Physiology of pain and pain sensitivity. Pain, inflammation and other troubles: the reverse side of sensations Large raphe nucleus, located in the midline between the bridge and the medulla oblongata; reticular paragiant cell nucleus

Physiology of pain

In the narrow sense of the word, pain is an unpleasant sensation that occurs under the action of superstrong stimuli that cause structural and functional disorders in the body. Pain differs from other sensations in that it does not inform the brain about the quality of the stimulus, but indicates that the stimulus is damaging. Another feature of pain sensory system is its most complex and powerful efferent control.

The pain analyzer launches several programs of the body's response to pain in the central nervous system. Therefore, pain has several components. The sensory component of pain characterizes it as an unpleasant, painful sensation; affective component - as a strong negative emotion; the motivational component as a negative biological need that triggers the body's behavior aimed at recovery. The motor component of pain is represented by various motor reactions: from unconditioned flexion reflexes to motor programs of anti-pain behavior. The vegetative component characterizes the dysfunction internal organs and metabolism in chronic pain. The cognitive component is associated with self-assessment of pain, while pain acts as suffering. During the activity of other systems, these components are weakly expressed.

The biological role of pain is determined by several factors. Pain plays the role of a signal about the threat or damage to body tissues and warns them. Pain has a cognitive function: a person learns through pain to avoid possible dangers of the external environment. The emotional component of pain performs the function of reinforcement in the formation of conditioned reflexes. Pain is a factor in the mobilization of protective and adaptive reactions of the body in case of damage to its tissues and organs.

There are two types of pain - somatic and visceral. Somatic pain is divided into superficial and deep. Superficial pain can be early (fast, epic) and late (slow, protopathic).

There are three theories of pain.

1. The intensity theory was proposed by E. Darwin and A. Goldsteiner. According to this theory, pain is not a specific feeling and does not have its own special receptors. It arises under the action of superstrong stimuli on the receptors of the five known sense organs. Convergence and summation of impulses in the spinal cord and brain are involved in the formation of pain.

2. The theory of specificity was formulated by the German physiologist M. Frey. According to this theory, pain is a specific feeling that has its own receptor apparatus, afferent fibers and brain structures that process pain information. This theory later received more complete experimental and clinical confirmation.

3. The modern theory of pain is based primarily on the theory of specificity. The existence of specific pain receptors has been proven. At the same time, in the modern theory of pain, the position on the role of central summation and convergence in the mechanisms of pain is used. The most significant achievements of modern pain theory are the development of mechanisms for the central perception of pain and the launch of the body's anti-pain system.

pain receptors

Pain receptors are free endings of sensitive myelinated nerve fibers Aδ and non-myelinated fibers C. They are found in the skin, mucous membranes, periosteum, teeth, muscles, joints, internal organs and their membranes, vessels. They are not found in the nervous tissue of the brain and spinal cord. Their greatest density is at the border of dentin and tooth enamel.

There are the following main types of pain receptors:

1. Mechanociceptors and mechanothermal nociceptors of Aδ fibers respond to strong mechanical and thermal stimuli, conduct rapid mechanical and thermal pain, quickly adapt; located mainly in the skin, muscles, joints, periosteum; their afferent neurons have small receptive fields.

2. Polysensory nociceptors of C-fibers respond to mechanical, thermal and chemical stimuli, conduct late poorly localized pain, slowly adapt; their afferent neurons have large receptive fields.

Pain receptors are excited by three types of stimuli:

1. Mechanical irritants that create a pressure of more than 40 g / mm 2 when squeezing, stretching, bending, twisting.

2. Thermal stimuli can be thermal (> 45 0 C) and cold (< 15 0 С).

3. Chemical stimuli released from damaged tissue cells, mast cells, platelets (K +, H +, serotonin, acetylcholine, histamine), blood plasma (bradykinin, kallidin) and nociceptive neuron endings (substance P). Some of them excite nociceptors (K + , serotonin, histamine, bradykinin, ADP), others sensitize them.

Properties of pain receptors: pain receptors have a high threshold of excitation, which ensures their response only to extreme stimuli. C-afferent nociceptors are poorly adapted to long-acting stimuli. It is possible to increase the sensitivity of pain receptors - a decrease in the threshold of their irritation with repeated or prolonged stimulation, which is called hyperalgesia. At the same time, nociceptors are able to respond to subthreshold stimuli, as well as to be excited by stimuli of other modalities.

