Modern painkillers: no morphine

Any pain requires a response. But the pain is chronic, unbearable, as in some cancer patients, may not respond to the usual analgesics from the medicine cabinet. This forces us to take drugs that are extremely powerful in their analgesic effect, opioid analgesics, such as morphine and its derivatives.

The discoverer of morphine was the hereditary pharmacologist Friedrich Serturner, who from an early age enthusiastically experimented in the family and then in the court laboratory in Westphalia. Opium, the mysterious potion from the tales of “One Thousand and One Nights, ” a chemist of the beginning of the 19th century, could not ignore. Highlighting a pure preparation, Serturner tested it on the first dogs that came across, and then on himself. The substance plunged everyone into deep, insensitive oblivion with vivid visions and was named morphine in honor of the Greek god of sleep. Its subsequent history is familiar to everyone: from widespread use and general enthusiasm to abuse and severe legislative restrictions.

Grace was replaced by prohibitions for good reason: people who are forced to take opioid analgesics quickly develop severe, and often dangerous side effects, up to a complete stop of breathing. This makes it necessary to carefully evaluate the appropriateness of using opioids, requires control over their turnover and dramatically reduces the availability of painkillers for those who really need them. This is how the “dual” nature of opioids manifests itself, originating in the biochemistry and physiology of their action on the nervous system and the whole organism.

Double edged sword

All effects of opioids are associated with exposure to the corresponding receptors of nerve cells. Today there are five species that are known, the most studied - mu (μ), delta (δ) and kappa (κ) receptors, which are found in neurons of the brain and spinal cord, gastrointestinal tract and in some other organs. Any opioid interacts with their different types, although each has its own “favorites”. For example, μ-receptors are key for morphine itself.

Essential Opioid Receptors
Localization Effects

Mu (m)

brain (cortex, thalamus, etc.), spinal cord, peripheral sensory neurons, gastrointestinal tractanalgesia, euphoria, miosis, weakening of intestinal motility, physical dependence

Delta (δ)

brain (bridge, tonsil, optic tubercle, etc.), peripheral sensory neuronsanalgesia, antidepressant effect, physical dependence

Kappa (κ)

brain (hypothalamus, fence, etc.), spinal cord, peripheral sensory neuronsanalgesia, miosis, sedation (inhibitory and hypnotic effect), dysphoria (depressed state)

The discovery of opioid receptors made me wonder what role they play without morphine preparations. Such questions have led to the discovery of enkephalins and endorphins, the “endogenous opioids” that are secreted by the brain itself. This is a kind of built-in system of protection against pain, from difficult experiences and adversities. Endogenous opioids, as well as exogenous, bind to opioid receptors and exhibit an analgesic effect.

The discovery of endorphins caused almost euphoria: a lot of attempts were made to get their synthetic analogues, substances that would remain powerful analgesics, but would not be burdened by a host of adverse effects. Unfortunately, these searches were unsuccessful: either the analgesic effect was weak compared with the external opioids, or the side effects were too strong - all the analogues were no better than the same morphine. To understand why this happened, you have to figure out how opioid receptors work.

New link

By binding to a ligand (endorphin, opiate, or other similar substance), the μ receptor changes its shape, triggering a cascade of intracellular reactions. At the same time, the receptor itself becomes a substrate for the action of protein kinase enzymes, which modify (phosphorylate) some of its amino acids. Such an altered receptor binds to other proteins - beta-arrestins. It is believed that they are guilty of developing dangerous side effects. It was shown that in mice genetically unable to produce beta-arrestin, the introduction of morphine caused analgesia without respiratory depression, digestion, and other dangerous effects.

Mechanism / Inhibition / Anesthesia Activation of the opioid receptor on the neuron membrane blocks the entry of calcium ions into the cell and at the same time stimulates the excretion of potassium from it. This leads to hyperpolarization of the charges on the membrane, inhibiting the excitation of a neuron.

Beta-arrestins are present in the cells of all tissues of our body and are always associated with the work of membrane receptors, activating or inhibiting their action. Why this can lead to suppression of breathing and peristalsis and other unpleasant effects is still not known exactly. There are only hypotheses on this score, and all of them do not exclude each other, and in the body, possibly, different options are realized simultaneously.

The most popular hypothesis (and the most recent in appearance) suggests that the receptor, opioid, and beta-arrestin form a common triple complex. This complex launches a cascade of regulatory processes that change the activity of individual genes and proteins. First of all, this affects the work of ion channels that pump potassium out of the cell. The rapid loss of potassium causes hyperpolarization of the cell membrane; in this state, the cell is not capable of generating an action potential and conducting impulses. Inhibition of all the processes in which it is involved occurs. For example, a neuron stops responding to signals from pathways conducting pain impulses, and ultimately blocks the occurrence of a pain effect. So the cell is involved in anesthesia, and at the same time losing sensitivity to other signals, it also creates side effects.

Mechanism / Stimulation / Euphoria Activation of opioid receptors in neurons of the adjacent nucleus of the brain leads to the release of gamma-aminobutyric acid (GABA) molecules. This causes neighboring cells to secrete another neurotransmitter, dopamine, leading to euphoria.

Molecule from the car

The long-awaited breakthrough in the search for a “golden bullet against pain” was brought by computer simulation. American scientists from the team of Nobel laureate Brian Kobilka received more than 3 million virtual molecules structurally suitable for binding to the μ receptor. Selecting the most promising options step by step, the researchers reduced their number to 2500, then to 23, and finally to only seven compounds that showed the highest affinity for the μ receptor. The favorite of this race was the PZM21 molecule. Remember its name - perhaps this is a future celebrity of world scale.

PZM21 not only binds to the μ receptor, but also changes its conformation so that even after phosphorylation, beta-arrestin is not able to contact it. This leads to a positive therapeutic effect (anesthesia), and side effects in the form of respiratory depression, decreased gastrointestinal motility, physical and mental dependence disappear. After evaluating the effect of PZM21 on laboratory animals, scientists found that the new molecule has an analgesic effect even faster than morphine - after 15 minutes versus 30. At the same time, morphine, as always, led to apnea, and PZM21 did not affect respiratory rhythm.

Number one candidate

A promising drug, glyceridine (TRV130), according to the creators, may even be a better analgesic than morphine itself: its analgesic effect begins within a couple of minutes after administration. Today, the TRV130 remains the only analogue of morphine that has been tested in humans. Now he is in the third phase of clinical trials, the results of which should become known this year. However, one should not be too hopeful. Firstly, there are some reasons to suspect that TRV130 still causes respiratory depression. Secondly, many examples are known when equally promising developments ended in nothing. It is enough to recall the story of desomorphine, better known as heroin.

It is very important that scientists try to solve the problem of adequate pain relief by moving in completely different ways. And while some are modeling and testing new molecules, others are trying to "refine" the existing ones. This hope is given by the discovery of a special group of endogenous opioids, short endomorphine peptides. Last year's work showed good prospects for obtaining modified endomorphins that act on μ receptors, triggering analgesia without side effects.

Of course, talking about getting the coveted molecules is still too early. Even Brian Kobilka and his co-authors note that PZM21 and the effects it creates require additional and comprehensive research, as well as the “analogs” of endorphins. It is necessary to find out the metabolic transformations that the substance undergoes in the human body, to verify the positive effects and the absence of negative ones. All this will take more than one year. But at least the scientists created a good basis for further discoveries, and the patients and doctors received new hope.

The article “Good Brother Morphine” was published in the journal Popular Mechanics (No. 5, May 2017).


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