the body itself does not produce excessive amounts of endogenous opioids, as this can lead to a number of side effects that have already been mentioned (addiction, respiratory depression up to apnea, nausea, constipation, etc.). Thus, one of the types of homeostasis occurs in the human body - the so-called state of “opioid sufficiency”. If a substance that can bind to the opioid receptor enters the body from the outside, then this state is disrupted.

Signs of a Pharmacy Addict

The external signs of drug addicts largely depend on the substance they use. But there are also common features that are characteristic of all drug addicts:

sudden weight loss,
loss of appetite,
unnatural pupil size,
bouts of vomiting,
convulsions, tremors of limbs,
anxiety,
panic attacks,
insomnia,
irritability,
thoughts about suicide.

On whom does the result depend?

The highest concentration of μ receptors was found in the caudate nucleus. These receptors are present in high concentrations in the cortex , thalamus , and hypothalamus . They are also found in moderate quantities in the periductal gray matter, body of the stomach, duodenum, ileum and in smaller quantities elsewhere [8], [9]. These receptors (GPCRs) are located on the cell membrane and interact through the G protein with a membrane enzyme [4]. G protein is a universal mediator in the transmission of signals from the receptor to enzymes of the cell membrane, catalyzing the formation of second messengers of the hormonal signal. When an opioid hits the receptor, the G protein is activated, changing its conformation, and actively interacts with the membrane enzyme. The result is a change in the speed and activity of processes in the cell.

“Biomolecule” has already written more than once about the wonderful GPCRs: “Nobel Prize in Chemistry (2012): for the receptors of our first, third and fourth senses” [10].

The interaction of the opioid with the μ-receptor leads to conformational changes not only of the G-protein, but also turns the receptor itself into a substrate for protein kinase. The ligand-activated receptor is phosphorylated at serine or threonine residues [10]. β-arrestins bind to the activated and phosphorylated receptor (Fig. 4). This is the one we need! It is β-arrestins that “decide” whether a side effect from taking an opioid will occur. The proof of the above came from studies on mice. It was found that if mice lacking μ-receptors are given morphine, they will have neither an analgesic effect nor side effects, in particular depression of the respiratory center. Scientists did not stop there and studied what would happen to mice without β-arrestins 1 and 2. It turned out that when such mice were administered morphine, they experienced an analgesic effect, which was stronger and longer than in mice with β-arrestins 1 and 2 But what is noteworthy is that there was no respiratory depression, constipation or other negative manifestations [11]. The conclusion was obvious. We need to continue working towards research into β-arrestins.

Figure 4. The occurrence of side effects is associated with binding to the activated and phosphorylated opioid μ-receptor β-arrestin. The diagram reflects the concept of the first hypothesis for the implementation of this dependence, which is described in detail in [11].

[11]

There are four proteins in the arrestin family of proteins. Arrestins 1 and 4 are expressed in rods and cones of the retina, respectively. Arrestins 2 and 3 (also known as β-arrestins 1 and 2) are present in all tissues. They control the activity of G protein-coupled receptors at three levels:

silencing - separation of the receptor from its G-protein;
internalization - removal of the receptor from the cytoplasmic membrane, re-return to the membrane and/or degradation;
signal conduction - activation or inhibition of intracellular signaling pathways independent of G-proteins.

The control abilities of β-arrestin are ensured by clathrin-dependent endocytosis—the entry of fragments of the cytoplasmic membrane along with all its contents into the cell in the form of vesicles coated on the outside with a lattice of polymerized clathrin. Clathrin is a protein that has the ability to form structures with an ordered network, they are also called clathrates. The formed vesicle, inside of which the receptor, undergoes endocytosis, and the further course of events can develop differently [12].

The beginning of a detailed study of opioids can be counted from the above-mentioned discovery of Serturner in 1804. Much has been clarified since then, but the specific molecular mechanism of side effects is still under debate. One thing is recognized by all scientists without exception: whether or not a negative effect occurs in the form of respiratory depression, decreased motility in the gastrointestinal tract, physical and mental dependence and other effects depends on β-arrestin. There are three main hypotheses for the implementation of this dependence [11]. They arose gradually, but they could not replace or exclude each other. Therefore, we will try to understand all three assumptions. I would like to emphasize that the hypotheses are not intended to exclude each other. Perhaps all mechanisms take place, because in the human body complex processes are found everywhere.

