Pain is its types of mechanisms of formation. Mechanisms of pain formation. Pain development mechanisms. Mechanism of central pain

Irritation of the internal organs often causes pain, which is felt not only in the internal organs, but also in some somatic structures that are quite far from the site of pain. Such pain is called reflected (radiating).

The best-known example of referred pain is heart pain radiating to the left arm. However, the future physician should be aware that areas of pain reflection are not stereotyped, and unusual areas of reflection are observed quite often. Heart pain, for example, may be purely abdominal, it may 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 posterior roots in a certain spatial order. The cutaneous afferent fibers of each dorsal root innervate a limited area of the skin called the dermatomere (Figures 9–9). Referred pain usually occurs in structures that develop from the same embryonic segment, or dermatomere. This principle is called the "dermatomer rule". For example, the heart and the left arm are of the same segmental nature, and the testicle migrated with its nerve supply from the urogenital fold from which the kidneys and ureters arose. Therefore, it is not surprising that pain that has arisen 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 the same segmental level, but also a large number of sensory nerve fibers that pass as part of the spinothalamic pathways 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. The high speed, constancy and frequency of information about somatic pain helps the brain to fix the information that the signals entering the corresponding nerve pathways are caused by pain stimuli in certain somatic areas of the body. When the same nerve pathways are stimulated by the activity of visceral pain afferent fibers, the signal reaching the brain is not differentiated and the pain is projected onto 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 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- are involved in the occurrence of referred pain.

The anatomical basis for the occurrence of pain is the innervation of organs by thin myelinated (A-) nerve fibers. The endings of these nerve fibers are excited by high-intensity stimuli and thus, under physiological conditions, exhibit potentially damaging (noxic) stimulus effects. Therefore, they are also called nocireceptors. Excitation of peripheral nocireceptors, after processing in the spinal cord, is conducted to the central nervous system, where, finally, a sensation of pain arises. Under pathophysiological conditions, the sensitivity of peripheral noci-receptors, as well as the central processing of pain, increases, for example, in the context of inflammation. So the alarm signal of pain becomes a symptom requiring treatment.

Hypersensitivity in the region of peripheral nocireceptors may manifest itself as spontaneous activity or as sensitization to thermal or mechanical stimuli. A powerful influx of nociceptive information (neuronal activity at nocireceptors) from the area of inflammation can also cause increased pain processing in the spinal cord (central sensitization). This central sensitization is mediated, on the one hand, directly and acutely by a higher frequency of incoming action potentials and, at the same time, neurotransmitters and co-transmitters released in the spinal cord.

On the other hand, certain growth factors are also perceived on the periphery through specific receptors of sensory endings and transported to the cell nuclei of the dorsal root ganglions. There, they cause subacute changes in the expression of genes, such as neuropeptides and neurotransmitters, which in turn can enhance the perception of pain.

Pain alarm becomes a symptom in need of treatment

Spinal nociceptive neurons activate the lateral and medial thalamocortical systems via ascending pathways. At the same time, the lateral system, through the activation of the primary and secondary sensory cortex, especially in the discriminatory aspect of pain perception, and the medial system, through the activation of the anterior Cingulum, the insula, and the prefrontal cortex, are of particular importance for affective components.

The central nervous system, via descending pathways, modulates the processing of nociceptive information in the spinal cord. The inhibitory pathways are mostly derived from the periaquaductular gray cavity and Nucleus raphe magnus. For pain therapy, these descending pathways are of particular interest, as they are especially activated by opiates.

In the following, the details of the occurrence of pain are described. At the same time, for many reasons, peripheral mechanisms are affected; this however is not related to the meaning of the central components.

Peripheral mechanisms - primary afferent nociceptors s

Sensory proteins

The simplest mechanism that can cause inflammatory pain is direct irritation or sensitization of nociceptive nerve endings by inflammatory mediators. For a large number of mediators, specific receptors on sensory endings are known. In some of these receptors, their activation leads to the activation of depolarization and, at the same time, can excite these nociceptors. How the sources of these mediators are considered:

damaged tissue cells (ATP, potassium, enzymes, pH decrease, etc.),
blood vessels (bradykinin, endothelin),
stem cells (histamine, proteases, nerve growth factor NGF, tumor necrotizing factor TNF, etc.),
leukocytes (cytokines, prostaglandins, leukotrienes, etc.).
Acetylcholine, bradykinin, serotonin, acidic pH, adenosine triphosphate (ATP) and adenonosine are especially important as direct direct activators of nociceptors. With respect to endothelin, it is believed to play a special role in tumor-associated pain.