Pathways of pain sensitivity

Neurons that receive pain impulses. From the pain receptors of the trunk, neck and limbs Aδ- and C-fibers of the first sensitive neurons (their bodies are located in spinal ganglia) are included in spinal nerves and enter through the posterior roots into spinal cord, where they branch out in the posterior columns and form synaptic connections directly or through interneurons with second sensory neurons, the long axons of which are part of the spinothalamic pathways. At the same time, they excite two types of neurons: some neurons are activated only by painful stimuli, while others - convergent neurons - are also excited by non-painful stimuli. The second neurons of pain sensitivity are predominantly part of the lateral spinothalamic pathways, which conduct most of the pain impulses. At the level of the spinal cord, the axons of these neurons pass to the side opposite to the stimulation, in the brainstem they reach the thalamus and form synapses on the neurons of its nuclei. Part of the pain impulses of the first afferent neurons are switched through the interneurons to the motoneurons of the flexor muscles and participate in the formation of protective pain reflexes. In the lateral spinothalamic pathway, the evolutionarily younger neospinothalamic pathway and the ancient paleospinothalamic pathway are distinguished.

The neospinothalamic pathway conducts pain signals along Aδ fibers mainly to specific sensory (ventral posterior) nuclei of the thalamus, which have a good topographic projection of the body periphery. In addition, a small part of the impulses enters the reticular formation of the trunk and further into the nonspecific nuclei of the thalamus. The transmission of excitation in the synapses of this pathway is carried out with the help of a fast-acting mediator glutamate. From the specific nuclei of the thalamus, pain signals are transmitted mainly to the sensory cortex of the cerebral hemispheres. These features form the main function of the neospinothalamic pathway - the conduction of "fast" pain and the perception of it with a high degree of localization.

The paleospinothalamic pathway conducts pain signals along C-fibers mainly to the nonspecific nuclei of the thalamus directly or after switching in the neurons of the reticular formation of the brainstem. The transmission of excitation in the synapses of this pathway occurs more slowly. The mediator is substance R. From nonspecific nuclei, impulses enter the sensory and other parts of the cerebral cortex. A small part of the impulse also enters the specific nuclei of the thalamus. Basically, the fibers of this pathway terminate on neurons of 1) nonspecific nuclei of the thalamus; 2) reticular formation; 3) central gray matter; 4) blue spot; 5) hypothalamus. Through the paleospinothalamic path, “late”, poorly localized pain is passed, affective-motivational manifestations of pain sensitivity are formed.

In addition, pain sensitivity is partially conducted along other ascending tracts: the anterior spinothalamic, subtle and sphenoid tracts.

The above paths also conduct other types of sensitivity: temperature and tactile.

The role of the cerebral cortex in the perception of pain

A full sensory perception of pain by the body is impossible without the participation of the cerebral cortex.

The primary projection field of the pain analyzer is located in the somatosensory cortex of the posterior central gyrus. It provides the perception of "fast" pain and identification of the place of its occurrence on the body. For a more accurate identification of the localization of pain, neurons of the motor cortex of the anterior central gyrus are necessarily included in the process.

The secondary projection field is located in the somatosensory cortex at the border of the intersection of the central sulcus with the upper edge of the temporal lobe. The neurons of this field have bilateral connections with the nuclei of the thalamus, which allows this field to selectively filter pain excitations passing through the thalamus. And this, in turn, allows this field to be involved in the processes associated with retrieving the engram of the necessary behavioral act from memory, its implementation in the activity of effectors and assessing the quality of the achieved useful result. The motor components of pain behavior are formed in the joint activity of the motor and premotor cortex, the basal ganglia, and the cerebellum.

The frontal cortex plays an important role in the perception of pain. It provides self-assessment of pain (its cognitive component) and the formation of purposeful pain behavior.

The limbic system (cingulate gyrus, hippocampus, dentate gyrus, amygdala complex of the temporal lobe) receives pain information from the anterior nuclei of the thalamus and forms the emotional component of pain, triggers vegetative, somatic and behavioral reactions that provide adaptive reactions to a painful stimulus.

Some types of pain

There are pains that are named projection or phantom. 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 region of the receptors of this sensory pathway. According to modern data, all parts of the pain sensory system are involved in the formation of this type of pain sensation.

There are also so-called reflected pain: when pain is felt not only in the affected organ, but also in the corresponding dermatome of the body. Areas of the body surface of the corresponding dermatome, where the sensation of pain occurs, called Zakharyin - Geda zones. The occurrence of reflected pain is due to the fact that neurons that conduct pain impulses from the receptors of the affected organ and skin of the corresponding dermatome 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 also felt in the area of ​​skin receptors.

Antinociceptive system

The anti-pain system consists of four levels: spinal, stem, hypothalamic and cortical.