What are pharmaceutical drugs?

Pharmacy drugs include potent drugs that have anticonvulsant, sedative, hypnotic or sedative effects, which, when taken in excess of doses or over a long period of time, form dependence.

It is believed that narcotic drugs

- These are the most easily accessible surfactants. Some pharmacy drug addicts began taking medications as prescribed by a doctor, but, constantly increasing the dose, were unable to stop taking them because an addiction had formed.

Others become drug addicts due to self-medication, taking strong drugs without consulting doctors. The third group of addicts are young people and teenagers looking for new experiences or established drug addicts. They begin to use medications purposefully and in large dosages to achieve a high.

The effect of pharmaceutical drugs

The narcotic effect of pharmaceutical drugs depends on the medications used:

Painkillers (codeine, tramadol, etc.) cause a feeling of relaxation, movements become heavy, and reactions slow down.
Medicines containing ephedrine stimulate the nervous system, leading to the release of adrenaline.
Sedatives inhibit reactions and cause hallucinations in large quantities.
Sleeping pills depress the nervous system.

What do drug pills look like?

Preparations with elements of narcotic drugs may look like ordinary medications - tablets, powders, capsules, drop suspensions, etc.

What pills are considered drugs?

According to official sources, all drugs containing narcotic elements are divided into three control groups:

Drugs of the first group are subject to strict testing
. When purchasing them at a pharmacy, the pharmacist must call the attending physician to confirm the authenticity of the prescription. When using such drugs in hospitals, medical personnel are required to hand over all used ampoules.
For drugs of group 2
hazards are also prescribed, but no additional testing is required.
Drugs of the third group are sold without a prescription
. It is believed that they contain narcotic substances in safe quantities. However, pill addicts use them in batches at once or invent ways to remove psychoactive substances from the general composition of the drug.

Consequences of drug use

All modern pharmaceutical euphoretics used for narcotic purposes are synthesized artificially. Therefore, when exposed to large doses over a long period of time, they are much more potent than many herbal drugs and many times more toxic. To form an addiction to most pharmaceutical drugs, it is enough to use several packs of the drug. And if you consider that drug addicts can take 2 standard pills at a time to achieve euphoria, then addiction occurs literally in 2-3 doses.

Without timely medical care, very dangerous consequences can develop, such as heart attack, stroke, respiratory arrest, pulmonary edema, liver failure, and convulsions.

With prolonged use of pharmaceutical drugs, a person deteriorates physically, spiritually and intellectually. The average lifespan of a pharmaceutical drug addict is 1-2 years.

Hypotheses that work

The first hypothesis (the youngest in origin) is the most reasonable and understandable. It states that β-arrestins 1 and 2 stimulate intracellular molecular signals independently of G proteins and G protein-coupled downstream cascades (Fig. 5). β-arrestins can activate the mitogen-protein kinase cascade. The basis of this cascade is MAP kinases - serine/threonine-specific protein kinases, which, in response to extracellular stimuli, regulate cellular activity (gene expression, mitosis, differentiation, cell survival, apoptosis, etc.).

Figure 5. Beta-arrestin binding stimulates a cascade of intracellular molecular signals independent of G protein and related pathways. At the stage of the beginning of endosome formation with the GPCR + ligand (opioid) + β-arrestin complex on the membrane, β-arrestin promotes the activation of a cascade of reactions. The cascade involves activation of the ERK1/2 pathway. Subsequently, through the activation of other unknown kinases or through the activation of unknown cytoplasmic substrates, stimulation of intranuclear transcription processes and subsequent expression of molecules occurs. Through the formation of these molecules, effects are realized at the multi-organ level. Read about how this happens in [12].

[12]

Once the opioid ligand has bound to the μ receptor, the complex binds to β-arrestin. At the same time, the receptor complex begins to sink into the cell with the formation of an endosome. The resulting complex (GPCRs + opioid ligand + β-arrestin) is able to further bind to MAP kinase. There are several signaling pathways associated with this system, but there is only one at work here. This system is the ERK (extracellular signal-regulated kinase) pathway, which includes a chain of activations and interactions of ERK1/2 proteins with other kinases, resulting in the passage of a signal into the cell nucleus. Here the processes of transcription and further expression of the corresponding molecules already take place, thanks to which the cell can in one way or another respond to external stimuli. The function of such a mechanism is not fully understood.