Along with activating receptors, nociceptive nerve endings are also equipped with inhibitory receptors. Opiate and cannabinoid receptors are considered the most important of them. The role of peripheral opioid receptors in modulating nociceptor responsiveness has already been studied in detail. Cannabinoid receptors (CB1 and CB2) have recently been described as a new target for analgesics, with the expression of CB2 receptors being particularly pronounced on inflammatory cells, while CB1 receptors among other experiments were carried out in peripheral nociceptors and the central nervous system.

The first results of the therapeutic use of cannabinoids are already available, but their place in pain therapy has not yet been established. It is worth noting that more recent research also proceeds from an interaction between opioids and cannabinoids, in which endogenous opiates are released upon administration of cannabinoids, or opiates release endogenous cannabinoids. In the following, receptors considered as a therapeutic target of analgesic therapy will be described in more detail.

Transient-Receptor-Potenzial (TRP) channels

Recently, a number of temperature-sensitive ion channels from the TRP (‘transient receptor potential) family of ion channels have been cloned. The best known representatives of this group is TRPV1 (Capsacin receptor), which can be activated by high temperature and low pH environment. Other members of the vanilloid family (TRPV1, TRPV2, TRPV3, TRPV4) are excited by heat stimulation, while the TRPM8 and TRPA1 (ANKTM1) channels respond to cooling or noxic cold stimuli. In addition to being activated by extreme cold, TPRA1 is also activated by the pungent natural constituents of mustard oil, ginger and cinnamon oil, as well as bradykinin.

TPRV1 activity is modified by rapid reversible phosphorylation and leads to sensitization or desensitization of the response to thermal stimulation and chemical irritability. A special role of TPRV1 is seen in the fact that this receptor, as an integrated element, determines chemical and physical irritability, which makes it a promising target for pain therapy. Along with short-term modulations of susceptibility, TRPV1 expression on nociceptive neurons is also regulated: increased expression is described in both inflammatory and neuropathic pain.

ASIC: "acid-sensing ion channels"

Tissue acidosis plays an important role in inflammation and exacerbates pain and hyperalgesia. Higher pH stimuli can activate TRPV1, whereas mild acidosis is primarily identified through activation of the ASIC (“acid-sensing ion channel”). Local administration of non-steroidal antiphlogistics can reduce the induced pain reaction by means of pH irritation, and this effect is most likely not based on the suppression of cyclooxygenase, but on the direct suppression of ASIC channels.

Bradykinin

Bradykinin - it is a vasoactive pro-inflammatory nonapeptide whose nociceptive effect on sensory terminals is mediated by bradykinin-B1 and B2 receptors. In this case, it is assumed that B1 receptors are expressed especially during the inflammatory process. Hypersensitivity to B1 and B2 agonists has also been described in humans as part of UV-induced inflammatory responses. Currently, there is still no clinical information on the therapeutic use of B1 and B2 antagonists; due to the special role of bradykinin receptors in pain and inflammation, they are of particular interest in chronic inflammatory diseases associated with pain, such as osteoarthritis.

Axonal proteins

Traditionally, the function of axonal ion channels to conduct an action potential in an all-or-nothing sense has been limited. Current data, however, indicate that the frequency of the action potential is also modulated axonally. In addition, ion channels important in the generation of neuronal membrane potentials are also potentially involved in the generation of spontaneous activity within neuropathic pain states. An example would be calcium-dependent potassium channels (sK), which, when conducting action potentials, cause slow hyperpolarization and, at the same time, a decrease in excitability. The reduction of these channels has already been described in traumatic nerve lesions with neuropathic pain.

The functional adversary of sK channels are hyperpolarization-induced currents (Ih), which are transmitted through cyclically nucleoid-modulated HCN channels (HCN: hyperpolarization-activated cyclic nucleotid-modulated). Increased expression of HCN channels is associated with the occurrence of spontaneous activity in neuropathic pain.

Sensitization of sensory or axonal neuronal ion channels will be considered separately for clarity, however, there are significant overlaps in the mechanisms of sensitization: thus axonal tetrodoxin-resistant voltage-dependent sodium channels (TTXr Na+) are also sensitized by such mediators that usually activate or sensitize sensory endings ( adenosine, prostaglandin E2 or serotonin).

Features of special classes of nociceptors

The strong relationship between axonal and sensory channels is also expressed in the fact that different classes of nerve fibers differ both in their sensory and axonal characteristics: with the functional distribution of primary afferencia according to their sensory features (for example, mechano-sensitive nociceptors, non-nociceptive cold receptors ) these groups exhibit highly specific patterns of activity-induced hyperpolarization. The pronounced high activity-induced hyperpolarization is specific to the so-called "silent nosoceptors", which play a special role in sensitization and neurogenic inflammation.

