Mechanisms of pain formation. Mechanisms of pain development. Peripheral and central mechanisms of nociception The concept of pain and its definitions

Pain and pain relief always remain the most important problems of medicine, and alleviating the suffering of a sick person, relieving pain or reducing its intensity is one of the most important tasks of a doctor. In recent years, some progress has been made in understanding the mechanisms of pain perception and formation. However, there are still many unresolved theoretical and practical issues.

Pain is an unpleasant sensation realized by a special system of pain sensitivity and higher parts of the brain related to the psycho-emotional sphere. It signals effects that cause tissue damage or pre-existing damage resulting from the action of exogenous factors or the development of pathological processes.

The system of perception and transmission of pain signals is called nociceptive system (nocere-damage, cepere-to perceive, lat.).

Classification of pain. Highlight physiological and pathological pain. Physiological (normal) pain occurs as an adequate reaction of the nervous system to situations dangerous to the body, and in these cases it acts as a warning factor about processes that are potentially dangerous to the body. Typically, physiological pain is that which occurs in the entire nervous system in response to damaging or tissue-destructive stimuli. The main biological criterion that distinguishes pathological pain is its disadaptive and pathogenic significance for the body. Pathological pain is produced by an altered pain sensitivity system.

By nature they distinguish acute and chronic(constant) pain. According to localization, the skin, head, facial, cardiac, liver, stomach, kidney, joint, lumbar, etc. are distinguished. In accordance with the classification of receptors, the superficial ( exteroceptive), deep (proprioceptive) and visceral ( interoceptive) pain.

There are somatic pains (during pathological processes in the skin, muscles, bones), neuralgic (usually localized) and vegetative (usually diffuse). Possible so-called irradiating pain, for example, in the left arm and shoulder blade with angina pectoris, girdle pain with pancreatitis, in the scrotum and thigh with renal colic. According to the nature, course, quality and subjective sensations of pain, pain is distinguished: paroxysmal, constant, lightning, diffuse, dull, radiating, cutting, stabbing, burning, pressing, squeezing, etc.

Nociceptive system. Pain, being a reflex process, includes all the main links of the reflex arc: receptors (nociceptors), pain conductors, formations of the spinal cord and brain, as well as mediators that transmit pain impulses.

According to modern data, nociceptors are found in large quantities in various tissues and organs and have many terminal branches with small axoplasmic processes, which are structures activated by pain. They are believed to be essentially free, unmyelinated nerve endings. Moreover, in the skin, and especially in the dentin of teeth, peculiar complexes of free nerve endings with cells of innervated tissue were discovered, which are considered as complex receptors of pain sensitivity. A feature of both damaged nerves and free unmyelinated nerve endings is their high chemosensitivity.

It has been established that any impact that leads to tissue damage and is adequate for the nociceptor is accompanied by the release of algogenic (pain-causing) chemical agents. There are three types of such substances.

a) tissue (serotonin, histamine, acetylcholine, prostaglandins, K and H ions);

b) plasma (bradykinin, kallidin);

c) released from nerve endings (substance P).

Many hypotheses have been proposed about the nociceptive mechanisms of algogenic substances. It is believed that substances contained in tissues directly activate the terminal branches of unmyelinated fibers and cause impulse activity in afferents. Others (prostaglandins) themselves do not cause pain, but enhance the effect of nociceptive effects of a different modality. Still others (substance P) are released directly from the terminals and interact with receptors localized on their membrane, and, depolarizing it, cause the generation of a pulsed nociceptive flow. It is also assumed that substance P, contained in the sensory neurons of the dorsal ganglia, also acts as a synaptic transmitter in the neurons of the dorsal horn of the spinal cord.

Chemical agents that activate free nerve endings are considered to be substances that have not been fully identified or products of tissue destruction that are formed under severe damaging influences, during inflammation, or during local hypoxia. Free nerve endings are also activated by intense mechanical action, causing their deformation due to tissue compression, stretching of the hollow organ with simultaneous contraction of its smooth muscles.

According to Goldscheider, pain does not arise as a result of irritation of special nociceptors, but as a result of excessive activation of all types of receptors of various sensory modalities, which normally respond only to non-painful, “non-nociceptive” stimuli. In the formation of pain in this case, the intensity of the impact is of primary importance, as well as the spatio-temporal relationship of afferent information, convergence and summation of afferent flows in the central nervous system. In recent years, very convincing data have been obtained on the presence of “nonspecific” nociceptors in the heart, intestines, and lungs.

It is now generally accepted that the main conductors of cutaneous and visceral pain sensitivity are thin myelinated A-delta and non-myelinated C fibers, which differ in a number of physiological properties.

The following division of pain is now generally accepted:

1) primary - light, short latent, well localized and qualitatively determined pain;

2) secondary - dark, long latent, poorly localized, painful, dull pain.

It has been shown that “primary” pain is associated with afferent impulses in A-delta fibers, and “secondary” pain is associated with C-fibers.

Ascending pathways of pain sensitivity. There are two main “classical” ones - lemniscal and extralemniscal ascending systems. Within the spinal cord, one of them is located in the dorsal and dorsolateral zone of the white matter, the other in its ventrolateral part. There are no specialized pathways for pain sensitivity in the central nervous system, and pain integration occurs at various levels of the central nervous system based on the complex interaction of lemniscal and extralemniscal projections. However, it has been proven that ventrolateral projections play a significantly larger role in the transmission of ascending nociceptive information.

Structures and mechanisms of pain integration. One of the main areas of perception of afferent influx and its processing is the reticular formation of the brain. It is here that the paths and collaterals of the ascending systems end and the ascending projections to the ventro-basal and intralaminar nuclei of the thalamus and further to the somatosensory cortex begin. In the reticular formation of the medulla oblongata there are neurons that are activated exclusively by nociceptive stimuli. Their largest number (40-60%) was found in the medial reticular nuclei. Based on information entering the reticular formation, somatic and visceral reflexes are formed, which are integrated into complex somatovisceral manifestations of nociception. Through connections of the reticular formation with the hypothalamus, basal ganglia and limbic brain, neuroendocrine and emotional-affective components of pain accompanying defense reactions are realized.

Thalamus. There are 3 main nuclear complexes that are directly related to the integration of pain: the ventro-basal complex, the posterior group of nuclei, the medial and intralaminar nuclei.

The ventro-basal complex is the main relay nucleus of the entire somatosensory afferent system. Basically, the ascending lemniscal projections end here. It is believed that multisensory convergence on neurons of the ventro-basal complex provides accurate somatic information about the localization of pain and its spatial correlation. Destruction of the ventro-basal complex is manifested by a transient elimination of “quick”, well-localized pain and alters the ability to recognize nociceptive stimuli.

It is believed that the posterior group of nuclei, along with the ventro-basal complex, is involved in the transmission and evaluation of information about the localization of pain and partly in the formation of the motivational-affective components of pain.

Cells of the medial and intralaminar nuclei respond to somatic, visceral, auditory, visual and pain stimuli. Various modal nociceptive irritations - dental pulp, A-delta, C-cutaneous fibers, visceral afferents, as well as mechanical, thermal, etc., cause distinct neuronal responses that increase in proportion to the intensity of the stimuli. It is assumed that cells of the intralaminar nuclei evaluate and decode the intensity of nociceptive stimuli, distinguishing them by duration and pattern of discharges.

Cortex. Traditionally, it was believed that the second somatosensory area is of primary importance in processing pain information. These ideas are due to the fact that the anterior part of the zone receives projections from the ventrobasal thalamus, and the posterior part - from the medial, intralaminar and posterior groups of nuclei. However, in recent years, ideas about the participation of various cortical areas in the perception and assessment of pain have been significantly supplemented and revised.

The scheme of cortical integration of pain in a generalized form can be reduced to the following. The process of primary perception is carried out to a greater extent by the somatosensory and fronto-orbital areas of the cortex, while other areas that receive extensive projections from various ascending systems are involved in its qualitative assessment, in the formation of motivational-affective and psychodynamic processes that ensure the experience of pain and the implementation of responses reactions to pain.

It should be emphasized that pain, unlike nociception, is not only and not so much a sensory modality, but also a sensation, emotion and “a peculiar mental state” (P.K. Anokhin). Therefore, pain as a psychophysiological phenomenon is formed on the basis of the integration of nociceptive and antinociceptive systems and mechanisms of the central nervous system.

Antinociceptive system. The nociceptive system has its own functional antipode - the antinociceptive system, which controls the activity of the structures of the nociceptive system.

The antinociceptive system consists of a variety of nerve formations belonging to different sections and levels of organization of the central nervous system, starting from the afferent input in the spinal cord and ending with the cerebral cortex.