1. Spinal level of the antinociceptive system. Its important component is the “gate control” of the spinal cord, the concept of which has the following main provisions: the transmission of pain nerve impulses from the first neurons to the neurons of the spinothalamic pathways (second neurons) in the posterior columns of the spinal cord is modulated by the spinal gate mechanism - inhibitory neurons located in the gelatinous substance spinal cord. Branching of axons of various sensory pathways ends on these neurons. In turn, the neurons of the gelatinous substance exert presynaptic inhibition at the switching points of the first and second neurons of pain and other sensory pathways. Some neurons are convergent: neurons form synapses on them not only from pain receptors, but also from other receptors. Spinal gate control is regulated by the ratio of impulses coming through afferent fibers of large diameter (non-pain sensitivity) and small diameter (pain sensitivity). An intense flow of impulses along large-diameter fibers limits the transmission of pain signals to the neurons of the spinothalamic pathways (closing the “gates”). On the contrary, an intense flow of pain impulses along the first afferent neuron, by inhibiting inhibitory interneurons, facilitates the transmission of pain signals to neurons of the spinothalamic pathways (opens the "gate"). The spinal gate mechanism is under the constant influence of nerve impulses of the brainstem structures, which are transmitted along descending pathways both to the neurons of the gelatinous substance and to the neurons of the spinothalamic pathways.

2. Stem level of the antinociceptive system. The stem structures of the analgesic system include, firstly, the central gray matter and the raphe nuclei, which form a single functional block, and secondly, the large and paragiant cell nuclei of the reticular formation and the blue spot. First complex blocks the passage of pain impulses at the level of relay neurons of the nuclei of the posterior horns of the spinal cord, as well as relay neurons of the sensory nuclei of the trigeminal nerve, which form ascending pathways of pain sensitivity. The second complex excites almost the entire antinociceptive system (see Fig. 1).

3. The hypothalamic level of the antinociceptive system, on the one hand, functions independently, and on the other hand, it acts as a setting that controls and regulates the antinociceptive mechanisms of the stem level due to the connections of hypothalamic neurons of different nuclear affiliation and different neurochemical specificity. Among them, neurons were identified, in the endings of the axons of which enkephalins, β-endorphin, noradrenaline, dopamine are released (see Fig. 2).

4. Cortical level of the antinociceptive system. The somatosensory area of ​​the cerebral cortex unites and controls the activity of antinociceptive structures of various levels. The most important role in the activation spinal and stem structures plays a secondary sensory area. Its neurons form the largest number fibers of downward control of pain sensitivity, heading to the posterior horns of the spinal cord and the nuclei of the brain stem. The secondary sensory cortex modifies the activity of the stem complex of the antinociceptive system. In addition, the somatosensory fields of the cerebral cortex control the conduction of afferent pain impulses through the thalamus. In addition to the thalamus, the cerebral cortex regulates the passage of pain impulses in the hypothalamus, limbic system, reticular formation, and spinal cord. The leading role in providing cortico-hypothalamic influences is given to the neurons of the frontal cortex.

Mediators of the antinociceptive system

Mediators of the analgesic system include peptides that are formed in the brain, adenohypophysis, adrenal medulla, gastrointestinal tract, placenta from inactive precursors. Now opiate mediators of the antinociceptive system include: 1) ά-, β-, γ-endorphins; 2) enkephalins; 3) dynorphins. These mediators act on three types of opiate receptors: μ-, δ-, κ-receptors. The most selective stimulator of μ-receptors are endorphins, δ-receptors - enkephalins, and κ-receptors - dynorphins. The density of μ- and κ-receptors is high in the cerebral cortex and in the spinal cord, medium - in the brain stem; the density of δ-receptors is average in the cerebral cortex and spinal cord, low - in the brain stem. Opioid peptides inhibit the action of pain-causing substances at the level of nociceptors, reduce the excitability and conduction of pain impulses, and inhibit the evoked reaction of neurons that are part of the chains that transmit pain impulses. These peptides are delivered to the neurons of the pain sensory system with blood and cerebrospinal fluid. Opioid mediators are released in the synaptic endings of neurons of the analgesic system. The analgesic effect of endorphins is high in the brain and spinal cord, the effect of enkephalins in these structures is average, the effect of dynorphins in the brain is low, and in the spinal cord it is high.

Fig.1. The interaction of the main elements of the pain relief system of the first level: the brainstem - the back of the brain. (light circles are excitatory neurons, black circles are inhibitory).

Fig.2. The mechanism of the second-level analgesic system of the body (hypothalamus - thalamus - brain stem) with the help of opioids.

Light circles are excitatory neurons, black circles are inhibitory.

The severity of pain sensation is not determined by the strength of exogenous or endogenous pain effects alone. In many ways, it depends on the ratio of the activities of the nociceptive and antinociceptive parts of the pain system, which has an adaptive value.