Neuro-immunological interactions

According to the clinical picture and the primary site of inflammation, inflammatory pain and neuropathic pain are distinguished. At the same time, in the first case, nociceptor terminals in the area of inflammation are excited or sensitized, and in neuropathic pain, on the contrary, the pain comes from damage that initially occurred on the nerve axon, but not on its sensitized ending.

Although the clinical picture of inflammatory and neuropathic pain differ from each other, however, current research suggests that local inflammation of the peripheral nerves plays a crucial role in the pathophysiology of neuropathic pain. In addition, non-neuronal cells appear to play an active role in the sensitization process: glial cells, which are activated as part of nerve injury, can sensitize neurons by releasing chemokines. This interaction illustrates the strong relationship between inflammation and nociception along with the already known and studied activity of inflammatory mediators in nociceptive nerve endings in clinically inflamed tissue.

There is a multifaceted interaction between myalinized nerve fibers, local tissue cells, and inflammatory cells. Keratinocytes can sensitize nociceptive endings through the release of acetylcholine and nerve growth factor (NGF); conversely, keratinocytes can be activated by neuropeptides (eg, substance P, CGRP) from nociceptors. A particular interaction exists between stem cells and nerve cells: a large number of stem cell mediators can sensitize nociceptive nerve endings (NGF, tryptase, TNF-a, histamine). NGF sensitizes nociceptors acutely by activating protein kinase A. In addition, NGF mediates increased expression of neuropeptides as well as sensory proteins such as the capsacin receptor, which is then again upregulated to the periphery.

There are multifaceted relationships between nerve fibers, local tissue cells and inflammatory cells.
Along with activating interactions between neurons, tissue cells, and inflammatory cells, there are also inhibitory interactions. As inhibitory mediators, neuropeptides are secreted by dermal neurons, such as vasointestinal vasopeptide, as well as endogenous opiates. Stem cells produce interleukin 10 and IL-1 receptor antagonists that act anti-inflammatory. Keratinocytes also synthesize melanin-stimulating hormone (a-MSH) and neutral neuropeptidase (NEP), which limits the action of activating neuropeptides.

Thus, a complex relationship of oppositely directed suppression and activation is manifested, and various "Reichweite" activating and inhibitory mediators are important for the spatial spread of inflammation.

Central mechanisms

Experience and common sense say that damaged areas of the body are more sensitive to pain. This form of hypersensitivity is called primary hyperalgesia and may be due to the local action of inflammatory mediators on the affected nerve endings. Primary hyperalgesia is contrasted with secondary hyperalgesia, which occurs in unaffected tissue around the injury site.

Around this lesion, cold, touch ("brush evoked hyperalgesia" or Allodinie) and needle-prick irritation (Pinprickhyperalgesia) are perceived as unpleasant or painful. The origin of this form of secondary hyperalgesia is not in the affected area itself. Rather, we are talking about the sensitization of spinal neurons by massive nociceptive stimulation and, as a result, altered spinal processing in the direction of nociception. Central sensitization can thus explain why pain and hypersensitivity do not remain strictly limited to the area of damage, but occupy much larger areas. The molecular mechanisms of central sensitization are not fully understood, but a significant role is played by glutamate receptors at the spinal level (NMDA and metabotropic receptors), which already serve as therapeutic targets (eg ketamine).

Many chronic pain conditions, however, cannot be explained by peripheral or spinal processing disorders, but are seen as the result of a complex interplay of genetic and psychosocial factors. Therefore, in clinical terms, there is a need for a multimodal and multidisciplinary approach to pain therapy. The importance of the learning process in the occurrence or treatment of chronic pain conditions has increased significantly in recent years.

The discovery of the role of cannabinoids in the elimination (erasing) of negative memory contents has demonstrated new possibilities for the combination of pharmacotherapy and behavior therapy. Comprehensive and promising possibilities for further analysis and therapeutic influence on the central mechanisms of pain, including electrical stimulation methods, cannot be described here due to lack of space.

Resume for practice

Peripheral mechanisms of pain are reflected in the strong interaction of neurons and surrounding tissue and inflammatory cells, which manifests itself in both irritating and inhibitory interactions and represents a variety of possible therapeutic targets. At the spinal level, sensitization processes lead to the spread of pain and contribute to chronicity. The processes of learning and erasure of adversive memory content are of great importance in chronic pain conditions for both pathophysiology and therapy.