The antinociceptive system plays a significant role in the mechanisms of preventing and eliminating pathological pain. By being involved in the reaction to excessive nociceptive stimulation, it weakens the flow of nociceptive stimulation and the intensity of the pain sensation, due to which the pain remains under control and does not acquire pathological significance. If the activity of the antinociceptive system is disrupted, nociceptive stimulation of even low intensity causes excessive pain.

The antinociceptive system has its own morphological structure, physiological and biochemical mechanisms. For its normal functioning, a constant influx of afferent information is necessary; with its deficiency, the function of the antinociceptive system is weakened.

The antinociceptive system is represented by segmental and central levels of control, as well as humoral mechanisms - opioid, monoaminergic (norepinephrine, dopamine, serotonin), choline-GABAergic systems.

Opiate mechanisms of pain relief. For the first time in 1973, the selective accumulation of substances isolated from opium, such as morphine or its analogs, in certain brain structures was established. These formations are called opiate receptors. The largest number of them is located in the parts of the brain that transmit nociceptive information. Opiate receptors have been shown to bind to substances such as morphine or its synthetic analogues, as well as to similar substances produced in the body itself. In recent years, the heterogeneity of opiate receptors has been proven. Mu-, delta-, kappa-, sigma-opiate receptors are identified. For example, morphine-like opiates bind to Mu receptors, opiate peptides bind to delta receptors.

Endogenous opiates. It has been found that in human blood and cerebrospinal fluid there are substances that have the ability to bind to opiate receptors. They are isolated from the brain of animals, have the structure of oligopeptides and are called enkephalins(met- and leu-enkephalin). Substances with an even greater molecular weight were obtained from the hypothalamus and pituitary gland, containing enkephalin molecules and called large endorphins. These compounds are formed during the breakdown of beta-lipotropin, and given that it is a pituitary hormone, the hormonal origin of endogenous opioids can be explained. Substances with opiate properties and a different chemical structure are obtained from other tissues - these are leu-beta-endorphin, kitorphin, dynorphin, etc.

Different areas of the central nervous system have different sensitivity to endorphins and enkephalins. For example, the pituitary gland is 40 times more sensitive to endorphins than to enkephalins. Opiate receptors reversibly bind to narcotic analgesics, and the latter can be displaced by their antagonists, restoring pain sensitivity.

What is the mechanism of the analgesic effect of opiates? It is believed that they connect to receptors (nociceptors) and, since they are large, prevent the neurotransmitter (substance P) from connecting to them. It is also known that endogenous opiates also have a presynaptic effect. As a result, the release of dopamine, acetylcholine, substance P, and prostaglandins decreases. It is assumed that opiates cause inhibition of adenylate cyclase function in the cell, a decrease in the formation of cAMP and, as a consequence, inhibition of the release of mediators into the synaptic cleft.

Adrenergic mechanisms of pain relief. It has been established that norepinephrine inhibits the conduction of nociceptive impulses both at the segmental (spinal cord) and brainstem levels. This effect is realized through interaction with alpha adrenergic receptors. When exposed to pain (as well as stress), the sympathoadrenal system (SAS) is sharply activated, tropic hormones, beta-lipotropin and beta-endorphin are mobilized as powerful analgesic polypeptides of the pituitary gland, enkephalins. Once in the cerebrospinal fluid, they affect the neurons of the thalamus, the central gray matter of the brain, and the posterior horns of the spinal cord, inhibiting the formation of the pain mediator substance P and thus providing deep analgesia. At the same time, the formation of serotonin in the raphe major nucleus is enhanced, which also inhibits the implementation of the effects of substance P. It is believed that the same analgesic mechanisms are activated during acupuncture stimulation of non-painful nerve fibers.

To illustrate the diversity of components of the antinociceptive system, it should be said that many hormonal products have been identified that have an analgesic effect without activating the opiate system. These are vasopressin, angiotensin, oxytocin, somatostatin, neurotensin. Moreover, their analgesic effect can be several times stronger than enkephalins.

There are other mechanisms of pain relief. It has been proven that activation of the cholinergic system strengthens, and its blockade weakens, the morphine system. It is believed that the binding of acetylcholine to certain central M receptors stimulates the release of opioid peptides. Gamma-aminobutyric acid regulates pain sensitivity, suppressing emotional and behavioral reactions to pain. Pain, by activating GABA and GABA-ergic transmission, ensures the body's adaptation to pain stress.

Acute pain. In modern literature one can find several theories explaining the origin of pain. The most widespread is the so-called "gate" theory of R. Melzack and P. Wall. It lies in the fact that the gelatinous substance of the dorsal horn, which provides control of afferent impulses entering the spinal cord, acts as a gate that passes nociceptive impulses upward. Moreover, T-cells of the gelatinous substance play an important role, where presynaptic inhibition of terminals occurs; under these conditions, pain impulses do not pass further into the central brain structures and pain does not occur. According to modern concepts, the closing of the “gate” is associated with the formation of enkephalins, which inhibit the implementation of the effects of the most important mediator of pain - substance P. If the influx of afferentation along the A-delta and C-fibers increases, T cells are activated and cells of the gelatinous substance are inhibited, which removes the inhibitory effect of substantia gelatinous neurons on T-cell afferent terminals. Therefore, the activity of T cells exceeds the threshold of excitation and pain occurs due to the facilitation of the transmission of pain impulses to the brain. The “entrance gate” for pain information in this case opens.

An important point of this theory is to take into account the central influences on “gate control” in the spinal cord, because processes such as life experience and attention influence the formation of pain. The central nervous system controls sensory input through reticular and pyramidal influences on the portal system. For example, R. Melzack gives the following example: a woman suddenly discovers a lump in her breast and, worrying that it is cancer, may suddenly feel pain in her chest. The pain may intensify and even spread to the shoulder and arm. If the doctor can convince her that the lump is not dangerous, the pain may stop immediately.

The formation of pain is necessarily accompanied by activation of the antinociceptive system. What affects the reduction or disappearance of pain? This is, first of all, information that comes through thick fibers and at the level of the dorsal horns of the spinal cord, enhancing the formation of enkephalins (we talked about their role above). At the level of the brain stem, the descending analgesic system (rape nuclei) is activated, which, through serotonin-, norepinephrine-, and enkephalinergic mechanisms, exerts descending influences on the dorsal horns and thus on pain information. Due to the excitation of the SAS, the transmission of pain information is also inhibited, and this is the most important factor in enhancing the formation of endogenous opiates. Finally, due to the stimulation of the hypothalamus and pituitary gland, the formation of enkephalins and endorphins is activated, and the direct influence of hypothalamic neurons on the dorsal horns of the spinal cord is enhanced.

Chronic pain.With long-term tissue damage (inflammation, fractures, tumors, etc.), the formation of pain occurs in the same way as in acute pain, only constant pain information, causing a sharp activation of the hypothalamus and pituitary gland, SAS, limbic formations of the brain, is accompanied by more complex and long-term changes in the psyche, behavior, emotional manifestations, attitude towards the outside world (departure from pain).

According to the theory of G.N. Kryzhanovsky chronic pain occurs as a result of suppression of inhibitory mechanisms, especially at the level of the dorsal horns of the spinal cord and thalamus. At the same time, an excitation generator is formed in the brain. Under the influence of exogenous and endogenous factors in certain structures of the central nervous system, due to insufficiency of inhibitory mechanisms, generators of pathologically enhanced excitation (PAE) arise, activating positive connections, causing epilepsy of neurons of one group and increasing the excitability of other neurons.

Phantom pain(pain in amputated limbs) are explained mainly by a deficiency of afferent information and, as a result, the inhibitory effect of T cells at the level of the spinal cord horns is removed, and any afferentation from the posterior horn region is perceived as painful.

ABOUT affected pain. Its occurrence is due to the fact that afferents of internal organs and skin are connected to the same neurons of the dorsal horn of the spinal cord, which give rise to the spinothalamic tract. Therefore, afferentation coming from the internal organs (if they are damaged) increases the excitability of the corresponding dermatome, which is perceived as pain in this area of ​​the skin.

The main differences between the manifestations of acute and chronic pain are as follows: : .

1. In chronic pain, autonomic reflex reactions gradually decrease and ultimately disappear, and autonomic disorders prevail.

2. With chronic pain, as a rule, there is no spontaneous relief of pain; to level it out, a doctor’s intervention is required.

3. If acute pain performs a protective function, then chronic pain causes more complex and long-term disorders in the body and leads (J. Bonica, 1985) to progressive “wear and tear” caused by sleep and appetite disturbances, decreased physical activity, and often excessive treatment.

