The perfect analgesic


Expert Pharmacologist
Jul 6, 2021
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In order to get rid of pain, modern man has an extensive choice 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 have done for these patients by reversing the historical basis of opioids at the molecular level is discussed in this article.
What a philosopher
Toothache was calmly borne!
And with immortal eloquence
Wrote against doom and misery.
William Shakespeare. Much ado about nothing
Beautiful 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. Regardless of the severity of pain, it always requires a response, the sooner the better. But the pain is chronic, intolerable, as in cancer patients, does not respond to the administration of "standard" non-narcotic analgesics or medications from the "forgotten medicine cabinet". Such patients are forced to take drugs stronger in their analgesic effect, most often opioids.

Drugs that reduce or stop pain are called analgesics.
The modern classification of analgesics divides them into four main groups:
  • Narcotic (opioid) analgesics;
  • Non-narcotic (non-opioid) analgesics;
  • Analgesics of mixed type of action;
  • Drugs of other pharmacological groups with analgesic effect.

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

Perhaps everyone knows the "star of the world" among the group of narcotic analgesics. Meet morphine. Its father can, without hesitation, be considered the pharmacist Friedrich Wilhelm Serturner, a young man in his twenties at the time. In the laboratory of his father, who was fond, as was fashionable at the time, of the art of alchemy, the young Sertürner acquired all the skills for his subsequent discovery. After his father's death, he begins experimenting with various substances in the court apothecary in Paderborn. Since opium was covered with a halo of mystery, of course, Sertürner did not ignore it either.

The isolated powder was boldly tried on all dogs that ran past the apothecary. The dogs did not mind, and after a treat with a dash of magic powder they fell asleep in a deep sleep, without feeling Sertürner's pinches. The young scientist immediately realized that a substance with such properties could become of great importance to mankind. After performing a series of experiments on himself, Serturner named it after the Greek god of sleep morphine. This happened in 1804. You know the subsequent history. From centuries of use and rapture to legislation to restrict opioid use and the emergence of black markets.


A stick sharpened at both ends: the positive and negative effects of opioids
The easiest way to understand the mechanism of action of opioids is to know that an opioid is a substrate that excites certain receptors. Modern pharmacology distinguishes five types of opioid receptors, the most studied of which are μ, δ, κ. All opioids interact to varying degrees with different types of opioid receptors, but there are the most typical agonists and antagonists for each type of opioid receptor.

The effects realized through these receptors are numerous, all of them very interesting and affect a person, if not on the organismal level, then certainly on the multi-organ level (starting with the CNS and ending with the urinary system). The pronounced activity of opium is manifested more through the effect on the μ-receptors.

μ-receptors are divided into subtypes. There are three of them in total, and different effects are realized by affecting a particular subtype. Exposure of the ligand to the μ1-receptor will produce 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, the following side effects occur: respiratory depression up to apnea, decreased peristalsis in the gastrointestinal tract, physical and mental dependence. In addition, effects such as suppression of the cardiovascular center in the medulla oblongata, oligo- or anuria, nausea, vomiting, constipation and many more very undesirable effects can occur. The function of the μ3-receptor is still unknown.

The main effect we are interested in - analgesic - is realized through inhibition of activity of the central nervous system structures. These structures are on different levels and perform a controlling (limiting) function in relation to painful stimuli. They can be divided into 3 levels:
  • Subcortical structures - periconductal gray matter, reticular formation, sutural nuclei;
  • Hypothalamus;
  • Cortex of the large hemispheres.
The analgesic effect is also realized through a decrease in excitability of the emotional and vegetative centers of the hypothalamus, limbic system and the large hemisphere cortex, which leads to a decrease in the negative emotional and mental evaluation of pain.