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 commonly accepted theories of pain perception are specificity, intensity, pattern theory, and gate control theories. However, in 1968 Melzack and Casey described pain as multi-dimensional, where the dimensions are not independent but rather interactive. These dimensions include sensory-discriminatory, affective-motivational and cognitive-evaluative components.

Determining the most likely mechanism(s) of pain is essential during clinical evaluation as it can provide guidance in determining the most appropriate treatment. Thus, the criteria on which clinicians can base their decisions regarding appropriate classifications have been established through an expert consensus list of clinical indicators.

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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 measures for each mechanism. Thus, these tables are in addition 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 the factors that can alter pain and pain perception can help determine the patient's pain mechanism. The following are risk factors that can change pain and the perception of pain.

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

Mechanism of nociceptive pain

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

Subjective indicators

Clear, proportional mechanical/anatomical nature of provoking and facilitating factors.
Pain associated with and proportional to injury, or pathological process (inflammatory nociceptive), or motor/postural dysfunction (ischemic nociceptive).
Pain localized in the area of injury/dysfunction (with/without reflected component).
Usually a rapid reduction/disappearance of pain in line with the expected healing/tissue repair time.
Efficacy of non-steroidal anti-inflammatory drugs/analgesics.
Periodic (sharp) nature of pain, which may be associated with movements / mechanical stress; may be constant dull aching or throbbing.
Pain associated with other symptoms of inflammation (eg, swelling, redness, heat).
No neurological symptoms.
Pain that started recently.
Clear daily or 24-hour pattern of symptoms (i.e. morning stiffness).
No or little association with maladaptive psychosocial factors (eg, negative emotions, low self-efficacy).

Objective indicators

A 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) hyperalgesia and/or allodynia.
Antalgic (that is, pain-relieving) postures/movements.
The presence of other cardinal signs of inflammation (edema, 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 hyperexcitability 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 similar to an electric shock.
History of nerve injury, pathology, or mechanical damage.
Pain associated with other neurological symptoms (eg, tingling, numbness, weakness).
Pain is characterized by dermatomal distribution.
Pain does not change in response to NSAIDs/analgesics and improves with antiepileptic drugs (eg, Neurontin, Lyrica) or antidepressants (eg, Amitriptyline).
Pain of high severity (i.e. easily provoked and taking longer to calm down).
Mechanical pattern to aggravating and mitigating factors associated with activity/posture associated with movement, loading or compression of the nervous tissue.
Pain associated with other dysesthesias (eg, goosebumps, electric current, heaviness).
Delayed pain in response to movement/mechanical stress.
The pain intensifies at night and is associated with sleep disturbance.
Pain associated with psychological factors (such as distress, emotional disorders).

Objective indicators

Provoking pain/symptoms with mechanical/motor tests (i.e. active/passive, neurodynamic) that move/load/compress nerve tissue.
Provocation of pain/symptoms on palpation of the relevant nerves.
Positive neurological outcomes (including altered reflexes, sensation, and muscle strength in dermatomal/myotomy or cutaneous distribution).
Antalgic position of the affected limb/body part.
Positive results of hyperalgesia (primary or secondary) and/or allodynia and/or hyperpathy within the area of distribution of pain.
Delayed pain in response to movement/mechanical testing.
Clinical studies confirming a peripheral neuropathic character (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 or resulting from a primary lesion or dysfunction of the central nervous system (CNS).

Subjective indicators

Disproportionate, non-mechanical, unpredictable nature of pain provocation in response to multiple/non-specific exacerbation/reduction factors.
Pain that persists beyond the expected time for tissue healing/pathology recovery.
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 morbid behavior altered by family/work/social life, medical conflict).
The pain does not decrease in response to NSAIDs, but becomes less intense against the background of taking antiepileptic drugs and antidepressants.
Reports of spontaneous (i.e., stimulus-independent) pain and/or paroxysmal pain (i.e., sudden relapses and worsening of pain).
Pain associated with severe disability.
More constant/unchanging pain.
Pain at night/sleep disturbance.
Pain associated with other dysesthesias (burning, cold, tingling).

Pain of high severity (i.e., easily provoked, taking a long 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 (discoloration of the skin, excessive sweating, trophic disorders).
History of CNS disorder/injury (eg, spinal cord injury).

Objective indicators

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

Clinical examples

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

Case #1

Patient A is a 58-year-old retired woman. The history of the current complaint - about 1 month ago, there was a sudden onset of pain 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, radiating down 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 leading, 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 make the pain worse. Patient "A" suffered a lumbar injury about 10 years ago, underwent a course of treatment with a good recovery. What is the mechanism of pain?

