Theories of pain physiology. Pain receptors Where are the most pain receptors?

Yaroslav Alekseevich Andreev - Candidate of Sciences (Biology), Senior Researcher, Laboratory of Neuroreceptors and Neuroregulators, Department of Molecular Neurobiology, Institute of Bioorganic Chemistry. Academicians M.M.Shemyakin and Yu.A. Ovchinnikov RAS. Research interests are related to the search and characterization of pain receptor modulators.

Yulia Alexandrovna Logashina - a junior researcher in the same laboratory. Searches for and characterizes new ligands for the TRPA1 receptor.

Ksenia Igorevna Lubova - Student of the Faculty of Biology, Moscow State University. M.V. Lomonosov. Studies TRP receptors and their modulators.

Alexander Alexandrovich Vasilevsky - Candidate of Science (Chemistry), Head of the Group of Molecular Instruments for Neurobiology, Department of Molecular Neurobiology, Institute of Bioorganic Chemistry. Academicians M.M.Shemyakin and Yu.A. Ovchinnikov RAS. Specialist in the field of ion channels and natural toxins.

Sergei Alexandrovich Kozlov - Doctor of Chemistry, Head of the Laboratory of Neuroreceptors and Neuroregulators of the same department. Research interests - protein receptors in nervous system and their ligands.

They say that life is pain. Although this phrase contains something negative, associated with unpleasant sensations, experiences or even severe suffering, we should not forget that pain (nociception) warns us of danger - signals about disturbances in the body, which immediately begins to eliminate them. At the same time, there is also pain that only brings torment.

The main reason for the appearance of such pain is disruptions in the transmission of pain signals (nerve impulses) from sensitive neurons to the brain, which forms unpleasant sensations. When exposure to non-hazardous stimuli is judged to be hazardous by recognizing neurons, a condition called hypersensitivity develops. And this is not always a bad thing, since at the right time it plays an important role in the process of recovery and restoration of the body. However, it also happens that there is no real reason, and hypersensitivity leads to debilitating chronic pain. In this case, the most common harmless stimuli (light touch or warmth) cause allodynia (from the Greek άλλος - another and οδύνη - torment), and painful stimuli - pain of even greater intensity, hyperalgesia (from the Greek ὑπέρ - in excess of- and ἄλγος - pain). Often abnormally intense and often chronic pain, which is exhausting both physiologically and psychologically, and also complicates recovery, arises as a result of diseases such as arthritis, shingles, AIDS, bone cancer, etc.

Before we blame the sensory neurons (nociceptors) for abnormalities, which perceive, analyze and transmit pain signals, let's figure out how they work in a healthy body and what happens in pathologies.

Why does it hurt so much?

The biological function of nociceptors consists not only in registering the stimulus and reporting this to our brain, but also in perceiving signals from the nearest neighbors. Neurons are surrounded by other cells of the body and the intercellular environment, for the safety and proper functioning of which our nervous system is responsible. Therefore, nociceptors have many molecular sensors (or receptors) tuned to recognize chemical stimuli, changes in the composition and properties of the intercellular environment, and the release of signaling molecules from nearby cells. The neuron independently "calculates" the contribution of each such molecular sensor according to the strength and duration of stimulation, and if stimuli are regarded as unwanted, it signals this - and we get hurt; it is "normal" physiological pain (nociception). Pathological pain occurs both in the case of the death of neurons due to damage to the conducting network of the peripheral or central nervous system, and in the case of erroneous operation of the neurons themselves, and they are mistaken due to improper operation of their sensors.

Pain sensors (or receptors) are membrane proteins that recognize physical or chemical effects on the membrane of a neuron. Moreover, they are cation-selective ion channels, that is, they provide the conduction of positively charged ions (sodium, potassium, calcium) through the cell membrane. Activation of receptors leads to the opening of cation channels and the excitation of sensitive neurons - the emergence of a nerve impulse. We will describe in more detail the most studied pain receptors below.

What happens when, say, a person inadvertently burns his hand with a hot object? Such a dangerous temperature effect is registered by receptors that are located in the membrane of the nociceptor. They instantly recognize strong stimuli and transmit the impulse to the central nervous system. The brain immediately reacts to such a strong arousal, and we reflexively withdraw our hand from the hot object. Interestingly, the same sensors react to capsaicin, the active ingredient in hot pepper, which causes a “fire” in the mouth.

For recognizing a number of dangerous chemical effects other receptors respond, which perceive stimuli only from the intracellular side, therefore, to activate them, dangerous substances must not only penetrate the skin, but also get inside the neuron, "making their way" through the lipid biomembrane. If a chemical burn is caused by acid, then the very receptor that is sensitive to changes in the acidity of the environment will work, and will also give a strong response as soon as the acid reaches the neuron.

We pulled our hand back, but during contact with the hot surface, part of our cells died, and in response to tissue damage, we begin to develop an inflammatory process. Our nervous system also takes part in this. From damaged cells through ruptured cytoplasmic membranes into the extracellular environment, molecules characteristic of the intracellular environment, in particular adenosine triphosphoric acid (ATP), begin to be released. For this case, neurons also have their own receptor, which is activated by ATP molecules and signals that cells die next to it and their restoration is required. The fact is that ATP, as has been known since school, is the main energy molecule of the body, and such a "value" is rarely found in the intercellular environment.

The neuron does not just signal, it emits special biologically active compounds, mediators of inflammation, into the extracellular environment, which leads to the long-term development of neurogenic inflammation - vasodilation and attraction of cells immune system... While the regeneration process is going on and inflammatory mediators are present in the environment, sensory neurons send a signal to the central nervous system, where it is also perceived as pain, but not as strong. Since the damaged tissue needs protection, the sensitivity of neurons to external influences increases, and even a slight mechanical or thermal effect will cause a strong pain reaction. This is "useful" hypersensitivity.