Endogenous opioids
As for the analgesic effect, opioids are excellent and have outperformed many! It is always interesting to discover the secrets of those who are great at something. The secret of opioids, on the other hand, was discovered at the end of the last century. First the receptors in the brain that responded to the effects of opiates were discovered. Then came one of the remarkable advances in neuroscience - the discovery of the neural mechanism of action of opiates. These studies led to the discovery of a class of brain-derived chemicals called enkephalins, and later to the discovery of endorphins. These are all morphine-like endogenous substances (endogenous opioids).

Endorphins have a rather long formation pathway: it all starts with proopiomelanocortin (POMC), which is produced in the anterior and intermediate lobes of the pituitary and in some other tissues (intestine, placenta). After the magical transformations of POMC into adrenocorticotropic hormone (ACTH) and β-lipotropin, a different set of peptides, including endorphins, is formed in different cells from these precursors.

Imagine that! Each of us has his own excellent defense system against any pain, any experience, any negative phenomena. After all, endogenous opioids, just like exogenous opioids, bind to opioid receptors and realize the effect of pain relief. But that's not how it works.

After the discovery of endorphins, attempts were indeed made to obtain their synthetic analogues, since it was now clear that opioids were not so evil, but, as is usually the case with pharmaceuticals, 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 successful. The analgesic effect of the obtained substances was weaker than that of morphine. And if scientists tried to make the effect comparable in pain relief to exogenous opiates, they got serious side effects as a result.


So why was this happening? Let's remember that our body has a homeostasis system. Everyone remembers what this is from school. You can even chorus: the body's ability to maintain the constancy of the internal environment. So, in a normal physiological state, there is a balance between synthesis, release, receptor binding, and reuptake of the neurotransmitter, which results in a sense of inner comfort. Importantly, the body itself does not produce excessive amounts of endogenous opioids, as this can lead to a number of the side effects already mentioned (addiction, respiratory depression up to apnea, nausea, constipation, etc.).

In this way, one kind of homeostasis - the so-called state of "opioid sufficiency" - is carried out in the human body. If a substance capable of binding to the opioid receptor enters the body from outside, this state is disrupted.

What does the result depend on?
The highest concentration of μ-receptors is found in the caudate nucleus. In high concentrations these receptors are present in the cortex, thalamus, hypothalamus. They are also found in moderate amounts in the perineal gray matter, stomach body, duodenum, ileum, and in smaller amounts elsewhere.

These receptors (GPCRs) are located on the cell membrane and interact via G-protein with the membrane enzyme. The G-protein is a universal mediator in the transmission from the receptor to the cell membrane enzymes of signals that catalyze the formation of secondary mediators of the hormone 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 cellular processes.


The interaction of an opioid with the μ-receptor leads to conformational changes not only in the G-protein, but also transforms the receptor itself into a substrate for the protein kinase. The ligand-activated receptor is phosphorylated by serine or threonine residues. The β-arrestins bind to the activated and phosphorylated receptor. This is the one we need!

It is the β-arrestins that "decide" whether the side effect of taking an opioid substance will appear. Proof of the above was provided by studies on mice.

It was found that if morphine was administered to mice deprived of μ-receptors, they would have neither an analgesic effect nor side effects, in particular the inhibition of the respiratory center. Scientists did not stop there and investigated what would happen in mice without β-arrestin 1 and 2. They found that when such mice were injected with morphine, the analgesic effect occurred, stronger and longer than in mice with β-arrestins 1 and 2.

But, remarkably, there was no respiratory depression, constipation, or other negative manifestations. The conclusion was obvious. It is necessary to continue working in the direction of β-arrestin research.

Four proteins belong to the arrestin family of proteins. Arrestins 1 and 4 are expressed in the 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 a receptor from its G-protein;
  • Internalization - removal of the receptor from the cytoplasmic membrane, its reemergence 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 provide clathrin-dependent endocytosis, i.e., the entry of cytoplasmic membrane fragments together with all their contents into the cell as vesicles covered by a polymerized clathrin lattice on the outside.

Clathrin is a protein with the ability to form structures with an ordered grid, they are also called clathrates. The formed vesicle with the receptor inside is subjected to endocytosis, and the further course of events can unfold in different ways.