Case #2

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

Case #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 been on 6 sessions of physiotherapy without any improvement in terms of persistent neck pain. The pain is localized on the left at C2-7 (VAS 3-9/10) and varies from dull pain to sharp pain depending on the position of the neck. The pain is aggravated by sitting and walking for more than 30 minutes and by turning to the left. At night, when turning in bed, the patient may wake up with pain, coughing / sneezing does not aggravate the pain. Pain is sometimes relieved by heat and stretching. NSAIDs are ineffective. The results of instrumental diagnostics without features. General health is generally good. Minor sprains during sports that never required treatment. The patient expresses concern about driving (never got behind the wheel after the accident). The patient also reported increased sensitivity in the lower extremities. What is the leading mechanism of pain?

Modern ideas about the functioning of the mechanisms of pain and anesthesia are based on the data of anatomical, morphological, neurophysiological and biochemical studies. Among them, two main scientific directions can be distinguished. The first of these includes the study of the anatomical nature and physiological properties of neuronal substrates that carry out the transmission of nociceptive impulses. The second direction is associated with the study of physiological and neurochemical mechanisms in individual brain formations under various types of influences leading to pain relief (Kalyuzhny, 1984).

Pain perception is provided by a complex nociceptive system, which includes a special group of peripheral receptors and central neurons located in many structures of the central nervous system and responding to damaging effects (Khayutin, 1976; Limansky, 1986; Revenko et al., 1988; La Motte et al. ., 1982; Meyer et al., 1985; Torebjork, 1985; Szoicsanyi, 1986).

pain receptors.

There are various types of nociceptors that control the integrity of the functioning of organs and tissues, and also respond to sharp deviations in the parameters of the internal environment of the body. Monomodal A-δ-mechanoreceptors and polymodal C-nociceptors predominate in the skin; bimodal (thermo- and mechanoreceptors) A-δ and C-nociceptors are also found (Cervero, 1985; Limansky, 1986; Revenko, 1988).

It is generally accepted that the somatic and visceral afferent systems differ in their properties. A-δ-fibers of the somatic afferent nociceptive system transmit somatically organized sensory information, which is subjected to spatial-temporal analysis in various parts of the brain and perceived as localized acute or stabbing pain. In the C-fibers of the somatic afferent nociceptive system, the intensity of the action of the nociceptive stimulus is encoded, which causes a feeling of diffuse burning, intolerable (secondary) pain and determines the complex motivational and emotional forms of behavior associated with it (Zhenilo, 2000).

Activation of the receptors of the visceral afferent nociceptive system usually manifests itself in vegetative reactions and is characterized by an increase in muscle tone, the development of an anxiety state, sensations of dull, diffuse (visceral) pain, often complicated by referred pain in the skin zones (Cervero, 1985; 1987; Zilber, 1984; Zhenilo, 2000 ).

Thus, nociceptors play a significant role in the formation of pain response. However, regardless of the mechanisms of the emergence of nociceptive information in the periphery, the processes occurring in the CNS are of key importance in the formation of pain. It is on the basis of the central mechanisms: convergence, summation, interaction of fast myelinated and slow unmyelinated systems at different levels of the CNS that the feeling and qualitative coloring of pain are created under the action of various nociceptive stimuli (Kalyuzhny, 1984; Mikhailovich, Ignatov, 1990; Bragin, 1991; Price, 1999).

Participation of the spinal cord in the transmission of pain impulses.

The first central link that perceives multimodal afferent information is the neuronal system of the dorsal horn of the spinal cord. It is a cytoarchitectonically very complex structure, which functionally can be considered as a kind of primary integrative center of sensory information (Mikhailovich, Ignatov, 1990; Valdman et al., 1990).

According to the data of A. V. Valdman and Yu. D. Ignatov (1990), convergent interneurons of the posterior horn of the spinal cord, most of which have ascending projections, are the first switching station of nociceptive impulses and are directly involved in the emergence of information of such a quality that the higher parts of the brain is regarded as pain and triggers complex mechanisms of response to pain. However, at present, there is every reason to believe that the activity of relay neurons associated with nociceptive afferentation, their responses to multimodal stimuli, the interaction of various afferent inputs on them, and, consequently, the formation of an ascending impulse flow, are modulated by neurons of the gelatinous substance (Rethelyi et al., 1982 ; Dubner and Bennett, 1983; Bicknell and Beal, 1984; Dubner et al., 1984; Perl, 1984; Iggo et al., 1985). After a very complex processing of pain afferentation in the segmental apparatus of the spinal cord, where it is affected by excitatory and inhibitory influences emanating from the peripheral and central parts of the nervous system, nociceptive impulses are transmitted through interneurons to the cells of the anterior and lateral horns, causing reflex motor and autonomic reactions. Another part of the impulses excites neurons whose axons form ascending pathways.