Almost everyone knows that it is recommended to apply cold to damaged tissue to relieve pain and reduce inflammation. Neuronal receptors are also involved in this effect. The main receptor "for cold" - menthol (remember the "mint" chill?) - is not located in the same neurons where the "heat" is located, and therefore the sensations of cold and heat are transmitted by various sensitive fibers. It turns out that information from different nociceptors is "summed up" in the spinal cord, the signal from the hot effect is corrected taking into account the signal from the cold one, and that is why the applied piece of ice can relieve severe pain.

The described scheme of pain development is greatly simplified (Fig. 1). In fact, to figure out the details of nociception, scientists examine each receptor separately in isolated conditions. Experiments are carried out on cell lines into which genes of certain receptors are inserted by genetic engineering methods. Let's talk a little about the study and function of several of the most important pain receptors. As it turned out, they are not always focused on the recognition and generation of a pain signal, but are involved in the regulation of many other processes, so the ability to adjust their work with various drugs will help treat a variety of diseases (Fig. 2).

Receptors for temperature and chemical irritants

Very often, sensory neurons, which are responsible for the perception of high temperature, play a role in the development of pain and inflammation. Back in the middle of the 20th century, it was discovered that large doses of capsaicin induce a new type of pain relief (analgesia) in experimental animals. After the introduction of capsaicin, a characteristic behavioral reaction caused by pain is initially observed, but then a long period of loss of sensitivity to a number of external stimuli occurs. Animals in this state normally respond to mild mechanical stimulation, but they lose their response to many painful stimuli, and they do not develop neurogenic inflammation. Thus, the neurons responsible for the perception of heat are also responsible for the perception of chemical stimuli and the neurogenic component of the inflammatory response. It became clear that a receptor that responds to the effects of temperature and capsaicin may be a useful target for the search for drugs aimed at treating inflammation and pain. At the end of the twentieth century. this receptor has been characterized at the molecular level and named TRPV1 (from the English. transient receptor potential channel vanilloid family member 1 - the first representative of the vanilloid family of receptors of variable receptor potential), or more simply - vanilloid receptor 1 (Fig. 3). The name "vanilloid receptors" is not given by chance: TRPV1 and other members of the family are activated by chemical compounds containing a vanillin group (for example, capsaicin). It has been established that TRPV1 is a cation-selective ion channel that is activated by various stimuli (temperatures above 43 ° C, low pH, capsaicin), and, in addition, its activity is regulated by inflammatory mediators, although not directly, but through intracellular mediators. TRPV1 knockout mice (that is, those in which the gene for this receptor is missing or damaged so that it does not work) respond significantly more slowly to heat, and they almost do not develop thermal hypersensitivity during inflammation. TRPV1 plays an important role in a number of pathological conditions: pain caused by inflammatory process, for cancer, neuropathic and visceral pain, as well as for diseases respiratory tract, pancreatitis and migraines.

TRPV1 research has led to intensive research on these receptors. So, another vanilloid receptor, TRPV3, was discovered. Interestingly, it responds to both pleasant warmth and painful fever: TRPV3 activity is recorded at temperatures above 33 ° C, with a stronger response to higher temperatures and increased with repeated heat stimulation. In addition to temperature, this receptor is also activated by camphor, acrid extracts of thyme, oregano and clove. TRPV3 is another candidate for the role of a participant in pain hypersensitivity, its activity is regulated by inflammatory mediators. Finally, it is directly activated by nitric oxide II (NO), a secondary messenger that increases the sensitivity of neurons to stimulation. It should also be noted that TRPV3 is present in keratinocyte skin cells, where its activation leads to the release of the inflammatory mediator interleukin-1, which underlines the important role of this receptor in inflammatory diseases skin.

TRP receptors are tetramers (Fig. 3), that is, they are formed by four polypeptide chains. In this case, both homomers, that is, receptors formed by the same chains (for example, TRPV1 or TRPV3, described above), and heteromers from different chains can be assembled. Heteromeric receptors (for example, built from the TRPV1 and TRPV3 chains) have different sensitivity to thermal stimuli, the threshold temperature of their activation lies between the values \u200b\u200bthat are threshold for homomeric receptors.

An interesting story is the discovery of the TRPM8 cold receptor (here "M" stands for "melastatin", which indicates the function of this family of receptors in melanocytes - skin cells responsible for pigmentation). At first, the gene encoding it was discovered, the activity of which increased in prostate cancer and some other oncological diseases. Much later, the ability of TRPM8 was shown to respond to menthol (a component of mint) and a number of other "refreshing" substances, as well as to lower temperatures (below 26 ° C). Now this receptor is considered the main cold sensor in the nervous system. Research has shown that TRPM8 is responsible for a wide range of perceptions of cold stimuli, from pleasant coolness to painful coldness and cold hypersensitivity. This variety of functions is explained by the existence of several subpopulations of sensory neurons that use TRPM8 as a multifunctional cold sensor tuned to a certain temperature with the participation of intracellular signaling systems.

The most incomprehensible and very important receptor TRPA1 (here "A" stands for "ankyrin", which indicates the presence in the structure of the receptors of this family of a large number of "ankyrin repeats", special protein elements) are found in sensitive neurons of the skin, epithelial cells of the intestine, lungs and urinary bladder, and TRPA1 is often adjacent to TRPV1. Substances that activate TRPA1 cause burning sensation, mechanical and thermal hypersensitivity, as well as neurogenic inflammation. Overexpression of the gene encoding TRPA1 leads to chronic pruritus and allergic dermatitis. Hereditary disease "Episodic pain syndrome", which is characterized by unexpected debilitating pain during fasting or exertion, is associated with a mutation in this receptor, leading to its overactivity.

The main function of TRPA1 is the recognition of chemical and inflammatory agents, and their range is so large that almost all vital processes of our body are connected with the correct functioning of this receptor. In the respiratory system, it recognizes volatile harmful substances: tear gas, ozone, aldehydes (acrolein, components of cinnamon), organosulfur compounds (burning components of mustard, onion and garlic), causing coughing, sneezing and mucus formation. In the intestine, TRPA1 records the presence of inflammatory agents. Overactive bladder in diabetes is caused by activation of this receptor by acrolein, which accumulates in the urine. The involvement of TRPA1 in the occurrence of migraine under the influence of cigarette smoke and formaldehyde in some people has been revealed.

