Human antinociceptive system to reduce pain. Mediators of the nociceptive system Pain suppression system Local and descending control

Pain is associated with many pathological conditions. They not only cause painful experiences, but also worsen the course of the underlying disease. The leading role in the formation of traumatic shock, which in some cases becomes the cause of death, can be severe pain.

Pain sensations are perceived by special receptors (nociceptors) and receptors of some other modalities (baro-, thermo-, chemoreceptors) with sufficient stimulation. Endogenous substances are known that, by acting on nociceptors, can cause pain (for example, bradykinin, histamine, serotonin, calcium ions, etc.). Prostaglandins increase the sensitivity of nociceptors to chemical (and thermal) stimulation.
Nociceptive system - a system that perceives, conducts a pain impulse and forms responses to pain. Pain-induced impulses travel to the dorsal horns of the spinal cord. Here is the first switch from the afferent

curl on intercalary neurons. From here, excitement spreads in three ways. One of them is the ascending afferent tracts. They conduct excitation to the overlying sections - the reticular formation, the thalamus, the hypothalamus, the basal ganglia, the limbic system and the cerebral cortex. Activation of this pathway leads to the perception and evaluation of pain with corresponding behavioral and autonomic responses. The second way is the transmission of impulses to the motor neurons of the spinal cord, which is manifested by a motor reflex. The third way is the excitation of the neurons of the lateral horns, as a result of which the sympathetic fibers are activated. The main mediators of the transmission of pain receptors are L-glutamate, substance P.
The antinociceptive system is a system of the central nervous system that disrupts the perception of pain, the conduction of a pain impulse and the formation of pain reactions. It primarily includes the accumulation of short-axon enkephalinergic neurons in the region of the central gray matter near the Sylvian aqueduct. Enkephalin neuropeptides act as a transmitter of nerve impulses in enkephalinergic neurons. The pain impulse activates these cells, which enhances enkephalinergic impulses along the descending pathways to the neurons of the posterior horns of the spinal cord (increases the threshold of pain sensitivity) and along the ascending pathways to the neurons of the reticular formation, thalamus and hypothalamus, and the limbic system (vegetative and emotional reactions are suppressed, i.e. increases the threshold of pain endurance). Enkephalins activate opioid receptors located on the presynaptic endings of neurons involved in the transmission of pain impulses. This leads to inhibition of the release of mediators into the synaptic cleft, i.e. to the blockade of synaptic transmission, therefore, to an increase in the threshold of pain sensitivity and the threshold of pain perception. The antinociceptive system also includes endorphins, which are produced in the pituitary and hypothalamus, are released into the cerebrospinal fluid, enter the bloodstream and also interact with opioid receptors. The release of endorphins into the blood increases during stress, pregnancy, childbirth, under the influence of nitrous oxide, which also leads to a decrease in pain sensitivity. The descending inhibitory effect on the transmission of pain impulses is also carried out due to serotonergic neurons. Thus, the destruction of the large core of the suture significantly reduces the analgesic effect of morphine.

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ENTERED 07.01.2014

UDC 616-009.77

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

THEM. Kotieva, A.E. Shumarin

ANTINOCICEPTIVE SYSTEM

Rostov State Medical University Department of Pathological Physiology Russia, 344022, Rostov-on-Don, per. Nakhichevan, 29. E-mail: [email protected]

It is known that as long as the antinociceptive system functions sufficiently, pain may not develop even in the presence of damage. One of the most important mechanisms of antinociception is humoral, i.e. the formation of substances that block the transmission of pain impulses and, thus, the formation of pain. The humoral mechanisms of pain relief include opioid, monoaminergic (norepinephrine, dopamine, serotonin), cholinergic and GABAergic, cannabinoid and orexin systems. The arrival of pain impulses along the pain pathways stimulates the formation and release of many chemicals, under the action of which the effect of pain relief is formed at various levels of the pain system.

Key words: antinociceptive system, analgesia, pain, humoral mechanisms.

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

I.M. Kotieva, A.E. Shumarin

ANTINOCICEPTIVE SYSTEM

Rostov State Medical University Department of pathological physiology Russia, 344022, Rostov on Don, Nakhichevansky str., 29. E-mail: [email protected]

It is known that as long as antinociceptive system functions adequately pain can develop as a component of different injuries. One of the most important mechanisms of antinociception is humoral that means production of substances that block transmission of pain and formation of pain feeling. Humoral mechanism includes: opioid, monoaminergic (norepinephrine, dopamine, serotonin), cholinergic, GABAergic, cannabinoid and orexin systems. Inflow of pain impulses induces production and excretion of various chemical substances which forms analgesia in different levels of pain system.