4. In addition to the fear characteristic of acute and chronic pain, the latter is also characterized by depression, hypochondria, hopelessness, despair, and withdrawal of patients from socially useful activities (even suicidal ideas).

Dysfunctions of the body during pain. Functional disorders N.S. with intense pain, they manifest themselves as disturbances in sleep, concentration, sexual desire, and increased irritability. With chronic intense pain, a person’s motor activity sharply decreases. The patient is in a state of depression, pain sensitivity increases as a result of a decrease in the pain threshold.

A slight pain speeds up the breathing, but a very strong one slows down breathing until it stops. The pulse rate and systemic blood pressure may increase, and peripheral vascular spasm may develop. The skin turns pale, and if the pain is short-lived, vascular spasm is replaced by their dilation, which is manifested by redness of the skin. The secretory and motor function of the gastrointestinal tract changes. Due to the stimulation of the SAS, thick saliva is first released (in general, salivation increases), and then, due to the activation of the parasympathetic part of the nervous system, liquid saliva is released. Subsequently, the secretion of saliva, gastric and pancreatic juice decreases, the motility of the stomach and intestines slows down, and reflex oligo- and anuria is possible. With very sharp pain, there is a threat of shock.

Biochemical changes manifest themselves in the form of increased oxygen consumption, glycogen breakdown, hyperglycemia, hyperlipidemia.

Chronic pain is accompanied by strong autonomic reactions. For example, cardialgia and headaches are combined with increased blood pressure, body temperature, tachycardia, dyspepsia, polyuria, increased sweating, tremor, thirst, and dizziness.

A constant component of the response to pain is blood hypercoagulation. An increase in blood clotting in patients at the height of an attack of pain, during surgical interventions, and in the early postoperative period has been proven. In the mechanism of hypercoagulation during pain, the acceleration of thrombinogenesis is of primary importance. You know that the external mechanism of blood coagulation activation is initiated by tissue thromboplastin, and during pain (stress), thromboplastin is released from the intact vascular wall. In addition, with pain, the content of physiological blood clotting inhibitors in the blood decreases: antithrombin, heparin. Another characteristic change in pain in the hemostatic system is redistribution thrombocytosis (the entry of mature platelets into the blood from the pulmonary depot).

Pain reception in the oral cavity.

Of particular importance for a dentist is the study of pain sensitivity in the oral cavity. A painful sensation can occur either when a damaging factor acts on a special “pain” receptor - nociceptor, or with extreme stimulation of other receptors. Nociceptors make up 25-40% of all receptor formations. They are represented by free, non-encapsulated nerve endings of various shapes.

In the oral cavity, the pain sensitivity of the mucous membrane of the alveolar processes and the hard palate, which are areas of the prosthetic bed, has been most studied.

Part of the mucous membrane on the vestibular surface of the lower jaw in the area of ​​the lateral incisors has pronounced pain sensitivity. The oral surface of the gum mucosa has the least pain sensitivity. On the inner surface of the cheek there is a narrow area devoid of pain sensitivity. The largest number of pain receptors are located in the tissues of the tooth. Thus, there are 15,000-30,000 pain receptors per 1 cm 2 of dentin; at the border of enamel and dentin, their number reaches 75,000. There are no more than 200 pain receptors per 1 cm 2 of skin.

Irritation of the dental pulp receptors causes an extremely strong pain sensation. Even a light touch is accompanied by acute pain. Toothache, one of the most severe pains, occurs when a tooth is damaged by a pathological process. Treatment of the tooth interrupts it and eliminates the pain. But the treatment itself is sometimes an extremely painful manipulation. In addition, during dental prosthetics, it is often necessary to prepare a healthy tooth, which also causes pain.

Excitation from nociceptors of the oral mucosa, periodontal receptors, tongue and dental pulp is carried out through nerve fibers belonging to groups A and C. Most of these fibers belong to the second and third branches of the trigeminal nerve. Sensory neurons are located in the trigeminal ganglion. The central processes are directed to the medulla oblongata, where they end on the neurons of the trigeminal complex of nuclei, consisting of the main sensory nucleus and the spinal tract. The presence of a large number of collaterals ensures a functional relationship between the various nuclei of the trigeminal complex. From the second neurons of the trigeminal complex of excitation nuclei, they are directed to the posterior and ventral specific nuclei of the thalamus. In addition, due to extensive collaterals to the reticular formation of the medulla oblongata, nociceptive excitation of the pallido-spino-bulbo-thalamic projection pathways is addressed to the median and intraplate groups of thalamic nuclei. This ensures broad generalization of nociceptive excitations in the anterior parts of the brain and the inclusion of the antinociceptive system.

Irritation of the internal organs often causes pain, which is felt not only in the internal organs, but also in some somatic structures located quite far from the place where the pain is caused. This kind of pain is called referred (radiating).

The best known example of referred pain is cardiac pain that radiates to the left arm. However, the future doctor should know that areas of pain reflection are not stereotypical, and unusual areas of reflection are observed quite often. Heart pain, for example, can be purely abdominal, it can radiate to the right arm and even to the neck.

Rule dermatomers. Afferent fibers from the skin, muscles, joints and internal organs enter the spinal cord along the dorsal roots in a certain spatial order. Cutaneous afferent fibers from each dorsal root innervate a limited area of ​​skin called the dermatomere (Figure 9-9). Referred pain usually occurs in structures developing from the same embryonic segment, or dermatomere. This principle is called the “dermatomer rule”. For example, the heart and left arm have the same segmental nature, and the testicle migrated with its nerve supply from the urogenital ridge, from which the kidneys and ureters arose. Therefore, it is not surprising that pain that originates in the ureters or kidneys radiates to the testicle.

Rice. 9 –9 . Dermatomers

Convergence and relief in the mechanism of referred pain

Not only the visceral and somatic nerves that enter the nervous system at one segmental level, but also a large number of sensory nerve fibers passing through the spinothalamic tracts take part in the development of referred pain. This creates conditions for the convergence of peripheral afferent fibers on thalamic neurons, i.e. somatic and visceral afferents converge on the same neurons (Fig. 9–10).

 Theoryconvergence. Greater speed, consistency and frequency of information about somatic pain helps the brain to consolidate information that signals entering the corresponding nerve pathways are caused by painful stimuli in certain somatic areas of the body. When the same nerve pathways are excited by the activity of visceral pain afferent fibers, the signal reaching the brain is not differentiated, and pain is projected to the somatic area of ​​the body.

 Theoryrelief. Another theory of the origin of referred pain (the so-called relief theory) is based on the assumption that impulses from internal organs lower the threshold of spinothalamic neurons to the effects of afferent pain signals from somatic areas. Under conditions of relief, even minimal pain activity from the somatic area passes to the brain.

Rice. 9 –10 . Reflected pain

If convergence is the only explanation for the origin of referred pain, then local anesthesia of the area of ​​referred pain should have no effect on the pain. On the other hand, if subthreshold relieving influences are involved in the occurrence of referred pain, then the pain should disappear. The effect of local anesthesia on the area of ​​referred pain varies. Severe pain usually does not go away, moderate pain may stop completely. Therefore, both factors are convergenceAndrelief- participate in the occurrence of referred pain.

UDC 616-009.7-092

V.G. Ovsyannikov, A.E. Boychenko, V.V. Alekseev, N.S. Alekseeva

INITIAL MECHANISMS OF PAIN FORMATION

Department of Pathological Physiology, Rostov State Medical University,

Rostov-on-Don.

The article analyzes modern literature data describing the classification, structure and functions of pain receptors, nerve fibers conducting pain impulses, as well as the roles of the structures of the dorsal horn of the spinal cord. The central and peripheral mechanisms of the formation of pain sensitivity are illuminated.

Key words: pain, pain receptor, nerve fiber, pain formation, hyperalgesia.

V.G. Ovsyannikov, A.E. Boichenko, V.V. Alekseev, N.S. Alekseeva

THE INITIAL FORMATION AND MECHANISMS OF THE PAIN

Department of pathological physiology The Rostov State Medical University.

The article analyzes the data of modern literature, describes the classification, structure and function of pain receptors; the nerve fibers conducting pain impulse and the role of structures of the posterior horns of the spinal cord. Lit Central and peripheral mechanisms of formation of pain sensitivity.

Key words: pain, pain receptor, nerve fiber, the formation of the pain, hyperalgesia.

Pain is the same sensation as touch, sight, hearing, taste, smell and, nevertheless, it differs significantly in its nature and consequences for the body.

Its formation is aimed, on the one hand, at restoring the site of damage and, ultimately, at preserving life by restoring disturbed homeostasis, and, on the other hand, it is an important pathogenetic link in the development of the pathological process (shock, stress).