Acting on the receptors of sensory neurons involved in temperature perception with drugs leads to the relief of pain and inflammation. This is exactly how, not knowing about molecular targets, traditional medicine in different time used tinctures of pepper (TRPV1), mustard (TRPA1), peppermint (TRPM8) and cloves (TRPV3) to treat a number of inflammatory diseases.

Purine receptors

We have already mentioned that it is very important for the body to be aware of tissue damage. With injuries, when the integrity of organs is violated and cell death occurs, with ischemia or inflammation, ATP molecules enter the intercellular space. This coenzyme of multiple reactions provides energy for many processes in the cell; it is too valuable for the functioning of cells, therefore it is rarely thrown out of their limits. The perception of an increase in local ATP concentration is carried out by purinergic receptors (P2X), which are cation-selective ion channels, they trigger a pain response resulting from tissue destruction, organ deformation and tumor development. Sensory neurons are characterized by the P2X2 and P2X3 subtypes, an important role of the latter in the development of pain during inflammation has been shown in studies on knockout mice. It is also known that P2X receptors are of fundamental importance for many physiological processes, such as the regulation of vascular tone, taste reception, etc.

Acid receptors

To register acidity in many types of cells of the nervous system, there are so-called acid-sensitive ion channels ( acid-sensing ion channels, ASIC). It is believed that they carry out signal transmission associated with local changes in pH during normal neuronal activity in the central nervous system. However, they are also involved in pathological processes. Recently, the receptor of the ASIC1a subtype has been considered as one of the main factors of neuronal death in the central nervous system in ischemic conditions. With ischemia and hypoxia, glycolysis increases, resulting in the accumulation of lactic acid and the subsequent "acidification" of the tissue. Disabling the ASIC1a receptor induces neuroprotective effects in an ischemic model that has been shown in knockout mice. In the peripheral nervous system and tissues of internal organs, ASICs are responsible for the sensitivity to pain arising from tissue acidosis in muscles, cardiac ischemia, corneal injury, inflammation, neoplasms, and local infection. In the neurons of the peripheral nervous system, receptors of the ASIC3 subtype are mainly represented, the activity of which must also be reduced to relieve pain.

Unlike TRP receptors, P2X receptors and ASICs are trimmers (Fig. 3); assembled from three polypeptide chains. But in the same way, these receptors can be homomers and heteromers, which increases their diversity and range of functions.

How to overcome pain?

So what if we are in pain? If this pain is acute or chronic, it cannot be tolerated, and it is necessary to use pain relievers to return our nociception system to normal, and ourselves to life in the truest sense of the word. Currently, many are used for pain relief drugs various pharmacological groups... The main place in this series is occupied by non-steroidal anti-inflammatory drugs (NSAIDs), anticonvulsants and antidepressants, as well as narcotic analgesics (morphine and other opiates and opioids). Currently available analgesics affect mainly the pathways of transmission and distribution of pain. For the specific regulation of the pain receptors described above, there are no drugs on the drug market yet.

The first "painful" target for pharmaceutical companies was the TRPV1 receptor, since the sensitive neurons containing it play the role of integrators of many stimuli perceived as pain. The screening of chemical libraries and the rational design of ligands based on knowledge of the capsaicin binding site have led to the creation of a significant number of highly effective low molecular weight TRPV1 inhibitors. These compounds had an analgesic effect, but led to the development of hyperthermia - an increase in body temperature (by 1.5–3 ° C). Hyperthermia has become the main reason for the refusal of pharmacological companies to develop drugs based on complete antagonists of the TRPV1 receptor. However, if this receptor is only partially inhibited, an increase in body temperature can be avoided. And such partial inhibitors of TRPV1 we, under the leadership of Academician E.V. Grishin (1946–2016), managed to find in the venom of the sea anemone Heteractis crispa... In the venom of the anemone, three peptides were found at once that inhibit TRPV1 and do not increase body temperature [,], but the peptide called ARNS3 had the mildest effect. It has a strong analgesic effect in doses of 0.01–0.1 mg / kg of body weight and weakly lowers body temperature (by only 0.6 ° C). In terms of the strength of pain relief, it is comparable to morphine, but does not cause narcotic effects and addiction. According to preclinical studies, the peptide is fully suitable for further clinical trials, since no side effects were found in laboratory animals. Moreover, lowering body temperature is necessary, for example, to provide neuroprotection in survivors of cardiac arrest, and the hypothermic effect of the peptide may serve as an added bonus.

Working under Grishin's direction, we also discovered an inhibitor of P2X3 receptors. This also turned out to be a peptide that was given the name PT1, and it was found in the venom of a spider Alopecosa marikovskyi ... By the way, PT1 has already successfully passed laboratory and preclinical trials, so after some time it may well become one of the first fundamentally new analgesics that specifically inhibit pain receptors. For the third of the mentioned similar receptors, ASIC3, we also found an inhibitor: peptide Ugr 9-1; the source was the poison of the sea anemone Urticina grebelnyi .

Note that natural poisons often contain toxins with the opposite effect, that is, substances that activate pain receptors. From the point of view of the biology of poisonous animals, this is understandable: "pain" toxins are used by them for protection. For example, in the poison of the Chinese tarantula Haplopelma schmidti contains the strongest activator TRPV1, and from the venom of the Texas coral snake Micrurus tenerreceived activator ASIC1a. Now we have already learned how to benefit from such substances: they are used as molecular tools to "freeze" pain receptors in an activated state and to study their structure (Fig. 3) [,]. On the other hand, the discovery of useful molecules in natural poisons is also quite common, and several natural toxins (or substances created on their basis) are now used in medicine as medicines. This is where the famous dictum of the medieval alchemist Paracelsus takes on special meaning: “Everything is poison, and nothing is devoid of poisonousness; just one dose makes the poison invisible. "

Sensory neuron receptors represent a tempting yet challenging target for drug discovery. Drugs, if they have good selectivity for these receptors, will be accepted by consumers with great joy, since almost all modern facilities limited in use due to side effects. Work on the search for selective drugs is underway, including in our country, and with a favorable set of circumstances, such drugs will soon be available in pharmacies. Long life to you without pain!