Key words: antinociceptive system, analgesia, pain, humoral mechanisms.

It is well known that the regulation of various functions in the body is carried out by systems that have opposite effects, due to which it is possible to maintain the function at a certain level. Thus, the regulation of sugar levels is ensured by the interaction between the effects of insulin and contrainsular hormones, the level of calcium and phosphorus - by the influence of calcitonin and parathyroid hormone, the maintenance of blood in a liquid state - by coagulation and anticoagulation systems, etc. The general philosophical category of dual unity objectively includes the sensation of pain, which is the result of the interaction of pain-forming and pain-limiting mechanisms.

Paying attention to the extremely important role of the antinociceptive system in the formation of pain sensation, it can be concluded that as long as the antinociceptive system functions sufficiently, pain may not develop even in the presence of damage. There is an opinion that the occurrence of pain is due to the insufficiency of the antinociceptive system.

The activation of the analgesic system occurs under the influence of pain impulses and this explains why the very occurrence of pain is also the reason for its leveling and disappearance.

According to L.V. Kalyuzhny and E.V. Golanov, the occurrence of pain or, conversely, the activation of the antinociceptive system is determined not by the nature of the stimulus acting on the body, but by its biological significance. Consequently, if the antinociceptive system is in a state of constant activation, pain in humans and animals does not occur due to the non-dangerous influence of external and internal environmental factors. In the process of evolution of the animal world, for the survival of the organism, mechanisms were formed that ensure the occurrence of pain only in response to a dangerous (ie, biologically excessive for the organism) stimulus.

The same authors, analyzing the sequence of formation of the antinociceptive system, come to the conclusion that in phylogenesis the control of pain sensitivity began to be carried out primarily by humoral factors, especially opiates, while the nervous mechanisms of pain regulation appeared at the later stages of evolution. The system "central gray periaqueductal substance - the core of the suture" predetermined the creation at the level of the bulbar-mesencephalic department of an independent mechanism for controlling pain sensitivity with the help of serotonin and catecholamines, and with the development of emotions, a hypothalamic level of pain sensitivity control appeared. The development of the cerebral cortex contributed to the formation of the cortical level of control of pain sensitivity, which is necessary for the conditioned reflex and behavioral activity of a person.

Currently, three major mechanisms of antinociception can be distinguished:

1. Receipt of afferent information in the posterior horns of the spinal cord through thick myelinated fibers from tactile, temperature and deep sensitivity receptors.

2. Descending inhibitory influences from the central nervous system (CNS) at the level of the posterior horns of the spinal cord (enkephalin -, serotoni -, adrenergic).

3. Humoral mechanisms of antinociception (the formation of substances that block the transmission of pain impulses and, thus, the formation of pain).

The antinociceptive system has its own morphological structure, physiological and biochemical (humoral) control mechanisms. For its normal functioning, a constant influx of afferent information is necessary; with its deficiency, the function of the antinociceptive system decreases. The antinociceptive system is formed at different levels of the CNS and is represented by segmental and central levels

control, as well as humoral mechanisms - opioid, monoaminergic (norepinephrine, dopamine, serotonin), choline- and GABA-ergic, cannabinoid and orexin systems).

According to current data, chemicals are involved in the modulation of pain at the level of receptors, the conduction of impulses in the CNS and the downward control of pain intensity.

This article is devoted to the humoral mechanisms of antinociception.

Opiate mechanisms of pain relief

For the first time in 1973, a selective accumulation of substances isolated from opium, such as morphine or its analogues, was established; opiate receptors were found in the brain structures of experimental animals. The greatest number of them is located in the brain regions that transmit nociceptive information. In particular, the largest number of opiate receptors is concentrated in such places of transmission of pain information as the gelatinous substance of the posterior horns of the spinal cord, the reticular formation of the brain stem, the central gray periaqueductal substance, the hypothalamus, thalamus, limbic structures and the cerebral cortex. In addition to the central nervous system, opiate receptors are found in autonomic ganglia, on nerve terminals innervating internal organs, adrenal glands, and smooth muscles of the stomach.

Opiate receptors have been found in living beings ranging from fish to humans. Morphine or its synthetic analogues, as well as similar substances formed in the body itself (endogenous opiates - enkephalins and endorphins) bind to opiate receptors. Presynaptic activation of opioid receptors on the terminal of the first neuron inhibits the release of such neurotransmitters as substance P and glutamate, which ensure the transmission of pain impulses to the CNS and the formation of pain. Postsynaptic excitation of opiate receptors causes suppression of neuron function due to membrane hyperpolarization and, ultimately, inhibits pain sensation.