In the complex mechanism of pain formation, an important role is played by the structures of the spinal cord and brain, as well as humoral factors that form the basis of the analgesic system, ensuring the disappearance of pain due to the activation of its various links.

Among the most important features of the formation of pain, it should be noted the development of peripheral and central sensitization, or hyperalgesia, and the formation as a result of this pain sensation, even when factors that do not damage cells act on the body (tactile, cold, heat). This phenomenon is called allodynia.

An equally important feature is the formation, especially with pathology of internal organs, of pain in other parts of the body (referred and projection pain).

A feature of pain is the involvement of all organs and systems of the body, the result of which is the formation of vegetative, motor, behavioral, emotional reactions during pain, changes in memory, including changes in the activity of various parts of the antinociceptive system.

Pain is a reflex process. As with any type of sensitivity, three neurons take part in its formation. The first neuron is located in the spinal ganglion, the second is in the dorsal horn of the spinal cord, and the third is in the optic thalamus (thalamus). Pain receptors, nerve conductors, and structures of the spinal cord and brain are involved in the occurrence of pain.

Pain receptors

Free nerve endings of A-delta and C-fibers of the skin, muscles, blood vessels, internal organs, excited by the action of damaging

factors are called nociceptors. They are considered to be specialized pain receptors. The process of pain perception itself was called nociception. During evolution, most pain receptors were formed in the skin and mucous membranes, which are most susceptible to the damaging effects of external factors. In the skin, per square centimeter of surface, from 100 to 200 pain points are found. On the tip of the nose, surface of the ear, soles and palms, their number decreases and ranges from 40 to 70. Moreover, the number of pain receptors is much higher than tactile, cold, and heat receptors (G.N. Kassil, 1969). Significantly fewer pain receptors in internal organs. There are many pain receptors in the periosteum, meninges, pleura, peritoneum, synovial membranes, inner ear, and external genitalia. At the same time, bones, brain tissue, liver, spleen, and alveoli of the lungs do not respond to damage by forming pain, since they do not have pain receptors.

Some pain receptors are not excited by the action of a pain factor and they are involved in the pain process only during inflammation, which contributes to an increase in pain sensitivity (sensitization, or hyperalgesia). Such pain receptors are called “dormant” receptors. Pain receptors are classified according to their mechanism, their activation pattern, their location, and their role in controlling tissue integrity.

Based on the nature of activation, neurophysiologists distinguish three classes of pain receptors:

Modal mechanical nociceptors; Bimodal mechanical and thermal nociceptors;

Polymodal nociceptors. The first group of nociceptors is activated only by strong mechanical stimuli 5 to 1000 times greater intensity than is necessary to activate mechanoreceptors. Moreover, in the skin these receptors are associated with A-delta fibers, and in the subcutaneous tissue and internal organs - with C-fibers.

A - delta fibers are divided into two groups (H.R. Jones et al, 2013):

a group of high-threshold mechanoreceptor fibers excited by high-intensity pain stimuli, and after sensitization, responding to the action of a thermal nociceptive factor and a group of mechanosensitive fibers responding to high-intensity temperature and cold influences. The resulting sensitization of these nociceptors causes the formation of pain under the action of a mechanical non-painful factor (touch).

The second group of receptors - bimodal, reacts simultaneously to mechanical (compression, pricking, squeezing the skin) and temperature influences (temperature increases above 400 C and decreases below 100 C). Mechanically and temperature-stimulated receptors are associated with myelin A-delta fibers. C-related receptors

fibers are also excited by mechanical and cold factors.

Polymodal pain receptors are associated predominantly only with C fibers and are excited by mechanical, temperature and chemical stimuli (Yu.P. Limansky, 1986, Robert B. Daroff et al, 2012, H.R. Jones et al, 2013).

According to the mechanism of excitation, pain receptors are divided into mechano- and chemonoreceptors. The bulk of mechanoreceptors are associated with A-delta fibers and are located in the skin, joint capsules and muscles. Chemonoreceptors are associated only with C fibers. They are mainly found in the skin and muscles, as well as in internal organs, and respond to both mechanical and thermal factors.

Somatic nociceptors are localized in the skin, muscles, tendons, joint capsules, fascia, and periosteum. Visceral are located in the internal organs. Polymodal nociceptors are found in most internal organs. There are no nociceptors in the brain, but there are quite a lot of them in the meninges. Both somatic and visceral nociceptors are free nerve endings.

All pain receptors perform a signaling function, because they inform the body about the danger of the stimulus and its strength, and not about its nature (mechanical, thermal, chemical). Therefore, some authors (L.V. Kalyuzhny, L.V. Golanov, 1980) divide pain receptors depending on their location, signaling damage to individual parts of the body:

Nociceptors that control the integument of the body (skin, mucous membranes).

Nociceptors that control tissue integrity and homeostasis. They are located in organs, membranes, including blood vessels, and respond to metabolic disorders, oxygen deficiency, and stretching.

Features of nociceptors

Nociceptors are characterized by the following features:

Excitability;

Sensitization (sensitization);

Lack of adaptation.

Pain receptors belong to high-threshold structures. This means that their excitation and the formation of a pain impulse is possible under the influence of high-intensity stimuli that can cause damage to tissues and organs. It should be noted that the threshold for excitation of nociceptors, although high, is still quite variable, and in a person depends on hereditarily determined characteristics, including personality traits, emotional and somatic state, weather and climatic conditions, and the action of previous factors. For example, pre-warming the skin increases the sensitivity of nociceptors to thermal influences.

Protein receptors (nociceptors) are specific protein molecules, the conformation of which, under the influence of high temperature, chemical damaging factors and mechanical damage, forms an electrical pain impulse. On the surface of nociceptors there are many other specific protein molecules, the excitation of which increases the sensitivity of nociceptors. The formation of substances that interact with them contributes to the development of inflammation. These include a number of cytokines, an increase in hydrogen ions due to circulatory disorders and the development of hypoxia, the formation of kinins due to activation of the kinin system of the blood plasma, excess ATP as a result of the release of destroyed cells, histamine, serotonin, norepinephrine and others. It is with their formation at the site of inflammation that increased sensitivity (hyperalgesia) or peripheral pain sensitization is associated.

It is believed that the generation of an action potential and its propagation occurs through the opening of calcium and sodium channels. It has been proven that exogenous and endogenous factors can facilitate or suppress (local anesthetics, antiepileptics) the spread of pain impulses through their influence on sodium, potassium, calcium, chloride ion channels (Mary Beth Babos et all, 2013). Moreover, the action potential is formed and propagated when sodium, calcium, chlorine enters the neuron or potassium leaves the cell.

Since inflammation produces many substances that form peripheral hyperalgesia, the use of non-steroidal anti-inflammatory drugs for the treatment of pain becomes clear.

The mechanism of excitation of pain receptors is complex and lies in the fact that algogenic factors increase the permeability of their membrane and stimulate the entry of sodium with the development of the depolarization process, which results in the occurrence of a pain impulse and its transmission along pain pathways.

The mechanism of formation of the pain impulse in the nociceptor is presented in detail in a number of articles (H.C. Hemmings, T.D. Eden, 2013; G.S. Firestein et al, 2013)

As studies by academician G.N. show. Kryzhanovsky and his many students, the occurrence of a pain impulse may be associated with a weakening of various parts of the anti-nociceptive system, when neurons begin to spontaneously undergo depolarization with the formation of impulses that form pain.

The pain system has neuroplasticity, that is, it changes its response to incoming impulses.

In normal tissue, pain nociceptors have a high pain threshold and therefore mechanical, physical, chemical algogens, in order to cause the formation of a pain impulse, must cause tissue damage. At the site of inflammation, the pain threshold decreases and sensitivity increases.

activity not only of nociceptors, but also of the so-called “sleeping” nociceptors, which may not be excited by the primary action of mechanical, physical and chemical algogens.

At the site of inflammation (Gary S. Firestein et al, 2013), high-threshold nociceptors (A - delta and C - fibers) are activated by low mechanical pressure with the release of excitatory amino acids (glutamate and aspartate), as well as neuropeptides, especially substance P and calcitonin gene-related peptide (calcigenin), which, through interaction with AMPA and NMDA receptors, neuropeptide, prostaglandin, interleukin (especially ^-1-beta, ^-6, TNF-alpha), activate the postsynaptic membrane of the second neuron of the dorsal horns of the spinal cord. According to (R.H. Straub et al, 2013, Brenn D. et al, 2007), the injection of IL-6 and TNF-alpha into the joint of experimental animals causes a sharp increase in impulses from the joint along the sensory nerve, which is considered as an important factor in peripheral sensitization.