This work was supported by the Russian Science Foundation (project No. 14-24-00118).

Literature
. Palermo N. N., Brown H. K., Smith D. L. Selective neurotoxic action of capsaicin on glomerular C-type terminals in rat substantia gelatinosa // Brain Res. 1981. V. 208. P. 506-510.
. O'Neill J., Brock C., Olesen A. E. et al.

Pain is the greatest evolutionary mechanism that allows humans to notice and react to danger in time. Receptors pain sensitivity - these are special cells that are responsible for receiving information, and then transmitting it to the brain in the pain center. You can read more about where these nerve cells are located and how they work in this article.

Pain

Pain is an unpleasant sensation that neurons transmit to our brain. Discomfort does not appear just like that: it signals actual or potential damage to the body. For example, if you bring your hand too close to the fire, a healthy person will immediately withdraw it. This is a powerful protective mechanism that instantly signals about possible or current problems and forces us to do everything to fix them. Pain is often indicative of specific injuries or injuries, but it can also be chronic, exhausting. In some people, pain receptors are hypersensitive, as a result of which they have a fear of any touch, as they cause discomfort.

Knowing the principle of action of nociceptors in a healthy body is necessary in order to understand what the pain syndrome is associated with, how to treat it, and what causes the excessive sensitivity of neurons. The World Health Organization has now recognized that no one should endure pain of any kind. There are many drugs on the market that can completely stop or significantly reduce pain even in cancer patients.

Why is pain needed?

Most often, pain occurs due to injury or illness. What happens in the body when, for example, we touch a sharp object? During this time, receptors on the surface of our skin recognize over-stimulation. We still do not feel pain, although the signal of it is already rushing through the synapses to the brain. After receiving the message, the brain gives a signal to act, and we withdraw our hand. This whole complex mechanism takes literally thousandths of a second, because a person's life depends on the reaction rate.

Pain receptors on the scalp are located literally everywhere, and this allows the skin to remain extremely sensitive and sensitive to the slightest discomfort. Nociceptors are able to respond to the intensity of sensations, an increase in temperature, and various chemical changes. Therefore, the expression “pain is only in your head” is true, since it is the brain that creates unpleasant sensations that make a person avoid danger.

Nociceptors

The pain receptor is a special type of nerve cells that are responsible for receiving and transmitting signals about various stimuli, which are then transmitted to the central nervous system. The receptors release chemicals called neurotransmitters, which travel at tremendous speed through the nerves, the spinal cord, to the person's main computer in the pain center. The entire signaling process is called nociception, and pain receptors, which are located in most known tissues, are called nociceptors.

The mechanism of action of nociceptors

How do pain receptors work in the brain? They are activated in response to any stimulation, be it internal or external. An example of external stimulation is a sharp pin that you accidentally touch with your finger. Internal stimulation can be caused by nociceptors located in internal organs or bones, such as osteochondrosis or curvature of the spine.

Nociceptors are membrane proteins that recognize two types of effects on the neuron membrane: physical and chemical. When human tissue is damaged, the receptors are activated, which leads to the opening of cation channels. As a result, they are excited and a pain signal is sent to the brain. Different chemicals are released depending on the type of effect on the tissue. The brain processes them and chooses a "strategy" according to which to act. In addition, pain receptors not only receive a signal and transmit it to the brain, but also release biologically active compounds. They dilate blood vessels, help attract cells of the immune system, which, in turn, help the body recover faster.

Where are they located

The whole body permeates a person from the fingertips to the abdomen. It allows you to feel and control the entire body, is responsible for the coordination and transmission of signals from the brain to various organs. This sophisticated mechanism also includes notification of trauma or any damage that begins with pain receptors. They are located in almost all nerve endings, although they are most often found in the skin, muscles and joints. They are also common in connective tissues and in the internal organs. One square centimeter of human skin contains from 100 to 200 neurons, which have the ability to respond to changes in the environment. Sometimes this amazing ability human body brings a lot of problems, but mostly it helps save lives. Although at times we want to get rid of pain and not feel anything, this sensitivity is necessary for survival.

Pain receptors in the skin are perhaps the most common. However, nociceptors can even be found in teeth and periosteum. In a healthy body, any pain is a signal of some kind of malfunction, and in no case should it be ignored.

Difference in nerve types

The science that studies the process of pain and its mechanisms is quite complex to understand. However, if we take knowledge about the nervous system as a basis, then everything can be much simpler. The peripheral nervous system is key to the human body. It goes beyond the brain and spinal cord, so with the help of it a person cannot think or breathe. But it serves as an excellent "sensor" that is able to capture the smallest changes both inside the body and outside. It consists of cranial, spinal and afferent nerves. It is the afferent nerves that are located in tissues and organs and transmit a signal to the brain about their condition. There are several types of afferent nociceptors in tissues: A-delta and C-sensory fibers.

A-delta fibers are covered with a kind of smooth protective shield, due to which they transmit pain impulses most quickly. They respond to acute and well-localized pain that requires immediate action. Such pain can include burns, wounds, trauma, and other injuries. Most often, A-delta fibers are located in soft tissues and in the muscles.

In contrast, C-sensory pain fibers are activated in response to non-intense but long-term painful stimuli that are not well localized. They are not myelinated (not covered with a smooth membrane) and therefore transmit a signal to the brain somewhat slower. Most often, these fighting fibers react to damage to internal organs.