Ascending paths of pain impulses.

Nociceptive information entering the dorsal horns of the spinal cord enters the brain via two "classical" ascending afferent systems, the lemniscal and extralemniscal systems (Martin, 1981; Chignone, 1986). 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. It was also noted that there are no specialized pathways of pain sensitivity in the CNS, and the integration of pain occurs at various levels based on the complex interaction of lemniscal and extralemniscal projections (Kevetter, Willis, 1983; Ralston, 1984; Willis, 1985; Mikhailovich, Ignatov, 1990; Bernard , Besson, 1990).

The ventrolateral system is divided into the spinothalamic, spinoreticular, and spinomesencephalic tracts. The spinothalamic tract is an important ascending pathway that exists for the transmission of a wide range of information about the properties of a painful stimulus and is designated as neospinothalamic, while the other two are combined into a paleospinothalamic tract (Willis et al., 2001; 2002).

Neurons of the spinothalamic tract are divided into four groups: the first - neurons with a wide dynamic range or multireceptive; the second - high-threshold neurons (nociceptive-specific); the third - low-threshold; the fourth - deep neurons activated by various proprioceptive stimuli. The terminals of neurons of the spinothalamic tract terminate in specific (relay) nuclei of the thalamus (ventroposteriolateral nucleus), as well as in diffusely associative (medial part of the posterior complex) and nonspecific (intralaminar complex - submedial nucleus) nuclei. In addition, a certain number of axons heading for the ventroposteriorolateral nucleus give off collaterals in the centrolateral nucleus, as well as to neurons of the medial reticular formation and central gray matter (Ma et al., 1987; Giesler, 1995; Willis et al., 2001; 2002) .

Most of the terminals of visceral nociceptive afferent fibers terminate on multireceptor neurons of the spinothalamic tract, which also receive information from somatic nociceptive afferents, which allows us to consider them as an important afferent nociceptive system capable of transmitting signals caused by the action of mechanical stimuli with a wide energy range (Bushnell et al., 1993 ; Zhenilo, 2000).

A significant amount of nociceptive information enters the brainstem through those axons of the spinoreticular tract, which is the second largest route for transmitting nociceptive information, the terminals of which are distributed in the medial reticular formation of the medulla oblongata, as well as in the relay nuclei of the thalamus (Chignone, 1986). Some spinoreticular neurons are enkephalin-containing (Mikhailovich and Ignatov, 1990). Spinoreticular neurons have small skin receptive fields and are activated by both non-nociceptive and nociceptive stimuli, and the frequency of their discharges increases with increasing stimulation intensity.

The spinomesencephalic tract is formed by axons and neurons lying together with neurons of the spinothalamic tract and accompanying them to the isthmus of the midbrain, where the terminals of the spinomesencephalic tract are distributed among integrative structures that form orientation reflexes and control autonomic reactions, as well as structures involved in the appearance of aversive responses. Some axons of the spinomesencephalic tract form collaterals in the ventrobasal and medial nuclei of the thalamus. Complex somatic and visceral antinociceptive reflexes are triggered through this system (Willis et al., 2001; 2002).

The spinocervicothalamic tract is predominantly formed by low-threshold and multireceptive neurons and carries information about the action of mechanical non-painful and thermal stimuli (Brown, 1981; Downie et al., 1988).

The main conductors through which afferent visceral information is transmitted from interoreceptors are the vagus, celiac, and pelvic nerves (Kerr and Fukushima, 1980). Propriospinal and proprioreticular projections, along with the paleospinothalamic tract, are involved in the transmission of poorly localized, dull pain and in the formation of autonomic, endocrine, and affective manifestations of pain (Yaksh and Hammond, 1990).

There is a clear somatotopic distribution of each afferent channel, whether it belongs to the somatic or visceral systems. The spatial distribution of these conductors is determined by the level of sequential entry into the spinal cord (Servero, 1986; Zhenilo, 2000).

Thus, several ascending projections can be distinguished, which differ significantly in morphological organization and are directly related to the transmission of nociceptive information. However, they should by no means be considered as pathways of exclusively pain, since they are also the main substrates of sensory input to various brain structures of a different modality. Modern morphological and physiological studies and extensive practice of neurosurgical interventions indicate that nociceptive information reaches the higher parts of the brain through numerous duplicating channels, which, due to extensive convergence and diffuse projections, involve in the formation of pain a complex hierarchy of various brain structures in which the interaction of multimodal afferent systems (Mikhailovich, Ignatov, 1990).