Pain is the greatest evolutionary mechanism that allows a person to notice danger in time and respond to it. Pain receptors 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 transmitted to our brain by neurons. Discomfort appears for a reason: it signals actual or potential damage in the body. For example, if you bring your hand too close to the fire, healthy man pulls it off right away. This is a powerful defense mechanism that instantly signals possible or ongoing problems and forces us to do everything to fix them. Pain is often indicative of a specific injury or injury, but it can also be chronic and debilitating. In some people, pain receptors are hypersensitive, as a result of which they develop 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 also what reasons cause excessive sensitivity of neurons. The World Health Organization has now recognized that no human being 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? At this time, receptors located on the surface of our skin recognize excessive stimulation. We do not yet feel pain, although the signal about it is already rushing through the synapses to the brain. Having received 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 speed of the reaction.

Pain receptors on the hairline 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, temperature rise, as well as various chemical changes. Therefore, the expression "pain is only in your head" is true, since it is the brain that forms discomfort causing a person to avoid danger.

Nociceptors

The pain receptor is a special type nerve cells, which are responsible for receiving and transmitting signals about various stimulations, which are then transmitted to the central nervous system. The receptors release chemicals called neurotransmitters that travel at great speed through the nerves, the spinal cord, to the human's main "computer" in the pain center. The whole process of signaling 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 in the brain work? They are activated in response to some kind of stimulation, be it internal or external. An example of external stimulation is a sharp pin that you accidentally touched with your finger. Internal stimulation can be caused by nociceptors located in the internal organs or bones, for example, osteochondrosis or curvature of the spine.

Nociceptors are membrane proteins that recognize two types of action on the neuron membrane: physical and chemical. When human tissues are 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. Depending on what kind of effect is exerted on the tissue, different chemicals are released. The brain processes them and chooses a “strategy” to follow. In addition, pain receptors not only receive a signal and transmit it to the brain, but also secrete it biologically. active compounds. They dilate blood vessels, help attract cells immune system which, in turn, help the body recover faster.

Where are they located

A person permeates the entire body from the fingertips to the abdomen. It allows you to feel and control the whole body, is responsible for the coordination and transmission of signals from the brain to various organs. This complex mechanism also includes notification of injury or any damage, which 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 internal organs. On one square centimeter of human skin, there are from 100 to 200 neurons that have the ability to respond to changes in environment. Sometimes this amazing ability human body brings a lot of problems, but mostly helps save lives. Although at times we want to be free of pain and not feel anything, this sensitivity is necessary for survival.

Pain receptors of the skin are perhaps the most widespread. However, nociceptors can be found even in the 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 difficult to understand. However, if we take knowledge of the nervous system as a basis, then everything can be much simpler. The peripheral nervous system is the 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", which is able to catch 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 screen, due to which they transmit pain impulses the fastest. 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.

C-sensory pain fibers, on the contrary, are activated in response to non-intense, but long-term pain stimuli that do not have a clear localization. They are not myelinated (not covered with a smooth membrane) and therefore transmit a signal to the brain somewhat more slowly. Most often, these combat fibers react to damage to internal organs.

Pain signal journey

Once a noxious stimulus is transmitted along the afferent fibers, it must pass through the dorsal horn of the spinal cord. This is a kind of repeater that sorts the signals and transmits them to the appropriate sections of the brain. Some pain stimuli are transmitted directly to the thalamus or brain, allowing for a quick action response. 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 occurs. Because of this mechanism, during emergency situations, we do not even have time to feel discomfort in the first seconds. For example, in case of a burn strong pain comes in a few minutes.

brain reaction

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

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 stimuli. The receptor responsible for the perception of these stimuli has been named TRPV1. It began to be studied in the 20th century in order to obtain a medicine that can relieve pain. TRPV1 plays a role in oncology, diseases respiratory tract and many others.
• Purine receptors respond to tissue damage. At the same time, ATP molecules enter the intercellular space, which in turn affect purinergic receptors that trigger a painful stimulus.
• acid receptors. Many cells have acid-sensitive ion channels that can respond to various chemical compounds.

A variety of types of pain receptors allows you to quickly send a signal to the brain about the most dangerous damage and produce the appropriate chemical compounds.

Types of pain

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

With chronic pain, the situation is somewhat more complicated. Doctors still cannot completely rid their patients of chronic injuries that have been bothering them for many years. Chronic pain is usually associated with long-term illness, unknown causes, cancer, or degenerative diseases. One of the main contributing factors chronic pain- 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 disturbed. Therefore, doctors do everything possible to determine the source of pain, and if this is not possible, they prescribe painkillers.

Painkillers

Painkillers, or painkillers, as they are sometimes called, usually work with the help of neurochemical mediators. If the drug inhibits the release of "second messengers", then the pain receptors are simply not activated, as a result of which the signal does not reach the brain. The same thing happens if the reaction of the brain in response to the stimulus is neutralized. In most cases, painkillers can only temporarily affect the situation, but cannot cure the underlying problem. All that is in their power is not to let a person feel the pain associated with chronic disease or injury.