Pain signal journey

As soon as the painful stimulus is transmitted along the afferent fibers, it must pass through the spinal horn of the spinal cord. It is a kind of repeater that sorts signals and transmits them to the appropriate sections of the brain. Some painful stimuli are transmitted directly to the thalamus or brain, allowing for a quick response in the form of action. Others are sent to the frontal cortex for further processing. It is in the frontal cortex that the conscious realization of the pain we feel arises. Because of this mechanism, during emergency situations, we do not even have time to feel unpleasant sensations in the first seconds. For example, with a burn, the worst pain occurs after a few minutes.

Brain reaction

The final step in the pain signaling process is the response from the brain, which tells the body how it needs to respond. These impulses are transmitted along the efferent cranial nerves. During the transmission of the pain signal, a variety of chemical compounds are released in the brain and spinal cord, which either decrease or increase the perception of the pain stimulus. They are called neurochemical mediators. They contain endorphins, which are natural analgesics, as well as serotonin and norepinephrine, which increase the perception of pain in humans.

Types of pain receptors

Nociceptors are divided into several types, each of which is sensitive to only one type of irritation.

• Receptors for temperature and chemical irritants. The receptor responsible for the perception of these stimuli is called TRPV1. It began to be studied back in the 20th century in order to obtain a medicine that could relieve pain. TRPV1 plays a role in cancer, respiratory diseases and many others.
• Purine receptors respond to tissue damage. In this case, ATP molecules enter the intercellular space, which in turn affect the purinergic receptors that trigger the pain stimulus.
• Acid receptors. Many cells have acid-sensitive ion channels that can respond to various chemical compounds.

The variety of types of pain receptors allows you to quickly transmit to the brain a signal about the most dangerous damage and produce the corresponding chemical compounds.

Types of pain

Why does something sometimes hurt so badly? How to get rid of pain? Mankind has been asking these questions for several centuries and now, finally, it has found the answer. There are several types of pain - acute and chronic. Acute often occurs due to tissue damage, such as a bone fracture. It can also be associated with headaches (which most of humanity suffers from). Acute pain goes away as quickly as it appears - usually immediately after the source of the pain (such as a damaged tooth) is removed.

Chronic pain is a little more complicated. Doctors still cannot completely rid their patients of the chronic injuries that have bother them for many years. Chronic pain is usually associated with long-term illness, unknown cause, cancer, or degenerative disease. One of the main co-factors of chronic pain is an unknown cause. In patients who experience pain for a long time, depression is often observed, and pain receptors are modified. The chemical reaction of the body is also disrupted. Therefore, doctors do their best to determine the source of pain, and if this is not possible, prescribe pain relievers.

Pain relievers

Pain relievers, or pain relievers, as they are sometimes called, usually work by using neurochemical mediators. If the drug inhibits the release of "secondary messengers", then pain receptors simply do not activate, with the result that the signal does not reach the brain. The same happens if the brain's response to a stimulus is neutralized. In most cases, pain relievers can only temporarily affect the situation, but cannot cure the underlying problem. All that is in their power is to prevent the person from feeling the pain associated with chronic disease or injury.

Outcome

Pain receptors in hair, lymph and blood allow the human body to quickly respond to external stimuli: temperature changes, pressure, chemical acids and tissue damage. The information activates nociceptors, which send signals through the peripheral nervous system to the brain. He, in turn, immediately reacts and sends a return impulse. As a result, we withdraw our hand from the fire before we have time to realize it, which can significantly reduce the degree of damage. Pain receptors have, perhaps, such an effect on us in emergency situations.

Pain, or nociceptive sensitivity, is the perception of stimuli that cause pain in the body.

There is currently no generally accepted concept of pain. In a narrow sense pain is an unpleasant sensation arising from the action of super-strong stimuli that cause structural and functional changes in the body.

The physiological role of pain is as follows:

1. It acts as a signal of a threat or damage to body tissues and warns them.
2. It is a factor in the mobilization of protective and adaptive reactions in case of damage to its organs and tissues
3. It has a cognitive function: through pain, a person learns from early childhood to avoid possible dangers of the external environment.
4. The emotional component of pain performs a function in the formation of conditioned stimuli even with a single combination of conditioned and unconditioned stimuli.

Causes of pain. Pain occurs when, firstly, the integrity of the protective integumentary membranes of the body (skin, mucous membranes) and internal cavities of the body ( meninges, pleura, peritoneum, etc.) and, secondly, the oxygen regime of organs and tissues to a level that causes structural and functional damage.

Pain classification.There are two types of pain:

1. Somatic, arising from damage to the skin and the musculoskeletal system. Somatic pain is divided into superficial and deep. Superficial pain is pain of skin origin, and if its source is localized in muscles, bones, and joints, it is called deep pain. Superficial pain manifests itself in tingling, tingling. Deep pain, as a rule, dull, poorly localized, tends to radiate to the surrounding structures, accompanied by discomfort, nausea, severe sweating, and a drop in blood pressure.
2. Visceral, arising from damage to internal organs and having a similar picture with deep pain.

Projection and reflected pain.There are special types of pain - projection and reflected.

As an example projection pain can lead to a sharp blow to the ulnar nerve. Such a shock causes an unpleasant, difficult to describe sensation, spreading to those parts of the arm that are innervated by this nerve. Their occurrence is based on the law of pain projection: no matter what part of the afferent pathway is irritated, pain is felt in the area of \u200b\u200bthis sensory pathway. One of the common causes of projection pain is pinching of the spinal nerves at their entry points as a result of damage to the intervertebral cartilaginous discs. Afferent impulses in nociceptive fibers with this pathology cause pain, which is projected into the area associated with the injured spinal nerve. Projection (phantom) pains also include pains felt by patients in the area of \u200b\u200bthe remote part of the limb.