The role of the brain in the formation of pain response.

An analysis of literature data indicates that during pain stimulation, the nociceptive flow is transmitted from the spinal cord to almost all brain structures: the nuclei of the reticular formation, the central periaqueductal gray matter, the thalamus, the hypothalamus, the limbic formations and the cerebral cortex, which perform a wide variety of functions such as sensory, motor, and vegetative support of defense reactions that occur in response to nociceptive stimulation (Durinyan et al., 1983; Gebhart, 1982; Fuchs, 2001; Fuchs et al., 2001; Guiibaud, 1985; Limansky, 1986; Ta, Mayakova, 1988; Mikhailovich and Ignatov, 1990; Bragin, 1991). However, in all areas of the brain, a wide convergence and interaction of somatic and visceral afferent systems was noted, which suggests the fundamental unity of the central mechanisms of regulation of pain sensitivity (Valdman and Ignatov, 1990; Kalyuzhny, 1991). At the same time, diffuse ascending projections transmit nociceptive information to many formations of different levels of the brain, which perform a wide variety of functions, both sensory, motor, and autonomic support of protective reactions that occur in response to nociceptive stimulation (Fuchs et al., 2001; Guilboud et al. , 1987; Ta, Mayakova, 1988).

In the thalamus, three main nuclear complexes can be distinguished that are directly related to the integration of pain: the ventrobasal complex, the posterior group of nuclei, the medial and intralaminar nuclei. The ventrobasal complex is the main structure of the somatosensory system, whose multisensory convergence on neurons provides accurate somatotopic information about the localization of pain, its spatial correlation, and sensory discriminatory analysis (Guilboud et al., 1987). The thalamic nuclei, along with the ventrobasal complex, are involved in the transmission and evaluation of information about the localization of pain exposure and, in part, in the formation of motivational-affective components of pain.

The medial and intralaminar nuclei of the thalamus, which, along with nociceptive inputs, receive a massive afferent inflow from the central gray matter of the hypothalamus, limbic and striopallidar systems and have extensive subcortical and cortical projections, play a fundamental role in the integration of "secondary", protopathic pain. These nuclei also form complex autonomic highly integrated defensive reactions to nociception, as well as motivational-behavioral manifestations of pain and its affective, uncomfortable perception (Cheng, 1983).

The cerebral cortex is involved both in the perception of pain and in its genesis (Porro and Cavazzuti, 1996; Casey, 1999; Ingvar and Hsieh, 1999; Treede et al., 2000; Churyukanov, 2003). The first somatosensory zone of the S1 cortex is directly involved in the mechanisms of formation of the perceptual-discriminative component of the systemic pain reaction, its removal leads to an increase in pain perception thresholds (Rainville et al., 1997; Bushnell et al., 1999; Petrovic et al., 2000; H Of Bauer et al., 2001). The second somatosensory area of the S2 cortex plays a leading role in the mechanisms of formation of adequate protective reactions of the body in response to pain stimulation, its removal leads to a decrease in the thresholds of perception. The orbito-frontal area of the cortex plays a significant role in the mechanisms of formation of the emotional-affective component of the systemic pain reaction of the body, its removal does not change the perception thresholds of the perceptual-discriminative component and significantly increases the perception thresholds of the emotional-affective component of pain (Reshetnyak, 1989). Studies using positron emission tomography in combination with the method of nuclear magnetic resonance revealed significant changes in blood flow and local metabolism in the fields of the cortex under nociceptive influences (Talbot et al., 1991; Jones, Derbyshire, 1994).

The data of morphological studies on the study of intracerebral connections using various methods (retrograde axonal transport of horseradish peroxidase, degeneration, immunoradiological, histochemical, etc.) are presented in Fig. 1. 2.5. (Bragin, 1991).

Thus, the pain reaction "is an integrative function of the body, which mobilizes a wide variety of functional systems to protect the body from influencing harmful factors and includes such components as consciousness, sensations, memory, motivations, autonomic, somatic and behavioral reactions, emotions" (Anokhin, Orlov, 1976).

Distinguish the mechanisms of pain formation(nociceptive system) and pain control mechanisms (antinociceptive system). The feeling of pain is formed at different levels of the nociceptive system: from sensitive nerve endings that perceive pain sensations to pathways and central nervous structures.

receiving apparatus.