Interestingly, this signaling paradigm has been confirmed in some GPCRs (eg, angiotensin GPCRs), but has not yet been confirmed in the μ-opioid receptors. Scientists suggest that if such a mechanism is characteristic of one type of GPCRs, then it extends to other systems [11–14]. One can try to assume that intranuclear processes realized through the MAP kinase cascade lead to the following changes: after intranuclear processes mediated through MAP kinases, the expression of certain molecules occurs that regulate ion exchangers, mainly affecting potassium and calcium channels. This is how all the subsequent effects in the body that were mentioned are realized - through the activation of potassium channels and the inhibition of calcium channels [14], [15]. It is necessary that a large amount of potassium leaves the cell according to concentration gradients, after which hyperpolarization of the membrane occurs. This condition is also called inhibitory postsynaptic potential. It is obvious that at this time the cell is not capable of generating action potentials and conducting impulses. The processes in which the cell takes part are inhibited. This is how the effect of anesthesia is realized (the cell is not able to respond to activating impulses from various neuropeptides responsible for conducting pain impulses), the effect of respiratory depression, and the occurrence of constipation due to inhibition of peristalsis in the gastrointestinal tract.

In addition, it is known for certain that respiratory depression is partially realized through inward rectifying potassium channels (IRK). An experiment examining the effect of systematic opioid infusion in mice lacking IRK showed that the opioid still ultimately led to a decrease in respiratory rate and subsequent depression. This shows that the implementation of effects is, after all, more complex than everyone thought and requires study. It is possible that these mechanisms are related to G-protein-independent signaling cascades first suggested by studies with β-arrestin-null mice reported previously [14]. In such a scenario, eliminating β-arrestin or reducing the affinity of the receptor molecule for it may eliminate the signal transduction pathway and the subsequent biological response. PZM21 was obtained . We'll talk about it later.

The second hypothesis is that β-arrestin acts differently in different μ-receptor subtypes (μ1 and μ2). The effect of the ligand on the μ1 receptor will lead to an analgesic effect, and the interaction of the ligand with the μ2 receptor will lead to the development of side effects. It seems logical for scientists that, accordingly, μ1 receptors are located in the nervous system (for example, in the periductal gray matter, reticular formation), and μ2 receptors are located in those areas in which they cause side effects. For example, inhibition of the respiratory center is associated with the location of μ2 receptors in the respiratory center. This hypothesis is currently considered insufficiently reliable and requires research [11], [13]. But still, the authors of the articles mention it even in 2016 (although this hypothesis has existed for more than 30 years without a 100% evidence base), so we still believe in its implementation in practice [14].

A third hypothesis states that β-arrestin acts through receptors other than GPCRs. For example, on serotonin 5-HT4 receptors, influencing their activity in neurons of the PBC complex (pre-Bötzinger complex). This complex refers to a cluster of neurons in the ventrolateral region of the medulla oblongata. Together they are responsible for generating the breathing rhythm. Accordingly, the effect of respiratory depression is realized by influencing this complex. Studies have been conducted in which scientists have shown that more than half of all 5-HT4 receptors in the PBC complex are interconnected with opiate μ receptors in the same complex. These receptors, according to a mechanism that has not yet been explained by scientists, are capable of acting as antagonists. The μ receptor is activated and the activity of 5-HT4 receptors is antagonistically inhibited. The result of the cascade of subsequent events is the effect of respiratory depression. To test this hypothesis, studies were conducted with 5-HT4 receptor agonists. Their effect on these receptors resulted in a reduction in opioid-induced respiratory depression. But interestingly, there was no loss of analgesic effect [11], [16].