Reflected pain pain sensations are called not in the internal organs from which pain signals come, but in certain parts of the skin surface (Zakharyin-Ged zone). So, with angina pectoris, in addition to pain in the region of the heart, pain is felt in the left arm and scapula. Reflected pain differs from projection pain in that it is caused not by direct stimulation of nerve fibers, but by irritation of any receptive endings. The appearance of these pains is due to the fact that the conductive pain impulses from the receptors of the affected organ and the receptors of the corresponding area of \u200b\u200bthe skin converge on the same neuron of the spinothalamic pathway. Irritation of this neuron from the receptors of the affected organ in accordance with the law of pain projection leads to the fact that pain is felt in the area of \u200b\u200bskin receptors.

Pain relief (antinociceptive) system.In the second half of the 20th century, data were obtained on the existence of a physiological system that limits the conduction and perception of pain sensitivity. Its important component is "gate control". It is carried out in the posterior columns by inhibitory neurons, which, by presynaptic inhibition, limit the transmission of pain impulses along the spinothalamic pathway.

A number of brain structures have a descending activating effect on the inhibitory neurons of the spinal cord. These include the central gray matter, suture nuclei, macula blue, lateral reticular nucleus, paraventricular and preoptic nuclei of the hypothalamus. The somatosensory area of \u200b\u200bthe cortex unites and controls the activity of the structures of the analgesic system. Violation of this function can cause unbearable pain.

The most important role in the mechanisms of the analgesic function of the central nervous system is played by the endogenous opiate system (opiate receptors and endogenous stimulants).

Endogenous stimulants of opiate receptors are enkephalins and endorphins. Some hormones, such as corticoliberin, can produce them. Endorphins act mainly through morphine receptors, which are especially abundant in the brain: in the central gray matter, suture nuclei, and middle thalamus. Enkephalins act through receptors located primarily in the spinal cord.

Pain theories.There are three theories of pain:

1. Intensity theory ... According to this theory, pain is not a specific feeling and does not have its own special receptors, but arises from the action of superstrong stimuli on the receptors of five. The formation of pain involves the convergence and summation of impulses in the spinal cord and brain.
2. Specificity theory ... In accordance with this theory, pain is a specific (sixth) sense that has its own receptor apparatus, afferent pathways and brain structures that process pain information.
3. Modern theory pain relief is based primarily on the theory of specificity. The existence of specific pain receptors has been proven.

However, in modern theory For pain, the position on the role of central summation and convergence in pain mechanisms was used. The most important achievement in the development of the modern theory of pain is the study of the mechanisms of central pain perception and the pain relief system of the body.

Pain receptors (nocireceptors)

Pain receptors are free endings of sensitive myelin and myelin-free nerve fibers located in the skin, mucous membranes, periosteum, teeth, muscles, chest and abdominal and other organs and tissues. The number of nocireceptors in human skin is approximately 100-200 per sq. see skin surface. The total number of such receptors reaches 2-4 million. The following main types of pain receptors are distinguished:

1. Mechanonocyceptors: respond to strong mechanical ones, conduct rapid pain and quickly adapt.
2. Mechanothermal nociceptors: respond to strong mechanical and thermal (more than 40 degrees) stimuli, conduct rapid mechanical and thermal pain, quickly adapt.
3. Polymodal nociceptors: respond to mechanical, thermal and chemical stimuli, conduct poorly localized pain, adapt slowly.

Pathways of pain sensitivity. Pain sensitivity of the trunk and extremities, internal organs, from the receptors of which the fibers of the first neurons depart, are located in the spinal nodes. The axons of these neurons enter the spinal cord and switch to second neurons located in the posterior horns. Part of the painful impulses of the first neurons is switched to flexor motor neurons and is involved in the formation of protective pain reflexes. The main part of pain impulses (after switching in the posterior horns) enters the ascending pathways, among which the main ones are the lateral spinothalamic and spinal-reticular ones.

Pain sensitivity of the face and oral cavity is transmitted through the fibers of the first neurons of the trigeminal ganglion, which switch to the second neurons, located mainly in the spinal nucleus (from) and pontine nucleus (from receptors of muscles, joints) trigeminal nerve... Pain impulses from these nuclei are carried out along the bulbothalamic pathways. Along these paths, part of the pain sensitivity from the internal organs along the afferent fibers of the vagus and glossopharyngeal nerves is carried out into the nucleus of a solitary pathway.

Thus, pain is transmitted to the brain using two systems - medial and lateral.

The medial system runs through the central regions of the brain. It is responsible for persistent pain, transmits signals to the limbic system, which is involved in the emotional. It is this medial system that provides the emotional component of pain, which is expressed in such characteristics as “terrible”, “unbearable”, etc. The medial system consists mainly of small fibers and ends in the thalamus. This system transmits signals slowly, not adapted to accurately and quickly transmit information about strong stimuli in critical situations. It conveys diffuse discomfort.

The lateral pain system consists of nerve tracts that project into the somatosensory cortex of the brain. It is most active with sudden, sharp (phasic) pain, pain with a pronounced localization. The lateral pathways are responsible for the sensory quality of pain, i.e. the nature of the sensation - throbbing pain, prick, burning, etc. The activity of the lateral system quickly dies out, therefore phasic pain is short-lived, it is subjected to powerful inhibition from other structures.

The role of brain structures in pain formation

Frontal cortex provides self-assessment of pain (its cognitive component) and the formation of purposeful pain behavior. (Cutting the connections between the frontal cortex and the thalamus - lobotomy - preserves pain in patients, but it does not bother them).