It is believed that pain (nociceptive) stimuli are perceived by free nerve endings (they are able to register the effects of various agents as pain). Probably, there are also specialized nociceptors - free nerve endings that are activated only under the action of nociceptive agents (for example, capsaicin).
- A superstrong (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) that act on sensitive nerve endings. Algogens include kinins (mainly bradykinin and kallidin), histamine (causes pain when administered subcutaneously even at a concentration of 1 * 10-18 g / ml), a high concentration of H +, capsaicin, substance P, acetylcholine, norepinephrine and adrenaline in non-physiological concentrations, some Pg.

Conducting paths.

1) Spinal cord.
- Pain afferent conductors enter the spinal cord through the posterior roots and contact the intercalary neurons of the posterior horns. It is believed that the conductors of epicritical pain terminate mainly on the neurons of plates I and V, and protopathic - in the Roland substance (substantia gelatinosa) of plates III and IV.
- Convergence of excitation for different types of pain sensitivity is possible in the spinal cord. Thus, C-fibers that conduct protopathic pain can contact spinal cord neurons that perceive epicritical pain from skin and mucous membrane receptors. This leads to the development of the phenomenon of segmental (“reflected”) cutaneous-visceral pain (a sensation of pain in a part of the body that is distant from the true place of pain impulses).

Examples of irradiation of pain sensations of "false" pain can serve:
- in the left arm or under the left shoulder blade during an attack of angina or myocardial infarction;
- osteochondrosis of the spine can cause pain in the region of the heart and simulate angina pectoris or myocardial infarction;
- under the right shoulder blade during the passage (exit) of the calculus through the bile ducts;
- above the clavicle in acute hepatitis or irritation of the parietal peritoneum;
- in the inguinal region in the presence of a calculus in the ureter.

The occurrence of these segmental skin-visceral ("reflected") pains due to the segmental structure of the innervation of the surface of the body and internal organs by afferents of the spinal cord.

1) Ascending pathways of the spinal cord.
- Conductors of epicritical pain switch on the neurons of plates I and V, cross and ascend to the thalamus.
- Conductors of protopathic pain switch on the neurons of the posterior horns, partially cross and ascend to the thalamus.

2) Conducting pathways of the brain.
- Conductors of epicritical pain pass through the brainstem in an extralemniscal way, a significant part of them switch on the neurons of the reticular formation, and a smaller part - in the visual tubercles. Further, the thalamocortical pathway is formed, ending on the neurons of the somatosensory and motor areas of the cortex.
- Conductors of protopathic pain also pass through the extralemniscal pathway of the brainstem to the neurons of the reticular formation. Here, “primitive” reactions to pain are formed: alertness, preparation for “avoiding” the pain effect and / or eliminating it (withdrawal of a limb, rejection of a traumatic object, etc.).

Central nervous structures.

Epicritical pain is the result of the ascent of pain impulses along the thalamocortical pathway to the neurons of the somatosensory zone of the cerebral cortex and excitation of them. The subjective sensation of pain is formed precisely in the cortical structures.
- Protopathic pain develops as a result of activation mainly of the neurons of the anterior thalamus and hypothalamic structures.
- A holistic sensation of pain in a person is formed with the simultaneous participation of cortical and subcortical structures that perceive impulses about protopathic and epicritical pain, as well as about other types of influences. In the cerebral cortex there is a selection and integration of information about the pain effect, the transformation of the feeling of pain into suffering, the formation of purposeful, conscious "pain behavior". The purpose of such behavior is to quickly change the vital activity of the body 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 kind of substance abuse, characterized by a painful addiction to alcohol (ethyl alcohol), with mental and physical dependence on it. Negative consequences can be expressed in mental and physical disorders, as well as violations of the social relations of a 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 organism. Some people are at greater risk of developing alcoholism due to specific socioeconomic environments, emotional and/or mental predispositions, and hereditary causes. The dependence of cases of acute alcoholic psychosis on the type of the hSERT gene (encodes the serotonin transporter protein) has been established. However, no specific mechanisms for the realization of the addictive properties of alcohol have been found so far.

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 specific alcoholic lesions of internal organs. The pathogenetic mechanisms of the effects of alcohol on the body are mediated by several types of ethanol effects on living tissues and, in particular, on the human body. The main pathogenetic link in the narcotic effect of alcohol is the activation of various neurotransmitter systems, especially the catecholamine system. At various levels of the central nervous system, these substances (catecholamines and endogenous opiates) determine various effects, such as an increase in the threshold of pain sensitivity, the formation of emotions and behavioral reactions. Violation of the activity of these systems due to chronic alcohol consumption causes the development of alcohol dependence, withdrawal syndrome, a change in a critical attitude towards alcohol, etc.

When alcohol is oxidized in the body, a poisonous substance, acetaldehyde, is formed, 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), brain tissue (alcoholic encephalopathy).

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