Results

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

Pain receptors (nociceptors) respond to stimuli that threaten the body with damage. There are two main types of nociceptors: Adelta-mechano-nociceptors and polymodal C-nociceptors (there are several other types). As their name implies, mechano-nociceptors are innervated by thin myelinated fibers, while polymodal C-nociceptors are innervated by unmyelinated C-fibers. Adelta-mechanociceptors respond to strong mechanical irritation of the skin, such as a prick with a needle or a pinch with tweezers. They usually do not respond to thermal and chemical noxious stimuli unless they have been previously sensitized. In contrast, polymodal C-nociceptors respond to pain stimuli different kind: mechanical, temperature (Fig. 34.4) and chemical.

For many years it was not clear whether pain results from the activation of specific fibers or from overactivity of sensory fibers that normally have other modalities. The latter possibility seems to be more in line with our common experience. With the possible exception of the sense of smell, any excessive sensory stimulus—blinding light, ear-tearing sound, hard blow, heat or cold outside of the normal range—results in pain. This common sense view was proclaimed by Erasmus Darwin in the late 18th century and by William James in the late 19th century. Common sense, however, here (as elsewhere) leaves much to be desired. At present, there is little doubt that in most cases the sensation of pain arises as a result of excitation of specialized nociceptive fibers. Nociceptive fibers do not have specialized endings. They are present as free nerve endings in the dermis of the skin and elsewhere in the body. Histologically, they are indistinguishable from C-mechanoreceptors (MECHANOSENSITIVITY) and - and A-delta thermoreceptors (chapter THERMOSENSITIVITY). They differ from the mentioned receptors in that the threshold for their adequate stimuli is above the normal range. They can be subdivided into several different types according to the criterion of which sensory modality represents an adequate stimulus for them. Painful thermal and mechanical stimuli are detected by small diameter myelinated fibers, Table 2.2 shows that they are category A delta fibers. Polymodal fibers that respond to a wide variety of stimulus intensities of different modalities also have a small diameter but are not myelinated. Table 2.2 shows that these fibers are class C. A delta fibers conduct impulses with a frequency of 5-30 m / s and are responsible for "quick" pain, a sharp stabbing sensation; C-fibers are slower - 0.5 - 2 m / s and signal a "slow" pain, often prolonged and often turning into dull pain. AMTs (mechano-thermo-nociceptors with A delta fibers) are divided into two types. Type 1 AMTs are mainly found in non-hairy skin. Type 2 AMTs are found primarily in hairy skin. Finally, C-fiber nociceptors (CMT fibers) have a threshold in the range of 38°C - 50°C and respond with a constant activity that depends on the intensity of the stimulus (Fig. 21.1a). AMT and SMT receptors, as their names indicate, respond to both thermal and mechanical stimuli. The physiological situation, however, is far from simple. The transmission mechanism of these two modalities is different. The application of capsaicin does not affect the sensitivity to mechanical stimuli, but inhibits the response to thermal ones. At the same time, while capsaicin has an analgesic effect on the thermal and chemical sensitivity of polymodal C-fibers in the cornea, it does not affect mechanosensitivity. Finally, it has been shown that mechanical stimuli, which generate the same level of activity in the CMT fibers as thermal ones, nevertheless cause less pain. Possibly, inevitably, the wider surface involved with a thermal stimulus involves the activity of more CMT fibers than with a mechanical stimulus.

Sensitization of nociceptors (increased sensitivity of afferent receptor fibers) occurs after their response to a harmful stimulus. Sensitized nociceptors respond more intensely to the repeated stimulus because their threshold is lowered (Fig. 34.4). At the same time, hyperalgesia is observed - more severe pain in response to a stimulus of the same intensity, as well as a decrease pain threshold. Sometimes nociceptors generate a background discharge that causes spontaneous pain.

Sensitization occurs when chemical factors such as K+ ions, bradykinin, serotonin, histamine, eicosanoids (prostaglandins and leukotrienes) are released near nociceptive nerve endings as a result of tissue damage or inflammation. Suppose a harmful stimulus, having hit the skin, destroyed the cells of the tissue area near the nociceptor (Fig. 34.5, a). K+ ions come out of the dying cells and depolarize the nociceptor. In addition, proteolytic enzymes are released; when they interact with blood plasma globulins, bradykinin is formed. It binds to the receptor molecules of the nociceptor membrane and activates the second messenger system that sensitizes the nerve ending. Other released chemicals such as platelet serotonin, mast cell histamine, eicosanoids of various cellular elements contribute to sensitization by opening ion channels or activating second messenger systems. Many of them also affect blood vessels, immune system cells, platelets, and other effectors involved in inflammation.