Table of contents of the subject "Temperature sensitivity. Visceral sensitivity. Visual sensory system.":
1. Temperature sensitivity. Heat receptors. Cold receptors. Temperature perception.
2. Pain. Pain sensitivity. Nociceptors. Pain pathways. Pain assessment. The gate of pain. Opiate peptides.
3. Visceral sensitivity. Visceroceptors. Visceral mechanoreceptors. Visceral chemoreceptors. Visceral pain.
4. Visual sensory system. Visual perception. Projection of light rays onto the retina. Optical system of the eye. Refraction.
5. Accommodation. Closest point of clear vision. Accommodation range. Presbyopia. Age-related hyperopia.
6. Anomalies of refraction. Emmetropia. Nearsightedness (myopia). Farsightedness (hyperopia). Astigmatism.
7. Pupillary reflex. Projection of the visual field onto the retina. Binocular vision. Convergence of eyes. Divergence of the eyes. Transverse disparity. Retinotopia.
8. Eye movements. Tracking eye movements. Rapid eye movements. Central fossa. Saccadams.
9. Conversion of light energy in the retina. Functions (tasks) of the retina. Blind spot.
10. Scotopic retinal system (night vision). Retinal photopic system (day vision). Retinal cones and rods. Rhodopsin.

Pain. Pain sensitivity. Nociceptors. Pain pathways. Pain assessment. The gate of pain. Opiate peptides.

Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Unlike other sensory modalities, pain is always subjectively unpleasant and serves not so much as a source of information about the world around us, but as a signal of injury or illness. Pain sensitivity encourages the termination of contact with damaging environmental factors.

Pain receptors or nociceptors are free nerve endings located in the skin, mucous membranes, muscles, joints, periosteum and internal organs. Sensory endings belong to either non-fleshy or thin myelinated fibers, which determines the speed of signal conduction in the central nervous system and gives rise to the distinction between early pain, short and acute, arising when impulses are conducted at a higher speed along the myelin fibers, as well as late, dull and prolonged pain, in the case of conducting signals along non-fleshy fibers. Nociceptors refer to polymodal receptors, since they can be activated by stimuli of a different nature: mechanical (impact, cut, prick, pinch), thermal (action of hot or cold objects), chemical (change in the concentration of hydrogen ions, the action of histamine, bradykinin and a number of other biologically active substances) ... Nociceptor sensitivity threshold is high, therefore, only sufficiently strong stimuli cause excitation of primary sensory neurons: for example, the threshold of pain sensitivity for mechanical stimuli is about a thousand times higher than the threshold for tactile sensitivity.

The central processes of primary sensory neurons enter the spinal cord as part of the dorsal roots and form synapses with second-order neurons located in the dorsal horns of the spinal cord. Axons of second-order neurons move to the opposite side of the spinal cord, where they form the spinothalamic and spinoreticular tracts. Spinothalamic tract ends on the neurons of the lower posterolateral nucleus of the thalamus, where there is a convergence of the pathways of pain and tactile sensitivity. Thalamus neurons form a projection onto the somatosensory cortex: this pathway provides a conscious perception of pain, allows you to determine the intensity of the stimulus and its localization.

Fiber spinoreticular tract end on neurons reticular formationinteracting with the medial nuclei of the thalamus. With painful stimulation, neurons of the medial nuclei of the thalamus exert a modulating effect on vast regions of the cortex and structures of the limbic system, which leads to an increase in human behavioral activity and is accompanied by emotional and autonomic reactions. If the spinothalamic pathway serves to determine the sensory qualities of pain, then the spinoreticular pathway is intended to play the role of a general alarm signal, to exert a general arousal effect on a person.

Subjective pain assessment determines the ratio of the neuronal activity of both pathways and the dependent on it activation of antinociceptive descending pathways that can change the nature of signal transmission from nociceptors... IN sensory system pain sensitivity an endogenous mechanism of its reduction is built in by regulating the threshold of synaptic switching in the posterior horns of the spinal cord (“ gate of pain"). The transmission of excitation in these synapses is influenced by the descending fibers of neurons of the gray matter around the aqueduct, the blue spot and some nuclei of the median suture. The mediators of these neurons (enkephalin, serotonin, norepinephrine) inhibit the activity of second-order neurons in the posterior horns of the spinal cord, thereby reducing the conduction of afferent signals from nociceptors.

Analgesic (pain relievers) have an action opiate peptides (dynorphin, endorphins), synthesized by the neurons of the hypothalamus, which have long processes that penetrate into other parts of the brain. Opiate peptides attach to specific receptors of the neurons of the limbic system and the medial region of the thalamus, their formation increases with some emotional states, stress, prolonged physical activity, in pregnant women shortly before childbirth, as well as as a result of psychotherapeutic influence or acupuncture... As a result of increased education opiate peptides antinociceptive mechanisms are activated and the pain threshold is increased. The balance between the sensation of pain and its subjective assessment is established with the help of the frontal areas of the brain involved in the process of perception of painful stimuli. On defeat frontal lobes (for example, as a result of injury or tumor) pain threshold does not change and therefore the sensory component of pain perception remains unchanged, but the subjective emotional assessment of pain becomes different: it begins to be perceived only as a sensory sensation, and not as suffering.

Superficial tissues are supplied with nerve endings of various afferent fibers. Thickest, myelinated Aβ fibershave tactile sensitivity. They are excited by non-painful touching and moving. These endings can serve as polymodal nonspecific pain receptors only under pathological conditions, for example, due to an increase in their sensitivity (sensitization) by inflammatory mediators. Mild irritation of polymodal nonspecific tactile receptors leads to an itching sensation. The threshold of their excitability is lowered histamineand serotonin.

Specific primary pain receptors (nonireceptors) are two other types of nerve endings - thin myelinated Аδ-terminals and thin unmyelinated C-fibersare phylogenetically more primitive. Both of these types of terminals are present in both surface tissues and internal organs. Nocireceptors give a feeling of pain in response to a variety of intense stimuli - mechanical action, thermal signal, etc. Ischemia always causes pain because it provokes acidosis. Muscle spasm can cause irritation of painful endings due to relative hypoxia and ischemia, which it causes, as well as due to direct mechanical displacement of nocireceptors. It is carried out along C-fibers at a speed of 0.5-2 m / s slow, protopathic pain, and for myelinated, fast-conducting Aδ-fibers, providing a conduction speed from 6 to 30 m / s, - epicritical pain... In addition to the skin, where, according to A.G. Bukhtiyarov, there are at least 100-200 pain receptors per 1 cm, mucous membranes and the cornea, the periosteum is abundantly supplied with pain receptors of both types, as well as vascular walls, joints, cerebral sinuses and parietal sheets serous membranes... There are much fewer pain receptors in the visceral sheets of these membranes and internal organs.