In neuropathic pain, an important role in the formation of sensitization belongs to such pro-inflammatory cytokines as interferon gamma, tumor necrosis factor alpha, IL-17. At the same time, anti-inflammatory cytokines such as IL-4 and IL-10 are believed to reduce the intensity of hyperalgesia (Austin P.J., Gila Moalem-Taylor, 2010).

These changes lead to long-term hypersensitivity of the dorsal root ganglion.

Substance P is formed in the spinal ganglion, 80% of which goes to the peripheral axons, and 20% to the terminal axons of the first pain neuron of the spinal cord (M.H. Moskowitz, 2008)

As mentioned earlier, when damaged, substance P and calcitonin gene-related peptide are released from the nociceptor of the first pain neuron. It is believed that these neurotransmitters have a pronounced vasodilator, chemotactic effect, also increase microvascular permeability and, thus, promote exudation and emigration of leukocytes. They stimulate mast cells, monocytes, macrophages, neutrophils, dendritic cells, providing a pro-inflammatory effect. Calcitonin gene-related peptide, as well as the amino acid glutamine, have the same proinflammatory and chemotactic effect. All of them are released by the peripheral nerve terminal and play an important role in the formation and transmission of the pain impulse and the development of not only local (at the site of injury), but also systemic reactions (H.C. Hemmings, T.D. Eden, 2013; G.S. Firestein et al, 2013). According to M.L. Kukushkina et al., 2011, such excitatory acids as glutamate and aspartate are found in more than half of the spinal ganglia and, when formed in them, enter the presynaptic terminals, where, under the influence of an incoming pain impulse, they are released into the synaptic cleft, facilitating the propagation of the impulse in the spinal and head

brain. Important importance in the formation of peripheral sensitization and hyperalgesia is attached to a number of biologically active substances formed at the site of damage. These are histamine, serotonin, prostaglandins, especially bradykinin, cytokines (TNF-alpha, interleukin-1, interleukin-6), enzymes, acids, ATP. It is believed that it is on the membrane of C-fibers that there are

the receptors with which they interact, forming peripheral hyperalgesia, including allergic reactions, and, ultimately, forming secondary non-localized somatic and visceral pain.

The structure and function of the multimodal nociceptor C-fibers are the most studied (Fig. 1).

Rice. 1. Approximate structure of a polymodal nociceptor C fiber. (S.Z.B^et, Ya.N^gaib, 2013). BR - pain substance, NA - norepinephrine, cytokines (TNF - alpha, IL-6, IL-1 beta), NGF - nerve growth factor.

Bradykinin increases intracellular calcium and increases the formation of prostaglandins; substance P increases nociceptor expression and promotes long-term sensitization; serotonin enhances the entry of sodium and calcium, increases the activity of AMPA receptors and forms hyperalgesia; prostaglandins increase nociception and promote hyperalgesia.

This means that inflammatory mediators formed at the site of injury not only cause excitation of numerous nociceptor receptors, but also increase its sensitivity. Therefore, taking non-steroidal anti-inflammatory drugs that block the formation of prostaglandins and other biologically active substances suppresses the manifestations of pain.

Nerve conductors of pain impulses

According to modern data, pain impulses, after their occurrence in nociceptors, are transmitted along thin myelinated (A - delta) and unmyelinated C - nerve fibers.

A - delta fibers are found in the skin, mucous membranes, and parietal peritoneum. These thin myelinated nerve fibers

drive pain impulses quite quickly, at a speed of 0.5 to 30 m/sec. It is believed that their nociceptors are quickly excited by the action of damaging factors (algogens) and form acute (primary) localized discriminative somatic pain when a person or animal accurately determines the location of the damage, in other words, the source of pain.

Thin unmyelinated nerve fibers (C fibers) are distributed in the same structures as A delta fibers, but they are significantly distributed in deep tissues - muscles, tendons, visceral peritoneum and internal organs. They take part in the formation of dull, burning and poorly localized (secondary) pain.

In muscles and joints there are A - alpha and A - beta fibers. The first fibers are important for proprioception, and A - beta responds to mechanical stimulation such as touch, vibration. They are given great importance in the mechanisms of acupuncture (Baoyu Xin, 2007). In acupuncture, afferent impulses along thick A-alpha and A-beta fibers cause inhibition of the substantia gelatinosa, forming the closure of the gate in accordance with the gate theory

Melzack and Wall. If the pain signal is significant, it undergoes gate control and forms the sensation of pain. In turn, the pain signal can cause the involvement of the central structures of the antinociceptive system and neutralize pain due to humoral and descending inhibitory influences.

A pain impulse is also generated, as a rule, by mediators formed at the site of damage (for example, at the site of inflammation). The pain impulse spreads along such fibers (C fibers) more slowly (at a speed of 0.5 - 2 m/sec). The speed of propagation of the pain impulse is approximately 10 times slower compared to A-delta fibers and their pain threshold is much higher. Therefore, the algogenic factor must be

much greater intensity. These fibers take part in the formation of secondary, dull, poorly localized, diffuse, prolonged pain. At the site of injury, a number of chemical pain mediators are formed, such as substance P, prostaglandins, leukotrienes, bradykinin, serotonin, histamine, catecholamines, cytokines, stimulating mainly C - nociceptors. (Henry M. Seidel et al, 2011) .

Most primary afferents are formed by neurons localized in the spinal ganglia. As for the visceral nociceptive afferent fibers (A-delta and C fibers), they are also derivatives of the dorsal root ganglion, but are part of the autonomic nerves (sympathetic and parasympathetic) (Fig. 2).

Paravertebral ganglia

Lumbar colonic n.

Rice. 2. Sympathetic (left) and parasympathetic (right) innervation of various internal organs. (Chg - celiac ganglion; Vbg - superior mesenteric ganglion; Nbg - inferior mesenteric ganglion). (S.EcebaL, 2000).

The role of spinal cord structures in the formation of pain

According to modern concepts, pain impulses arrive only along thin myelinated (A-delta) and unmyelinated C-fibers to cells I - VI of the laminae of the dorsal horn (gray matter of the spinal cord). A - delta and C - fibers form branches or collaterals that penetrate the spinal cord over short distances, forming synapses. This ensures the involvement of several segments of the spinal cord in the formation of pain. According to A.B. Danilova and O.S. Davydova, 2007, A-delta fibers end in plates I, III, V. C-fibers (unmyelinated) enter II

plate. In addition to the posterior horns of the spinal cord, impulses enter the nucleus of the trigeminal nerve, as an analogue of the spinal cord. As for the primary pain afferents from the visceral organs, according to Bayers and Bonica (2001), they enter diffusely into the I, V, X plates of the dorsal horns of the spinal cord. According to H.R. Jones et al, 2013; M.H. Moskowitz, 2008 specific pain neurons that respond exclusively to painful stimuli are found in plates I, II, IV, V, VI of the dorsal horns of the spinal cord, causing the formation of postsynaptic potentials.

According to Susuki R., Dickenson A.N. (2009), peripheral terminals of pain and non-pain fibers enter different layers of the spinal cord (Fig. 3).

Oncephalic new neuron

A - alpha, A - beta

A - delta, C - fibers - o-

Second neuron

Rice. 3. Receipt of painful and non-painful information into various layers of the lumbar spinal cord (R. Susuki, A.H. Dickenson, 2009; E. Ottestad, M.S. Angst, 2013).

In the dorsal horn of the spinal cord, the terminal of the primary pain neuron forms synapses with the secondary neuron (laminas I and II) and interneurons located in various layers of the dorsal horn.

It is believed that visceral afferent fibers end in plate V and less in plate I of the posterior horn. According to J. Morgan Jr. and S. Magid (1998), plate V reacts to noci- and non-nociceptive sensory impulses and takes part in the formation of somatic and visceral pain.

Neurons localized in layer V (plate) of the posterior horn of the spinal cord are important in the formation of pain and anti-nociception (A.D. (Bud) Craig, 2003). These are big

nerve cells whose dendrites extend into most layers of the dorsal horn of the spinal cord. They receive afferent information from mechano- and proprioceptors along large myelinated afferent fibers from the skin and deep structures, as well as pain impulses along A-delta and C-fibers. In layer V of the dorsal horn there are large cells, the dendrites of which are distributed in most layers of the dorsal horn. They receive information from large-diameter myelinated primary afferents from the skin and deep structures, as well as from A-delta fibers and polymodal C-fibers, that is, information from mechano-, proprio-, as well as nociceptors comes here (Fig. 4).

Acute burning cold

Pain bsgl

Rice. 4. Anatomical basis for afferent flow to specific cells of the dorsal horn of the spinal cord to lamina I and integration with cells of lamina V. (A.D. Craig 2003).