The beginning of the detailed study of opioids can be traced back to Serturner's discovery above in 1804. Much has been clarified since then, but the specific molecular mechanism of side effects is still debated.

One thing is recognized by all scientists without exception: whether or not a negative effect in the form of respiratory depression, reduced peristalsis in the gastrointestinal tract, physical and mental dependence and other effects will occur depends on β-arrestin.

There are three main hypotheses of the realization of this dependence. They emerged gradually, but they could not replace and exclude each other. Therefore, we will try to understand all three hypotheses. We would like to emphasize that the hypotheses are not intended to exclude each other. It is possible that all mechanisms have a place, because in the human organism complex processes are found everywhere.

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-related further cascades. β-arrestins can activate the mitogen-protein kinase cascade.

The basis of this cascade is MAP-kinases, serine/threonine-specific protein kinases that regulate cell activity (gene expression, mitosis, differentiation, cell survival, apoptosis, etc.) in response to extracellular stimuli.

After the ligand-opioid is attached to the μ-receptor, this complex binds to β-arrestin. At the same time, the receptor complex begins to sink inside the cell with the formation of an endosome. The resulting complex (GPCRs + ligand-opioid + β-arrestin) is able to further bind to MAP-kinase.

There are several signaling pathways associated with this system, but one works here. This system is the ERK (extracellular signal-regulated kinase) pathway, which involves a chain of activations and interactions of ERK1/2 proteins with other kinases, resulting in the passage of the signal to the cell nucleus. Here the processes of transcription and further expression of the corresponding molecules occur, due to which the cell can respond to external stimuli in one way or another. The function of such a mechanism is not fully understood.

The second hypothesis is related to the fact that β-arrestin acts in different subtypes of μ-receptors (μ1 and μ2) differently. Exposure of the ligand to the μ1-receptor will result in an analgesic effect, while interaction of the ligand with the μ2-receptor will result in the development of side effects. It seems logical to scientists that, respectively, μ1-receptors are located in the nervous system (e.g., in the periconducting gray matter, reticular formation) and μ2-receptors are located in the areas in which they produce side effects.

For example, respiratory center depression is associated with the location of μ2-receptors in the respiratory center. This hypothesis is currently considered to be insufficiently reliable and requires research. But still the authors of articles even in 2016 mention it (although this hypothesis has existed for more than 30 years without a 100% proof base), so we still believe in its implementation in practice.

The third hypothesis states that β-arrestin acts through other receptors, i.e., not through GPCRs. For example, on serotonin receptors 5-HT4, affecting their activity in neurons of the PBC (pre-Bötzinger complex). This complex is understood as a cluster of neurons in the ventrolateral region of the medulla oblongata. Together, they are responsible for generating the rhythm of breathing. Accordingly, the influence on this complex realizes the effect of suppression of breathing.


There have been studies in which scientists have shown that more than half of all 5-HT4 receptors in the PBC complex are associated with opiate μ-receptors in the same complex. These receptors, by a mechanism not yet explained by scientists, can act as antagonists. When the μ-receptor is activated, the activity of 5-HT4-receptors is antagonistically inhibited. The result of the cascade of subsequent events is the effect of respiratory suppression. To test this hypothesis, studies were conducted with 5-HT4-receptor agonists. Their effect on these receptors led to a decrease in opioid-induced respiratory depression. But, interestingly enough, there was no loss of the analgesic effect.

This hypothesis explains only the mechanism of one side effect. At the same time, it, as well as the previous hypotheses, is only 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 state of affairs that has arisen.

For example, current concepts claim that the actions of ERK1/2 (discussed earlier in the first hypothesis) lead to inhibition of opioid tolerance in periconductor gray matter neurons.

Studies such as these indicate that the mechanism of opioid action is not one-sided. Each cascade of signals, molecular pathways, and molecular interaction possibilities 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 the patient forced to take them quickly develops side effects. This raises questions about the appropriateness and legality of opioid use, which drastically reduces their availability to patients.