In addition, activation of the end of a nociceptor can release regulatory peptides such as substance P (SP) and calcitonin-encoded peptide (CGRP) from other ends of the same nociceptor via the axon reflex (Fig. 34.5b). The nerve impulse that originated in one of the branches of the nociceptor is sent along the maternal axon to the center. At the same time, it spreads antidromically along the peripheral branches of the axon of the same nociceptor, as a result of which substance P and CGRP are released in the skin (Fig. 34.5, b). These peptides cause

Superficial tissues are supplied with nerve endings of various afferent fibers ( J. Erlanger, G.S. Gasser, 1924). The thickest, myelinated Ab fibers have tactile sensitivity. They are excited by non-painful touches and by movement. 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. Weak stimulation of polymodal non-specific tactile receptors leads to a feeling itching. Their excitability threshold is lowered by histamine and serotonin ( G.Stuttgen, 1981).

Specific primary pain receptors (nocireceptors) are two other types of nerve endings - thin myelinated Ad-terminals and thin unmyelinated C-fibers, phylogenetically more primitive. Both of these types of terminals are present both in superficial tissues and in internal organs. Some areas of the body, such as the cornea, are innervated only by Ad and C afferents. Nocireceptors give a feeling of pain in response to a variety of intense stimuli - mechanical impact, thermal signal (usually with a temperature of more than 45-47 0 C), irritating chemicals, such as acids. Ischemia always causes pain because it provokes acidosis. Muscle spasm can cause irritation of pain endings due to the relative hypoxia and ischemia that it causes, as well as due to direct mechanical displacement of nocireceptors.

Slow, protopathic pain is carried out along C-fibers at a speed of 0.5-2 m / s, and epicritical pain is carried out along myelinated, fast-conducting Ad-fibers, providing a conduction speed of 6 to 30 m / s. In addition to the skin, where, according to A.G. Bukhtiyarova(1966), there are at least 100-200 pain receptors per 1 cm 2, mucous membranes and cornea, pain receptors of both types are abundantly supplied to the periosteum (as every football player who receives a blow to the anterior-inner surface of the lower leg when rolling is convinced), and also vascular walls, joints, cerebral sinuses and parietal sheets of serous membranes.

There are much fewer pain receptors in the visceral layers of these membranes and internal organs. In addition, in the parenchyma of the internal organs there are exclusively C-fibers of protopathic sensitivity, reaching the spinal cord as part of autonomic nerves. Therefore, visceral pain is more difficult to localize than superficial pain. In addition, the localization of visceral pain depends on the phenomenon of “reflected pain”, the mechanisms of which are discussed below. The parietal peritoneum, pleura, pericardium, capsules of retroperitoneal organs, and part of the mesentery have not only slow protopathic C-fibers, but also fast epicritical Ad associated with the spinal cord by spinal nerves. Therefore, the pain from their irritation and damage is much sharper and more clearly localized. Even in the pre-anesthesiological era, surgeons noticed that intestinal incisions are less painful than dissection of the parietal sheet of the peritoneum. Pain during neurosurgical operations is maximal at the time of dissection of the meninges, while the cerebral cortex has a very slight 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. An extracranial cause of headache can be processes localized in the sinuses of the bones of the head, spasm of the ciliary and other eye muscles, tonic tension of the muscles of the neck and scalp. Intracranial causes of headache are, first of all, irritation of nocireceptors of the meninges. With meningitis, severe headaches cover the entire head. A very serious headache is caused by irritation of nocireceptors in the cerebral sinuses and arteries, especially in the basin of the middle cerebral artery. Even slight losses of cerebrospinal fluid (about 20 ml) can provoke a headache, especially in the vertical position of the body, since 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 in 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 the “most common complaint” - headache, so how, in this case, the mechanical effect on the pain receptors of the structures surrounding the brain itself increases. The general principle of the localization of headaches is such that occipital pains often reflect irritation of the nocireceptors of the vessels and meninges under the tentorium, and suprapaltal stimuli and stimulation of the upper surface of the tent itself are manifested by fronto-parietal pains. Familiar to a very significant part of mankind, the “hangover headache” has a complex pathogenesis, including alcohol-induced plethora of the meninges and intracellular overhydration. The pathophysiology of some forms of headache, closely related to the humoral mediators of the pain and anti-pain systems and to the conduction mechanisms of these systems, in particular migraine, is considered separately below.

The parenchyma of the spleen, kidney, liver and lung is completely devoid of nocireceptors. But they are richly supplied with bronchi, bile ducts, capsules and vessels of these organs. Even large liver or lung abscesses can be almost painless. However, pleurisy or cholangitis sometimes gives a serious pain syndrome, without being severe in itself. Visceral pain receptors are also distinguished by the fact that they develop a relatively weak response to strictly local damage to an organ, for example, a surgical incision. However, with diffuse tissue involvement in alteration (against the background of ischemia, under the action of lytic enzymes and irritating chemicals, with spasms and overstretching of hollow organs), their sensitivity under the influence of inflammatory mediators increases rapidly, and strong impulses come from them.