Pain impulses entering the spinal cord along thin unmyelinated C fibers release two important neurotransmitters - glutamate and substance P.

Glutamate acts instantly and its effect lasts several milliseconds. It stimulates calcium entry into the presynaptic terminal and forms central pain sensitization. Realization occurs through the stimulation of NMDA and AMPA receptors.

Substance P is released slowly, increasing in concentration over seconds or minutes. It activates NMDA, AMPA and neurokinin-1 receptors, forming short-term and long-term sensitization.

Substance P, which potentiates the release of glutamate and aspartate, which, as well as substance P, calcitonin gene-related peptide, neurokinin-A and galanin, increase pain sensitivity in the spinal cord. ATP interacts with p2Y receptors and increases the flow of calcium into the terminal of the first neuron. Serotonin increases the entry of sodium and calcium into the terminal, increases the activity of AMPA receptors and also produces hyperalgesia. Prostaglandins increase sensitivity, forming central hyperalgesia. Norepinephrine, through alpha-1 adrenergic receptors, increases sensitivity. (Gary S. Firestein at al, 2013) (Figure 5).

Rice. 5. Neurotransmitters that promote the transmission of nerve impulses and form the central

hyperalgesia. (M.V. Baobov e!a1, 2013) .

Studies show that the terminal section of spinal ganglion neurons forms synapses with interneurons of the dorsal horn of the spinal cord, promoting the release of substances that inhibit the transmission of pain impulses (GABA, encephalins, norepinephrine, glycine).

Interneurons transmit impulses to various structures of the brain. They also play an important role in the transmission of descending inhibitory influences from the structures of the brainstem and interstitial brain at the level of the dorsal horns of the spinal cord. Two groups of receptors are widely distributed in the dorsal horn of the spinal cord (monoaminergic, including adrenergic, dopamine and serotonergic and GABA/glycinergic). All of them are activated during descending pain control. In addition, with the help of interneurons of the posterior horn, they are transmitted to the motor and sympathetic neurons of the anterior horn of the spinal cord, forming an unconscious motor reaction at the segmental level and a sympathetic effect.

Most interneurons, as already mentioned, are localized in the I and II plates of the dorsal horn of the spinal cord, have a tree-like shape, the dendrites of which penetrate deep into several plates.

According to E.Ottestad, M.S.Angst, 2013, in layer II of the dorsal horn, depending on the structure and function, insular, central, radial and vertical interneurons are distinguished. Islet cells are inhibitory (they secrete GABA) and have an elongated dendritic shape, extending along the rostrocaudal axis. The central cells are of a similar configuration, but with shorter dendritic branches. It is believed that their function is inhibitory and excitatory. Radial cells have compact dendrites of a vertical conical fan shape. Radial and most vertical interneurons perform the function of transmitting impulses (excitation), since they secrete the main neurotransmitter of pain - glutamate.

There is evidence that islet interneurons and most central interneurons receive pain information via C fibers, while vertical and radial cells receive pain information via C and A delta afferents.

Receptors of synapses of the dorsal horn of the spinal cord, such as NMDA, AMPA, take part in the transmission and spread of pain impulses

and NK - 1. It has now been established that NMDA receptors are found on the membranes of all neurons of the nervous system. Their activity, as well as AMPA receptors, neurokinin - 1

receptors is suppressed by the presence of magnesium ions. Their excitation is associated with the supply of calcium (C.W. Slipman et al, 2008; M.H. Moskowitz, 2008; R.H. Straub, 2013) (Fig. 6).

Glutamate

Psesynapgic

terminal

Rice. 6. Scheme of synaptic transmission of pain impulses in the dorsal horn of the spinal cord.

As mentioned earlier, the arrival of a pain impulse into the presynaptic terminal stimulates the release of the main neurotransmitters of pain (glutamate, substance P), which, entering the presynaptic terminal, interact with NMDA-, AMPA-, neurokinin-1- (N^1-) receptors, providing the supply of calcium ions and displacing magnesium ions, which normally block their activity. The released glutamate is a source for the formation of GABA, the most important humoral mechanism of antinociception at the level of the spinal cord.

When NMDA receptors of the postsynaptic membrane are activated, the formation of nitric oxide (NO) is stimulated, which, entering the presynaptic terminal, enhances the release of glutamate from the presynaptic terminal, causing

contributing to the formation of central hyperalgesia at the level of the spinal cord.

Neurotransmitters in the dorsal horn of the spinal cord, interacting with receptors, open depolarizing sodium and calcium channels, allowing pain impulses to enter the central nervous system. Glutamate binds to NMDA and AMPA receptors, ATP binds to P2X receptors, and substance P binds to N^1 receptors. Released here, under the influence of impulses from the central nervous system, GABA-A and -B cause hyperpolarization of chloride and potassium channels, and opiates and norepinephrine stimulate hyperpolarization of potassium channels and, thus, block impulse transmission to the central nervous system. (M.V. Babos, 2013) . This is the basis of the so-called system of descending inhibitory influences at the level of the posterior horn of the spinal cord (Fig. 7).

Rice. 7. Mechanisms of descending inhibitory influences at the level of the posterior horn of the spinal cord.

Glial cells and astrocytes play an important role in the mechanism of pain formation. They perform an integral function in the formation of pain sensation. Microglial cells are macrophages of the central nervous system that provide immunological surveillance and host defense. In addition to phagocytic activity, they secrete complement and cytokines. Since astrocytes are located next to neurons, they form synapses and release not only ATP, but also bind to chemokines, cytokines and prostanoids. Glial cells are thought to be involved in pain modulation when activated by injury and inflammation. Neurons in the dorsal horn of the spinal cord form the neospinothalamic tract, which produces rapid or primary localized pain. Secondary neurons located in plastic V

not the dorsal horn, known as broadly dynamic neurons, since they are activated by both painful stimuli of somatic and visceral origin, and impulses from tactile, temperature and deep sensitivity receptors. These neurons form the paleospinothalamic tract, which produces secondary or non-localized pain. (Mary Beth Babos et al, 2013)

In the spinal cord, pain impulses enter the brain through the lateral (neospinothalamic, neotrigeminothalamic, posterocolumnar, spinocervical tract) and medial systems (paleospinothalamic, paliotrigeminothalamic tract, multisynaptic propriospinal ascending systems) (A.B. Danilov, O. S. Davydov, 2007, Reshetnyak V.K., 2009).

LITERATURE

1. Kassil, G.N. The Science of Pain. - M., 1969. - 374 p.

2. Jones H.R., Burns T.M., Aminoff M.J., Pomeroy S.L. Pain. Pain Anatomy Ascending Pathways Endorphin System // Netter Collection of Medical Illustrations: Spinal Cord and Peripheral Motor and Sensory Systems. - 2013. -Second Edition, Section 8. - P. 201 - 224.

3. Limansky, Yu.P. Physiology of pain. - Kyiv, 1986. - 93 p.

4. Robert B. Daroff, Gerald M. Fenichel, Joseph Jankovic, John C. Mazziotta. Principles of Pain Management // Bradley's Neurology in Clinical Practice. - 2012. - Sixth Edition, Ch. 44. - P. 783 - 801.

5. Mary Beth Babos, BCPS, PharmD, CDE, Brittany Grady, Warren Wisnoff, DO, Christy McGhee, MPAS PA-C. Pathophysiology of Pain. Disease-a-Month, 2013 -10-01, volume 59, Issue 10, P. 330-335

6. Hemmings H.C., Eden T.D. Pharmacology and Physiology for Anesthesia // Nociceptive physiology. - 2013. - Chapter 14. - P. 235-252.

7. Straub R.H., Gary S. Firestein, R.C. Budd, S.E. Gabriel, I.B. Mclinnes, J.R. O Doll. Neural Regulation of Pain and Inflammation // Kelly's Textbook of Rheanimatology, Ninth edition. - 2013. - Chapter 29. - P. 413-429.

8. Austin P.J., Gila Moalem - Taylor. The neuro-immune balance in neuropathic pain: Involvment of inflammatory immune cells and cytokines // Journal of Neuroimmunology. - 2010. - No. 229. - P. 26-50.

9. Moskowitz M.H. Central influences on Pain // Inventional spine an algorithmic approach / Curtis W., Slipman M.D., Richard Derby M.D. et al. - Elsevier. - 2008. - P. 39-52.

10. Seidel H.M., Ball J.W., Dains J.E., Flynn J.A., Solomon B.S., Stewart R.W. Assessment of Pain // In Mosby's Guide to physical Examination. - 2011. - Seventh edition. - Chapter 7. - P. 140 - 149.