Currently, the heterogeneity of a number of receptors (adrenergic (a1, a2, 01, 02), dopaminergic (D1 and D2), cholinergic (M and H) and histaminergic (H1 and H2)) to chemicals is known.

In recent years, the heterogeneity of opiate receptors has also been proven. Five groups of opiate receptors have already been discovered: c-, 5-, k-, £-, £-opiate receptors. M receptors are the main target of opiates, including morphine and endogenous opiates. Many opiate receptors are found in the central gray periaqueductal substance of the brain and the posterior horns of the spinal cord, especially in the gelatinous substance. It is believed that high concentrations of c-receptors are located in the same areas that are responsible for the formation of pain, and 5-receptors in areas involved in the regulation of behavior and emotions.

In different structures of the brain, the number of opiate receptors is not the same. Individual structures differ by a factor of 40 in terms of the density of the presence of receptors. A lot of them are found in the amygdala, the central gray periaqueductal substance, the hypothalamus, the medial thalamus, the brain stem (the nucleus of the solitary tract

and trigeminal sensory nuclei), I and III plates of the posterior horns of the spinal cord.

Opiate peptides regulate the transmission of pain impulses at the level of the spinal cord, excite the neurons of the raphe nuclei, the giant cell nucleus, the central gray periaqueductal substance, i.e. the most important anti-nociceptive structures of the brain, which play an important role in the descending inhibitory control of pain at the level of the posterior horns of the spinal cord.

Analyzing the role of opiate peptides in the regulation of hemodynamics, Yu.D. Ignatov et al. it is believed that the enhancement of sympathetic activity and nociceptive vasomotor reflexes is realized through 6-opiate receptors at different levels of the brain. Inhibition of hypertensive reactions is mediated through the n-opiate receptors of the brain. With this in mind, the authors propose to correct cardiovascular reactions in pain by creating and administering antagonists with selective n-receptor action.

According to E.O. Bragin, the brain is characterized by heterogeneity in the distribution of opiate receptors: from minimal concentrations in the region of primary analyzers (S1 and 82-somatosensory cortex zones, temporal, occipital) to maximum concentrations in the frontal and limbic structures.

It has been found that in the blood and cerebrospinal fluid of humans and animals 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 (meth- and leuenkephalins). In the brain, the precursors of opioid peptides are proopiomelanocortin, proenkephalin A, and proenkephalin B.

From the hypothalamus and pituitary gland, substances with an even greater molecular weight were obtained, containing enkephalin molecules and called large endorphins. These compounds are formed during the breakdown of ß-lipotropin, and given that it is released with pituitary hormones, the hormonal origin of endogenous opioids can be explained. ß-endorphin is 1833 times more active than morphine, and with constant administration of it to rats, they, like humans, become addictive. Enkephalins and endorphins produced in the body are called endogenous opiates.

Endogenous opiates such as enkephalin and large endorphins in the highest concentrations were found in the localization of opiate receptors. ß-endorphins and cells containing them are located in the hypothalamus, limbic structures, medial thalamus, and central gray periaqueductal substance. Part of the cells form a continuous line crossing the bottom of the 3rd ventricle of the brain. Enkephalin-containing fibers are found at all levels of the CNS, especially in the arcuate nucleus, peri- and paraventricular nuclei of the hypothalamus.

Endogenous opioids (endorphins) are also produced in neurons of the spinal ganglion and dorsal horn of the spinal cord and transported to peripheral nociceptors. Peripheral opioids reduce the excitability of nociceptors, the formation and release of excitatory neurotransmitters.

Accumulation of substances

peptide nature with analgesic properties. Moreover, extracts of the spinal cord obtained from the area of ​​the generator of pathologically enhanced excitation have pronounced analgesic properties. A direct relationship was found between the analgesic properties of the identified peptides and the intensity and duration of the pain syndrome. Providing analgesia is the most important property of endogenous opiates, and this is confirmed experimentally when they are introduced into the brain of animals.

Different areas of the central nervous system have different sensitivity to endorphins and enkephalins. Brain cells are more sensitive to enkephalins than to endorphins. Pituitary cells are 40 times more sensitive to endorphins. The diurnal fluctuations of opioid peptides that have been found so far are probably responsible for diurnal changes in the threshold of human pain sensitivity. Opiate receptors reversibly bind to narcotic analgesics, and the latter can be displaced by their antagonists with the restoration of pain sensitivity, for example, by the administration of nalaxone. It is now believed that both opiate and adrenergic mechanisms are involved in stress-induced analgesia.