Pain receptors claim a unique position in human body. This is the only type of sensitive receptor that is not subject to any kind of adaptation or desensitization under the influence of a continuous or repeated signal. At the same time, nocireceptors do not increase their excitability threshold, as others do, for example, cold sensors. Therefore, the receptor does not "get used" to pain. Moreover, in nocireceptive nerve endings, the opposite phenomenon takes place - sensitization of pain receptors by a signal. With inflammation, tissue damage (especially internal organs), and with repeated and prolonged pain stimuli, the excitability threshold of nocireceptors decreases. Even the lightest touch to the burn surface is extremely painful. This phenomenon is called primary hyperalgesia. Palpation of the internal organs, even if it is intense, does not cause pain if there is no inflammation. However, during inflammation, the sensitivity of silent internal nocireceptors increases so much that the doctor registers pain symptoms. Tapping over the kidneys, painless in the absence of damage to them, leads to pain if the renal nocireceptors are sensitized by inflammatory mediators ( positive symptom Pasternatsky). It is easy to note that if adaptation of pain receptors took place, all chronic destructive processes would be painless and pain would lose its signal function, which, according to the expression I.P. Pavlova, "induces to discard that which threatens the life process."

Calling pain sensors receptors, we must emphasize 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 nocireceptor stimulation are well studied. Their main stimulant is bradykinin. In response to damage to cells near the nocireceptor, this mediator is released, as well as prostaglandins, leukotrienes, and 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. The excitation spreads not only afferently, but also antidromicly, to the neighboring branches of the terminal. There it leads to the secretion of substance P. This neuropeptide, which has already been mentioned, causes hyperemia, edema, and degranulation around the terminal in a paracrine way. mast cells and platelets. The released histamine, serotonin, prostaglandins sensitize nocireceptors, and mastocyte chymase and tryptase enhance the production of their direct agonist, bradykinin. Consequently, when damaged, nocireceptors act both as sensors and as paracrine provocateurs of inflammation. Near the 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, the so-called causalgia- pathologically hypersensitivity nocireceptors in the area innervated by the damaged nerve, accompanied by burning pain and even signs of inflammation without visible local damage. The mechanism of causalgia is associated with the hyperalgic action of sympathetic nerves, in particular, norepinephrine secreted by them, on the state of pain receptors. It is possible that this is accompanied by the secretion of substance P and other neuropeptides by sympathetic nerves, which causes inflammatory symptoms. The phenomenon of causalgia is, in the fullest sense, a neurogenic inflammation, although it is caused not by a nervous, but by a paracrine way (see also above, on the role of nervous regulation in inflammation).

As first suggested W. Cannon and A. Rosenbluth(1951) paracrine impulseless neuropeptidergic activity of nerve endings in tissues is the real basis of the phenomenon, which for more than 100 years, from F. Magendie(1824) to L.A. Orbeli(1935) and HELL. Speransky, (1937), called nervous trophism.

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Pain is a symptom of many diseases and injuries of the body. A person has developed a complex pain perception mechanism that signals damage and forces them to take measures to eliminate the causes of pain (pull up their hand, etc.).

Nociceptive system

For the perception and conduction of pain in the body is responsible for the so-called nociceptive system. In a simplified form, the pain conduction mechanism can be represented as follows (Figure ⭣).

When pain receptors (nociceptors) localized in various organs and tissues (skin, blood vessels, skeletal muscles, periosteum, etc.) are irritated, a stream of pain impulses occurs, which enter the posterior horns of the spinal cord through afferent fibers.

There are two types of afferent fibers: A-delta fibers and C-fibers.

A-delta fiber are myelinated, which means they are fast-conducting - the speed of conducting impulses through them is 6-30 m / s. A-delta fibers are responsible for transmission acute pain. They are excited by high-intensity mechanical (pin prick) and sometimes thermal skin irritations. Rather, they have an informational value for the body (they make you withdraw your hand, jump away, etc.).

Anatomically, A-delta nociceptors are represented by free nerve endings, branched in the form of a tree. They are located mainly in the skin and at both ends of the digestive tract. They are also present in the joints. The transmitter (nerve signal transmitter) A-delta fibers remains unknown.

C fibers- unmyelinated; they carry out powerful but slow streams of impulses at a speed of 0.5-2 m/s. It is believed that these afferent fibers are intended for the perception of secondary acute and chronic pain.

C-fibers are represented by dense non-encapsulated glomerular bodies. They are polymodal nociceptors; therefore, they respond to both mechanical and thermal and chemical stimuli. They are activated chemicals, arising from tissue damage, being at the same time chemoreceptors, are considered optimal tissue-damaging receptors.