11. Danilov, A.B., Davydov, O.S. Neuropathic pain. - M., 2007. - 191 p.

12. Ottesad E. Nociceptive Physiology/ E. Ottestad, M.S. Angst // Pharmacology and Physiology for Anesthesia // H.C. Hemmings et al. - Philadelphia: Saunders; Elsevier. - 2013. - Ch. 14. - P. 235-252.

13. Morgan Edward J. Jr., Magid S. Clinical anesthesiology: a guide for anesthesiologists, resuscitators and medical students. universities / Transl. from English edited by A.A.Bunyatyan. - St. Petersburg: Nevsky Dialect: M.: BINOM. - 1998. - Book. 1: Equipment and monitoring. Regional anesthesia. Treatment of pain. - 431 p.

14. Crage A.D. (Bud). Pain mechanisms: Labeled lines versus convergence in Central processing // Ann. Rev. Neurosci. - 2003. - No. 26. - P. 1-30.

15. Slipman C.W., Derby R. Frederic, A. Simione, Tom G. Mayer. Chou, L.H., Lenrow D.A., Salahidin Abdi, K.R.Chin / Interventional Spine: An Algorithmic Approach, First Edition, / Elsevier Inc. - Chapter 5, 39-52. 2008, Central influences on Pain.

16. Reshetnyak V.K. Mechanisms of pain regulation // Russian Journal of Pain. - 2009. - No. 3 (24). - P. 38-40.

The most common and current definition of pain, developed by the International Association for the Study of Pain (IASP), is that “pain is an unpleasant sensory and emotional experience associated with acute or potential tissue damage, or described in terms of such damage, or both.” , and other". Although several theoretical frameworks have been proposed to explain the physiological basis of pain, no single theory has been able to fully capture all aspects of pain perception.

The four most widely accepted theories of pain perception are specificity theory, intensity theory, pattern theory, and gate control theories. However, in 1968, Melzack and Casey described pain as multidimensional, where the dimensions are not independent but rather interactive. These dimensions include sensory-discriminative, affective-motivational, and cognitive-evaluative components.

Determining the most likely pain mechanism(s) is critical during clinical evaluation as this can guide the determination of the most appropriate treatment. Thus, criteria on which clinicians can base their decisions regarding appropriate classifications have been established using an expert consensus list of clinical indicators.

Friends, on November 30 - December 1, a seminar from the authors of the legendary bestseller Explain Pain will take place in Moscow.

The tables below were taken from Smart et al. (2010), who classified pain mechanisms as “nociceptive”, “peripheral neuropathic” and “central”, and identified both subjective and objective clinical indicators for each mechanism. Thus, these tables are complementary to any generally accepted data and serve as a basis for clinical decision-making in determining the most appropriate pain mechanism(s).

In addition, knowledge of factors that may alter pain and pain perception can help determine the patient's pain mechanism. The following are risk factors that can change pain and pain perception.

• Biomedical.
• Psychosocial or behavioral.
• Social and economic.
• Professional/work related.

Mechanism of nociceptive pain

Nociceptive pain is associated with activation of peripheral terminals of primary afferent neurons in response to noxious chemical (inflammatory), mechanical, or ischemic stimuli.

Subjective indicators

• Clear, proportional mechanical/anatomical nature of precipitating and relieving factors.
• Pain associated with and proportional to injury or pathological process (inflammatory nociceptive), or motor/postural dysfunction (ischemic nociceptive).
• Pain localized to the area of ​​injury/dysfunction (with or without a referred component).
• Typically rapid reduction/disappearance of pain consistent with expected tissue healing/repair time.
• Efficacy of non-steroidal anti-inflammatory drugs/analgesics.
• Periodic (sharp) nature of pain, which may be associated with movements/mechanical load; may be a constant dull aching or throbbing sensation.
• Pain combined with other symptoms of inflammation (eg, swelling, redness, heat).
• No neurological symptoms.
• Pain that started recently.
• A clear daily or 24-hour pattern of symptoms (ie, morning stiffness).
• No or insignificant association with maladaptive psychosocial factors (eg, negative emotions, low self-efficacy).

Objective indicators

• Clear, consistent and proportional mechanical/anatomical pattern of pain reproduction during movement/mechanical testing of target tissues.
• Localized pain on palpation.
• Absence or expected/proportional ratio of results (primary and/or secondary) of hyperalgesia and/or allodynia.
• Antalgic (i.e. pain-relieving) postures/movements.
• The presence of other cardinal signs of inflammation (swelling, redness, heat).
• Absence of neurological signs: negative neurodynamic tests (eg, straight leg raise test, brachial plexus tension test, Tinel test).
• Absence of maladaptive pain behavior.

Mechanism of peripheral neuropathic pain

Peripheral neuropathic pain is initiated or caused by a primary lesion or dysfunction of the peripheral nervous system (PNS) and involves multiple pathophysiological mechanisms associated with altered nerve function and reactivity. Mechanisms include increased excitability and abnormal impulse generation, as well as increased mechanical, thermal and chemical sensitivity.

Subjective indicators

• The pain is described as burning, shooting, sharp, aching, or electric shock-like.
• History of nerve injury, pathology, or mechanical injury.
• Pain in combination with other neurological symptoms (eg, tingling, numbness, weakness).
• The pain is characterized by a dermatomal distribution.
• Pain does not change in response to NSAIDs/analgesics and is relieved by antiepileptic drugs (eg, Neurontin, Lyrica) or antidepressants (eg, Amitriptyline).
• Pain of high severity (ie, easily provoked and requiring more time to calm down).
• Mechanical pattern to aggravating and mitigating factors associated with activity/posture associated with movement, loading or compression of nervous tissue.
• Pain in combination with other dysesthesias (eg, crawling, electric shock, heaviness).
• Delayed pain in response to movement/mechanical stress.
• The pain is worse at night and is associated with sleep disturbances.
• Pain associated with psychological factors (such as distress, emotional disturbances).

Objective indicators

• Provoking pain/symptoms using mechanical/motor tests (i.e. active/passive, neurodynamic) that move/load/compress neural tissue.
• Provoking pain/symptoms when palpating the relevant nerves.
• Positive neurological findings (including altered reflexes, sensation and muscle strength in dermatomal/myotomy or cutaneous distribution).
• Antalgic position of the affected limb/body part.
• Positive findings of hyperalgesia (primary or secondary) and/or allodynia and/or hyperpathia within the pain distribution area.
• Delayed pain in response to movement/mechanical testing.
• Clinical studies confirming a peripheral neuropathic pattern (eg, MRI, CT, nerve conduction tests).
• Signs of autonomic dysfunction (such as trophic changes).

Note: Ancillary clinical studies (eg, MRI) may not be necessary for clinicians to classify pain as peripheral neuropathic.

Mechanism of central pain

Central pain is pain initiated by or resulting from a primary lesion or dysfunction of the central nervous system (CNS).

Subjective indicators

• Disproportional, non-mechanical, unpredictable nature of pain provocation in response to multiple/non-specific exacerbation/relief factors.
• Pain that persists beyond the expected tissue healing/recovery time.
• Pain that is disproportionate to the nature and extent of the injury or pathology.
• Widespread, non-anatomical distribution of pain.
• History of unsuccessful interventions (medical/surgical/therapeutic).
• Strong association with maladaptive psychosocial factors (i.e., negative emotions, low self-efficacy, maladaptive beliefs and illness behaviors modified by family/work/social life, medical conflict).
• Pain does not decrease in response to NSAIDs, but becomes less intense when taking antiepileptic drugs and antidepressants.
• Reports of spontaneous (ie, stimulus-independent) pain and/or paroxysmal pain (ie, sudden relapses and worsening pain).
• Pain combined with severe disability.
• More constant/unchanging pain.
• Pain at night/sleep disturbance.
• Pain in combination with other dysesthesias (burning, cold, pins and needles).

• Pain of high severity (i.e., easily provoked, requiring a lot of time to calm down).
• Acute pain in response to movement/mechanical stress, activities of daily living.
• Pain in combination with symptoms of dysfunction of the autonomic nervous system (changes in skin color, excessive sweating, trophic disorders).
• History of CNS disorder/injury (eg, spinal cord injury).

Objective indicators

• Disproportional, inconsistent, non-mechanical/non-anatomical pattern of pain in response to movement/mechanical testing.
• Positive findings of hyperalgesia (primary, secondary) and/or allodynia and/or hyperpathia within the pain distribution.
• Diffuse/non-anatomical areas of pain/tenderness on palpation.
• Positive identification of various psychosocial factors (eg, catastrophizing, avoidance, distress).
• No signs of tissue damage/pathology.
• Delayed pain in response to movement/mechanical testing.
• Muscle atrophy.
• Signs of dysfunction of the autonomic nervous system (changes in skin color, sweating).
• Antalgic postures/movements.