Pain in neurosurgical operations is maximal at the time of dissection of the meninges, while the cerebral cortex has very little and strictly local pain sensitivity. In general, such a common symptom as headache is almost always associated with irritation of pain receptors outside the brain tissue itself. The extracranial cause of headache can be processes localized in the sinuses of the head bones, spasm of the ciliary and other eye muscles, tonic tension of the muscles of the neck and scalp. Intracranial causes of headache are primarily irritation of the nocireceptors of the meninges. With meningitis, violent headaches cover the whole head. Very serious headache causes irritation of nocireceptors in the cerebral sinuses and arteries, especially in the middle cerebral artery basin. Even minor losses of cerebrospinal fluid can provoke headaches, especially in upright position body, because the buoyancy of the brain changes, and when the hydraulic cushion decreases, the pain receptors of its membranes are irritated. On the other hand, an excess of cerebrospinal fluid and a violation of its outflow during hydrocephalus, cerebral edema, its swelling during intracellular hyperhydration, plethora of the vessels of the meninges caused by cytokines during infections, local volumetric processes - also provoke a headache, because this increases the mechanical effect on pain receptors of the structures surrounding the brain itself.

Pain receptors claim a unique position in the human body. It is the only type of sensory receptor that does not undergo any adaptation or desensitization under the influence of a continuous or repetitive signal. In this case, nocireceptors do not exceed the threshold of their excitability, like, for example, cold sensors. Therefore, the receptor does not "get used" to the pain. Moreover, in nocireceptive nerve endings, the opposite phenomenon takes place - sensitization of pain receptors by a signal... With inflammation, tissue damage and with repeated and prolonged painful stimuli, the threshold for pain excitability of nocireceptors decreases. Calling pain sensors receptors, it must be emphasized that the application of this term to them is conditional - after all, these are free nerve endings, devoid of any special receptor adaptations.

The neurochemical mechanisms of irritation of nocireceptors are well understood. Their main stimulant is bradykinin... In response to damage to cells near the nocireceptor, this mediator is released, as well as prostaglandins, leukotrienes, potassium and hydrogen ions... Prostaglandins and leukotrienes sensitize nocireceptors to kinins, while potassium and hydrogen facilitate their depolarization and the appearance of an electrical afferent pain signal in them. Excitation spreads not only afferently, but also antidromically, to the adjacent branches of the terminal. There it leads to secretion substance P... This neuropeptide causes hyperemia, edema, degranulation of mast cells and platelets around the terminal paracrine way. Released in this case histamine, serotonin, prostaglandins sensitize nocireceptors, and chymase and tryptase of mast cells enhance the production of their direct agonist - bradykinin.Therefore, when damaged, nocireceptors act as sensors, and as paracrine inflammatory provocateurs. Near nocireceptors, as a rule, there are sympathetic noradrenergic postganglionic nerve endings, which are able to modulate the sensitivity of nocireceptors.

With injuries of peripheral nerves, it often develops like this called causalgia - a pathologically increased sensitivity of nociceptors in the area innervated by the damaged nerve, accompanied by burning pains and even signs of inflammation without visible local damage. The mechanism of causalgia is associated with the hyperalgizing effect of sympathetic nerves, in particular, the norepinephrine secreted by them, on the state of pain receptors. It is possible that in this case the secretion of substance P and other neuropeptides by sympathetic nerves occurs, which causes inflammatory symptoms.

5.2. Endogenous pain modulation system.

In the control of the excitability of neurons that transmit pain impulses to the central nervous system, mainly opiatergic, serotoninergic and noradrenergic effects are involved. Anatomically, the structures where the elements of the modulating system are concentrated are the thalamus, the gray matter in the circumference of the Sylvian aqueduct, the suture nucleus, the gel-like substance of the spinal cord and the nucleus tractus solitarii.

Input signals from the frontal cortex and hypothalamus can activate enkephalinergic neurons around the Sylvia aqueduct, in the midbrain and pons. From them, excitement descends to the large nucleus of the suture, penetrating the lower part of the bridge and the upper - the medulla oblongata. The neurotransmitter in the neurons of this nucleus is serotonin... The anti-pain central effect of serotonin is associated with its antidepressant and anti-anxiety effects.

The nucleus of the suture and the rostventricular neurons of the medulla oblongata, close to it, conduct antinocireceptive signals to the posterior horns of the spinal cord, where they are perceived by the substantia grisea enkephalinergic neurons. Enkephalin produced by these inhibitory neurons mediates presynaptic inhibition on afferent pain fibers. Thus, enkephalin and serotonin transmit the pain signaling relay to each other... That is why morphine and its analogs, as well as agonists and blockers of serotonin uptake, have taken an important place in anesthesiology. Not only both types of pain sensitivity are blocked. Inhibition extends to protective painful spinal reflexes, and it is carried out at the supraspinal level. Opiatergic systems inhibit stressor activity in the hypothalamus (β-endorphin is the most important here), inhibit the activity of anger centers, activate the reward center, cause a change in the emotional background through the limbic system, suppressing negative pain emotional correlates and lowering the activating effect of pain on all parts of the central nervous system.

Endogenous opioids via cerebrospinal fluid can enter the systemic circulation for endocrine regulation, which suppresses systemic responses to pain.

All ways of spreading neuropeptides constitute the so-called transventricular pathway of hypothalamic regulation.

Depression accompanied by a decrease in the production of opiates and serotonin is often characterized by an exacerbation of pain sensitivity... Enkephalins and cholecystokinin are peptide co-transmitters in dopaminergic neurons. It is well known that dopaminergic hyperactivity in the limbic system is one of the pathogenetic features of schizophrenia.