It is hoped that most, if not all, of the problems in the use of opioid analgesics will soon be solved. In 2016 Nature magazine published an article "Structure-based discovery of opioid analgesics with reduced side effects," which describes an interesting and important study. The authors managed to come closer to solving a long unsolvable and already familiar problem - to create a narcotic analgesic without the side effects inherent to this group of drugs. Through lengthy mental and computer searches, scientists tried to find a suitable molecule.


Initially, more than three million molecules were obtained that conformationally fit the structure of the μ-receptor. The 2,500 best compounds were then analyzed manually for interaction with the key polar sites of the receptor's active center. Of the 23 molecules selected, seven showed the highest affinity for the μ-receptor. The most highly selective compound was named PZM21 (remember the name - it may be a future celebrity!).

This substance affects the opioid μ-receptor as follows. It was stated earlier that β-arrestin attaches to the GPCR (μ-receptor) activated and phosphorylated after sequential reactions. Its attachment provides a further course of events, the outcome of which is the occurrence of side effects.

But PZM21 works in such a way that even after phosphorylation, activation, and change of GPCR conformation the β-arrestin is not attached 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.

Thus, the experience with the presence of overexpressed GRK2 (G-protein-coupled receptor kinase2) was a confirmation of the above. This is a family of serine/threonine protein kinases that recognize and phosphorylate agonist-activated GPCRs. That is, they phosphorylate the μ-receptor after the ligand-opioid has attached to it. This is the only moment β-arrestin is waiting for, ready to contribute to the realization of unwanted side effects. But the conformation of the μ-opioid receptor changes so that β-arrestin is unable to bind to it. And in the experiment it was shown that even under conditions of GRK2 overexpression at the maximum concentration of PZM21 the β-arrestin content is still low.


Conclusion: when PZM21 is used as a μ-opioid agonist, the reaction chain is further formed not by the β-arrestin pathway but by the G-protein-related pathway. As a result, this leads to a positive therapeutic effect (analgesia), and side effects in the form of respiratory depression, reduced peristalsis in the gastrointestinal tract, physical and mental dependence are leveled. The maximum analgesic effect of PZM21 in vivo lasted for 180 minutes with no side effects. An interesting comparison of the effects of PZM21 and morphine. For example, with the same dose of the two substances, PZM21 caused an analgesic effect in 87% of the mice after 15 minutes and morphine in 92% of the mice after 30 minutes.

The authors of the study emphasize, however, that it is possible that some such positive effects compared to other opioid μ-receptor agonists occurred accidentally, and therefore require further extensive testing. In addition, whether such unprecedented positive effects will persist in vivo in the face of a variety of reactions and all the vital processes of the human body. What the metabolism, pharmacokinetics, and pharmacodynamics of such a drug will be is still unknown to us.

Pain can be treated in different ways: it can be endured and attempted to be conquered according to Immanuel Kant's treatise On the Power of the Spirit to Conquer Painful Feelings by the Force of Will alone. We can philosophize about it, in the words of Delia Guzmán: "We should not fight pain, but rather regard it as a guiding light, as a way of warning us and making us reconsider our actions and adjust our actions.

You can see pain as a function of a highly organized system and as a protective reaction, but all this is left behind when you feel it yourself or see how someone else feels it. Pain must be fought, all possible measures must be taken to make life easier for the person, to improve its quality.


Now it remains for us to watch for further numerous clinical trials and studies of this extremely interesting and important discovery, perhaps wait for new works related to blocking the effects of β-arrestin, and perhaps participate in the discoveries ourselves. All so that a person in pain would not live the Count of Monte Cristo principle of "wait and hope", but live a full life, as far as possible to include everything positive in this notion.


Don't buy from me
Apr 25, 2023
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Amazing and well written guide, thank you!


Expert Pharmacologist
Jul 6, 2021
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thx bro!
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