This hypothesis explains only the mechanism of one side effect. Moreover, it, like previous hypotheses, is just a hypothesis, which does not yet have 100% reliable evidence. It should be clarified that scientists do not give up and are not satisfied with the current state of affairs. For example, current concepts argue that the actions of ERK1/2 (as discussed earlier in the first hypothesis) lead to inhibition of opioid tolerance in periconductal gray matter neurons [17]. Such studies indicate that the mechanism of action of opioids is not simple. Each cascade of signals, molecular pathways, and molecular interaction capabilities is important and carries information that together will give us a complete understanding of the problem. Knowing the essence of the problem, we can solve it.

Is there a solution?

Opioid analgesics act in such a way that a sick person forced to take them quickly develops side effects. This raises questions about the appropriateness and legality of opioid use, which dramatically reduces their availability to patients.

Until recently, opioid analgesics, which do not yet have an effective alternative to pain relief, were a “headache” for scientists and doctors. The subject of the research was a special group of patients for whom all possible undesirable manifestations are just a speck compared to the pain that only opioids can cope with. In May 2021, at the second Russian conference on maintenance therapy in oncology, one of the speakers noted that although opioids are the drugs of choice for the treatment of chronic pain syndrome in the range of moderate to severe pain, Russia is still in last place in terms of their medical consumption among narcotic analgesics compared to other countries (Canada - 57.9%, USA - 31.0%, Western Europe - 34.2%, Eastern Europe - 4.2%, Baltic countries - 2.3%, Russia - 0 .5%) [18]. This is due to both legislative aspects and numerous negative factors: frequent use (every 4 hours), rapid development of tolerance, the need for frequent visits to the doctor, the difficulty of self-administration at home, side effects mentioned many times, etc.

It is hoped that most, if not all, of the problems in the use of opioid analgesics will soon be resolved. In 2016, the journal Nature published the article “Structure-based discovery of opioid analgesics with reduced side effects,” which describes an interesting and important study (Fig. 6) [14]. The authors managed to come closer to solving a problem that has long been insoluble, and has already become commonplace - to create a narcotic analgesic without the side effects characteristic of this group of drugs. Through extensive mental and computer research, scientists tried to find a suitable molecule.

Figure 6. One of the authors of the article “Structure-based discovery of opioid analgesics with reduced side effects” is Aashish Manglik. The scientist describes his range of interests on social networks: “I am a physician-scientist with an interest in understanding human physiology from a biochemical perspective. I am particularly motivated to leverage recent advances in the understanding of G protein-coupled receptors to study and address various clinical diseases." with G-protein receptors for the study and treatment of various clinical diseases").

Initially, more than three million molecules were obtained that were conformationally suitable for the structure of the μ-receptor. The top 2,500 compounds were then manually analyzed for interactions with key polar active site regions of the receptor. Of the 23 molecules selected, seven showed the highest affinity for the μ receptor. The most highly selective compound is called PZM21 (remember the name - it may be a future celebrity!).

This substance acts on the opioid μ receptor as follows (Fig. 7). It was previously stated that β-arrestin binds to the activated and phosphorylated GPCR (μ-receptor) after sequential reactions. Its addition ensures the further course of events, the result of which is the occurrence of side effects. But PZM21 works in such a way that even after phosphorylation, activation and change in GPCR conformation, β-arrestin does not bind to the receptor. This is due to a change in the conformation of the μ-receptor itself in favor of further activation of the G-dependent pathway, through which no side effects occur.

Figure 7. Synthesized compound PZM21 and its interaction with the opioid μ receptor. Comparison of the configuration and active interaction of PZM21 with TRV130 in relation to the μ receptor. Computer model based on the crystal structure of molecules.

[14]

Thus, the above was confirmed by the experiment with the presence of overexpressed GRK2 (G-protein-coupled receptor kinase2). This is a family of serine/threonine protein kinases that recognize and phosphorylate agonist-activated GPCRs. That is, the μ-receptor is phosphorylated after the opioid ligand attaches to it [19]. Only this moment awaits β-arrestin, ready “at full speed” to contribute to the implementation of undesirable side effects. But the conformation of the μ-opioid receptor changes so that β-arrestin is unable to bind to it. And the experiment showed that even under conditions of overexpression of GRK2 at the maximum concentration of PZM21, the content of β-arrestin still remains low. Conclusion: when PZM21 is used as a μ-opioid agonist, further formation of a chain of reactions occurs not through the β-arrestin pathway, but through the G-protein coupled pathway. As a result, this leads to a positive therapeutic effect (analgesia), which eliminates side effects such as respiratory depression, decreased motility in the gastrointestinal tract, and physical and mental dependence. The maximum analgesic effect of PZM21 in vivo lasted 180 minutes without side effects. It was interesting to compare the effects of PZM21 and morphine. Thus, at the same dose of the two substances, PZM21 caused an analgesic effect in 87% of mice after 15 minutes, morphine in 92% of mice after 30 minutes.