C-fibers are distributed to all tissues except the central nervous system. Fibers that have receptors that perceive tissue damage contain substance P, which acts as a transmitter.

In the posterior horns of the spinal cord, the signal is switched from the afferent fiber to the intercalary neuron, from which, in turn, the impulse branches off, exciting motor neurons. This branch is accompanied by a motor reaction to pain - pull the hand away, jump away, etc. So intercalary neuron the flow of impulses, rising further through the central nervous system, passes through the medulla oblongata, in which there are several vital centers: respiratory, vasomotor, centers vagus nerve, cough center, vomiting center. That is why the pain in some cases has a vegetative accompaniment - palpitations, sweating, jumps blood pressure, salivation, etc.

Next, the pain impulse reaches the thalamus. The thalamus is one of the key links in the transmission of the pain signal. It contains the so-called switching (SNT) and associative nuclei of the thalamus (AJN). These formations have a certain, rather high threshold of excitation, which not all pain impulses can overcome. The presence of such a threshold is very importance in the mechanism of pain perception, without it, any slightest irritation would cause a painful sensation.

However, if the impulse is strong enough, it causes depolarization of the PJT cells, the impulses from them arrive in the motor areas of the cerebral cortex, determining the sensation of pain itself. This way of conducting pain impulses is called specific. It provides a signal function of pain - the body perceives the fact of the occurrence of pain.

In turn, the activation of AAT causes impulses to enter the limbic system and hypothalamus, providing an emotional coloring of pain (a nonspecific pathway for pain). It is because of this pathway that the perception of pain has a psycho-emotional coloring. In addition, through this pathway, people can describe the perceived pain: sharp, throbbing, stabbing, aching, etc., which is determined by the level of imagination and the type of human nervous system.

Antinociceptive system

Throughout the nociceptive system there are elements of the antinociceptive system, which is also an integral part of the pain perception mechanism. The elements of this system are designed to suppress pain. The mechanisms of development of analgesia, controlled by the antinociceptive system, involve the serotoninergic, GABAergic and, to the greatest extent, the opioid system. The functioning of the latter is realized due to protein transmitters - enkephalins, endorphins - and their specific opioid receptors.

Enkephapins(meth-enkephalin - H-Tyr-Gly-Gly-Phe-Met-OH, leu-enkephalin - H-Tyr-Gly-Gly-Phe-Leu-OH, etc.) were first isolated in 1975 from the brain of mammals . According to their chemical structure, they belong to the class of pentapeptides, having a very similar structure and molecular weight. Enkephalins are neurotransmitters of the opioid system; they function throughout its entire length from nociceptors and afferent fibers to brain structures.

Endorphins(β-endofin and dynorphin) - hormones produced by corticotropic cells of the middle lobe of the pituitary gland. Endorphins have a more complex structure and a larger molecular weight than enkephalins. So, β-endofin is synthesized from β-lipotropin, being, in fact, the 61-91 amino acid part of this hormone.

Enkephalins and endorphins, by stimulating opioid receptors, carry out physiological antinociception, and enkephalins should be considered as neurotransmitters, and endorphins as hormones.

Opioid receptors- a class of receptors that, being targets for endorphins and enkephalins, are involved in the implementation of the effects of the antinociceptive system. Their name comes from opium - the dried milky juice of the sleeping pills poppy, known since ancient times as a source of narcotic analgesics.

There are 3 main types of opioid receptors: μ (mu), δ (delta), κ (kappa). Their localization and the effects arising from their excitation are presented in table ⭣.

Enkephalins and endorphins, by stimulating opioid receptors, cause the activation of the G₁-protein associated with these receptors. This protein inhibits the enzyme adenylate cyclase, which under normal conditions promotes the synthesis of cyclic adenosine monophosphate (cAMP). Against the background of its blockade, the amount of cAMP inside the cell decreases, which leads to the activation of membrane potassium channels and the blockade of calcium channels.

As you know, potassium is an intracellular ion, calcium is an extracellular ion. These changes in the operation of ion channels cause the release of potassium ions from the cell, while calcium cannot enter the cell. As a result, the membrane charge decreases sharply, and hyperpolarization develops - a state in which the cell does not perceive and does not transmit excitation. As a result, suppression of nociceptive impulses occurs.

Sources:
1. Lectures on pharmacology for higher medical and pharmaceutical education / V.M. Bryukhanov, Ya.F. Zverev, V.V. Lampatov, A.Yu. Zharikov, O.S. Talalaeva - Barnaul: Spektr Publishing House, 2014.
2. General human pathology / Sarkisov D.S., Paltsev M.A., Khitrov N.K. - M.: Medicine, 1997.