Clinical examples

The following clinical examples will complement the information given above regarding the likely mechanisms of pain.

Case No. 1

Patient “A” is a 58-year-old retired woman. History of current complaint: about 1 month ago, pain suddenly occurred in the lower back, radiating to the right leg. The patient complains of constant dull pain in the lower back on the right (B1), VAS 7-8/10, extending along the front of the right leg to the knee (B2), which is intermittent 2/10 and associated with burning pain above the knee. B1 is aggravated during curling, when the right leg is the dominant one, when walking for more than 15 minutes, driving for more than 30 minutes and climbing stairs. B2 appears when sitting on hard surfaces for more than 30 minutes and prolonged bending. Coughing and sneezing do not increase pain. Patient “A” suffered a lower back injury about 10 years ago and underwent treatment with a good recovery. What is the mechanism of pain?

Case No. 2

Patient “B” is a 30-year-old man, an accountant. History of current complaint - sudden onset - inability to turn and tilt the neck to the right, which began 2 days ago. In this case, the patient's head is in a position of slight rotation and tilt to the left. The patient reports a low level of pain (VAS 2-3/10), but only when turning the head to the right, and the movement is “stuck.” The patient denies any numbness, tingling, or burning pain, but NSAIDs are ineffective. Heat and gentle massage are also known to reduce symptoms. Objective examination indicates that passive physiological and incremental movements to the right have a smaller amplitude. All other cervical movements are within normal limits. What is the dominant mechanism of pain?

Case No. 3

Patient “C” is a 25-year-old student. The history of the current complaint is a traffic accident about a month ago on the way to school - the patient was hit from behind. Since then, the patient has had 6 sessions of physical therapy without any improvement in her persistent neck pain. The pain is localized on the left at the level of C2-7 (VAS 3-9/10) and varies from dull pain to sharp pain depending on the position of the neck. The pain gets worse when sitting or walking for more than 30 minutes and when turning to the left. At night, when turning in bed, the patient may wake up from pain; coughing/sneezing does not increase the pain. The pain is sometimes relieved by heat and stretching. NSAIDs are ineffective. The results of instrumental diagnostics are unremarkable. General health is generally good. Minor sprains while playing sports that never required treatment. The patient expresses concern about driving (she has never driven since the accident). The patient also reported increased sensitivity in the lower extremities. What is the leading mechanism of pain?

There are different mechanisms of pain formation(nociceptive system) and mechanisms for controlling the feeling of pain (antinociceptive system). The feeling of pain is formed at different levels of the nociceptive system: from the sensory nerve endings that perceive pain to the pathways and central nervous structures.

Perceiving apparatus.

It is believed that painful (nociceptive) stimuli are perceived by free nerve endings (they are able to register the effects of various agents as painful). There are probably specialized nociceptors - free nerve endings that are activated only by the action of nociceptive agents (for example, capsaicin).
- An extremely strong (often destructive) effect on sensitive nerve endings of other modalities (mechano-, chemo-, thermoreceptors, etc.) can also lead to the formation of a sensation of pain.
- Algogens - pathogenic agents that cause pain - lead to the release of a number of substances from damaged cells (they are often called pain mediators) acting on sensitive nerve endings. Algogens include kinins (mainly bradykinin and kallidin), histamine (causes a feeling of pain when administered subcutaneously even at a concentration of 1 * 10-18 g/ml), high concentration of H+, capsaicin, substance P, acetylcholine, norepinephrine and adrenaline in non-physiological concentrations, some Pg.

Conducting pathways.

1) Spinal cord.
- Afferent pain conductors enter the spinal cord through the dorsal roots and contact the interneurons of the dorsal horns. It is believed that epicritic pain conductors end mainly in the neurons of laminae I and V, and protopathic pain - in the Rolandic substance (substantia gelatinosa) of laminae III and IV.
- In the spinal cord, convergence of excitation for different types of pain sensitivity is possible. Thus, C-fibers that conduct protopathic pain can contact neurons of the spinal cord that perceive epicritic pain from receptors in the skin and mucous membranes. This leads to the development of the phenomenon of segmental (“referred”) cutaneous-visceral pain (a feeling of pain in an area of ​​the body distant from the true place of pain impulse).

Examples of pain irradiation sensations of “false” pain may serve as:
- in the left hand or under the left shoulder blade during an attack of angina or myocardial infarction;
- spinal osteochondrosis can cause pain in the heart area and simulate angina or myocardial infarction;
- under the right shoulder blade when a stone passes (exits) through the biliary tract;
- above the collarbone in acute hepatitis or irritation of the parietal peritoneum;
- in the groin area if there is a stone in the ureter.

The occurrence of these segmental skin-visceral (“referred”) pain due to the segmental structure of innervation of the surface of the body and internal organs by spinal cord afferents.

1) Ascending tracts of the spinal cord.
- Epicritic pain conductors switch on neurons of laminae I and V, cross and ascend to the thalamus.
- The conductors of protopathic pain switch on the neurons of the dorsal horns, partially cross and ascend to the thalamus.

2) Brain pathways.
- The conductors of epicritic pain pass in the brain stem through the extralemniscal pathway, a significant part of them switches on the neurons of the reticular formation, and a smaller part - in the visual thalamus. Next, a thalamocortical pathway is formed, ending on neurons of the somatosensory and motor areas of the cortex.
- Protopathic pain conductors also pass through the extralemniscal pathway of the brain stem to the neurons of the reticular formation. Here “primitive” reactions to pain are formed: alertness, preparation for “escape” from the painful influence and/or elimination of it (withdrawing a limb, throwing away a traumatic object, etc.).

Central nervous structures.

Epicritic pain is the result of pain impulses ascending along the thalamocortical pathway to the neurons of the somatosensory zone of the cerebral cortex and excitation them. The subjective sensation of pain is formed precisely in the cortical structures.
- Protopathic pain develops as a result of activation mainly of neurons of the anterior thalamus and hypothalamic structures.
- A person’s holistic sensation of pain is formed with the simultaneous participation of cortical and subcortical structures that perceive impulses about protopathic and epicritic pain, as well as other types of influences. In the cerebral cortex, the selection and integration of information about the pain effect, the transformation of the feeling of pain into suffering, and the formation of purposeful, conscious “pain behavior” occur. The purpose of this behavior is to quickly change the body’s functioning to eliminate the source of pain or reduce its degree, to prevent damage or reduce its severity and scale.

148. Alcoholism: etiology, pathogenesis (stages of development, formation of mental and physical dependence). Fundamentals of pathogenetic therapy. Alcoholism is a disease, a type of substance abuse, characterized by a painful addiction to alcohol (ethyl alcohol), with mental and physical dependence on it. Negative consequences can be expressed by mental and physical disorders, as well as disturbances in the social relationships of the person suffering from this disease

Etiology (origin of the disease)

The emergence and development of alcoholism depends on the volume and frequency of alcohol consumption, as well as individual factors and characteristics of the body. Some people are at greater risk of developing alcoholism due to specific socioeconomic backgrounds, emotional and/or mental predispositions, and hereditary factors. The dependence of cases of acute alcoholic psychosis on the type of hSERT gene (encodes the serotonin transporter protein) has been established. However, to date, no specific mechanisms for the implementation of the addictive properties of alcohol have been discovered.

Pathogenesis (disease development)

Alcoholization in 76% of cases begins before the age of 20, including 49% in adolescence. Alcoholism is characterized by increasing symptoms of mental disorders and alcohol-specific damage to internal organs. The pathogenetic mechanisms of the effects of alcohol on the body are mediated by several types of action of ethanol on living tissues and, in particular, on the human body. The main pathogenetic link of the narcotic effect of alcohol is the activation of various neurotransmitter systems, especially the catecholamine system. At different levels of the central nervous system, these substances (catecholamines and endogenous opiates) determine various effects, such as increasing the threshold of pain sensitivity, the formation of emotions and behavioral reactions. Disruption of the activity of these systems due to chronic alcohol consumption causes the development of alcohol dependence, withdrawal syndrome, changes in critical attitudes towards alcohol, etc.

When alcohol oxidizes in the body, a toxic substance is formed - acetaldehyde, which causes the development of chronic intoxication of the body. Acetaldehyde has a particularly strong toxic effect on the walls of blood vessels (stimulates the progression of atherosclerosis), liver tissue (alcoholic hepatitis), and brain tissue (alcoholic encephalopathy).

Chronic alcohol consumption leads to atrophy of the mucous membrane of the gastrointestinal tract and the development of vitamin deficiency.