The authors of the study still emphasize that it is possible that some of the effects that are so positive compared to other μ-opioid agonists occurred by chance and therefore require further extensive testing. In addition, will such an unprecedented positive effect be maintained in vivo under the conditions of a variety of reactions and all vital processes of the human body. What the metabolism, pharmacokinetics and pharmacodynamics of such a drug will be like is still unknown to us.

The authors of the study indicate that their source of inspiration was previous experiments in the search for μ-receptor agonists [14]. For example, in 2014, the article “Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: a randomized, double-blind, placebo-controlled, crossover study in healthy volunteers” was published [20 ]. 30 healthy men were observed, some of whom received the drug TRV130 (μ-receptor agonist), some received placebo, and some received morphine. Numerous endpoints were studied, including the safety, tolerability, and analgesic effect of TRV130. The analgesic effect of the drug was excellent even compared to the effects of morphine, but respiratory depression, albeit to a lesser extent, still occurred. Plus, a number of additional side effects were observed, for example, nausea [20].

In a 2021 study, researchers also compared the newly minted PZM21 with TRV130 and morphine for respiratory depression. It was found that morphine leads to apnea after 30 minutes, TRV130 induces temporary, transient depression for an average of 15 minutes, but PZM21 does not affect the respiratory rhythm [14]. Even if the problem of opioid side effects is not solved, I want this study to serve as a basis for further discoveries. I especially want the research to concern not only pharmacological effects and the synthesis of new molecules, but also to clarify the above hypotheses. Still, when reading a modern article, I don’t want to see the phrase “the mechanism is not fully understood.”

Indications for use

Narcotic analgesics are used for conditions that are accompanied by severe or very severe pain:

extensive injuries, multiple injuries (polytraumas);
burns or frostbite of a large surface of the body;
any cancer in the final stages;
pain after major operations;
myocardial infarction;
renal, hepatic, intestinal colic;
pain relief during labor (only some narcotic analgesics, for example, trimeperidine).

In addition, narcotic analgesics are used before operations (so-called premedication - preparation for general anesthesia), which makes it possible to enhance the effect of anesthesia and reduce their dose.

Certain narcotic analgesics (for example, codeine) are used to treat dry cough that is not accompanied by sputum production.

The narcotic analgesic fentanyl can be used together with the neuroleptic (antipsychotic) droperidol for neuroleptanalgesia, a special type of general anesthesia in which the patient is conscious. Neurolepanalgesia is often used during brain surgery.

conclusions

Pain can be treated differently: you can endure it and try to overcome it, according to Immanuel Kant’s treatise “On the ability of the spirit to overcome painful sensations by the power of will alone.” You can philosophize about it and speak in the words of Delia Guzman: “We should not fight pain, but rather perceive it as a guiding light, as a way of warning us and forcing us to reconsider our actions and adjust our actions.” You can view pain as a function of a highly organized system and a defensive reaction, but all this is left behind when you feel it yourself or see how someone else feels it. It is necessary to fight pain, it is necessary to take all possible measures to make a person’s life easier and improve its quality. Now we just have to watch the numerous further clinical trials and studies of this extremely interesting and important discovery, perhaps wait for new work related to blocking the effects of β-arrestin, and, perhaps, participate in the discoveries ourselves. Everything so that a person experiencing pain does not live according to the Count of Monte Cristo’s principle of “waiting and hoping,” but lives a full life, as far as possible to include everything positive in this concept.

The article was written in collaboration with G. Z. Seregin.

Literature

WHO recommendations for drug treatment of persistent pain in children with somatic diseases. M.: Practical Medicine, 2014. - 208 pp.;
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