Studies have shown that in addition to exogenous and endogenous opiates, the opiate antagonist nalaxone plays an important role in the regulation of pain sensitivity. Artificial administration of nalaxone against the background of anesthesia with opiates not only restores pain sensitivity, but also enhances it, because. This drug completely blocks c-opiate receptors. The predominant affinity of nalaxone for the n-receptors was found, it is 10 times less for 5- and 30 times less for k-receptors. Anesthesia caused by stress is not eliminated by nalaxone even at very high doses (20 mg/kg).

Recent studies have made it possible to distinguish, depending on the effects of nalaxone, two types of analgesia: nalaxone-sensitive, which can be obtained under conditions of prolonged nociceptive irritations, and nalaxone-insensitive, which occurs with acute pain effects. The difference in the effects of nalaxone is explained by the inclusion of different mechanisms of antinociception, tk. with prolonged and intermittent nociceptive effects, the opioid and less adrenergic mechanism is activated first of all. In acute pain, the adrenergic mechanism is of paramount importance, rather than the opioid one.

Thus, both exogenous and endogenous opiates regulate pain sensitivity at the level of pre- and postsynaptic formations. When connected to the receptors of the presynaptic membrane, the release of the most important neurotransmitters - glutamate and substance P is blocked. As a result, impulse transmission is impossible. When interacting with the opiate receptors of the postsynaptic membrane, its hyperpolarization occurs and the transmission of a pain impulse is also impossible.

Adrenergic mechanisms of pain relief

The value of monoamines is extremely high in the mechanism of pain formation. Depletion of monoamines in the CNS enhances the perception of pain by reducing

effectiveness of the endogenous antinociceptive system.

In addition, it has been shown that the introduction of the precursor of norepinephrine (L-DOPS) causes an antinociceptive effect due to an increase in the level of norepinephrine in the CNS, which, according to H. Takagi and A. Harima, inhibits the conduction of impulses at the level of the posterior horns of the spinal cord and supraspinally . It is known that nora-renaline inhibits the conduction of nociceptive impulses both at the segmental (spinal cord) and stem levels. This effect is associated with its interaction with a2-adrenergic receptors, tk. norepinephrine is not detected with the preliminary administration of a-blockers, for example, phentolamine. Moreover, a1- and a2-adrenergic receptors exist as postsynaptic formations.

Opiate and adrenergic receptors in the spinal cord mediate animal responses to strong stimuli, i.e. only certain types of somatic stimulation will increase the release of monoamines and opiate substances in the spinal cord. At the same time, activation of inhibitory neurons by noradrenaline was found at the level of the brainstem, especially the giant cell nucleus, the nuclei of the raphe major, the locus coeruleus, and the mesencephalic reticular formation.

Noradrenergic neurons are concentrated in the lateral brainstem and diencephalon; the reticular formation of the brain is especially rich in them. Some of their axons go to the cerebral cortex, and the other - to the formations of the forebrain. If the central adrenergic structures are activated, analgesia is formed with the suppression of emotional and behavioral reactions and hemodynamic manifestations of pain. Moreover, the adrenergic mechanisms of the suprasegmental level regulate hemodynamic reactions with the participation of a2-adrenergic receptors, and the segmental ones regulate behavioral manifestations realized through a1-adrenergic receptors. According to A.A. Zaitseva, the preservation of the reaction of the circulatory system to pain against the background of opiates suggests that sharp hemodynamic changes in pain (including an increase in blood pressure) include analgesic mechanisms due to direct and baroreceptor effects. In addition, it has been shown that the action of agonists on central a2-adrenergic receptors, which regulate the circulatory system, eliminates pressor reactions and simultaneously increases analgesia caused by both narcotic and non-narcotic analgesics. With a strong pain effect, the emotiogenic zones of the hypothalamus are activated and the adrenergic mechanism is excited, which is why the blockade of pain impulses occurs, followed by the involvement of the opiate mechanism. E. O. Bragin believes that the peripheral catecholamine system suppresses, and the central one activates the mechanism of antinociception.

Transplantation of chromaffin cells into the spinal subarachnoid space reduces the manifestations of acute and chronic pain in the experiment, which once again confirms the role of catecholamines (adrenaline and norepinephrine) in antinociception. Depletion of the depot of monoaminergic compounds by the introduction of reserpine, tetrabenzamine blocks analgesia, and the restoration of the level of catecholamines normalizes it. The conjugate involvement of opioidergic drugs has now been proven.

and adrenergic mechanisms in the regulation of pain sensitivity. Hence, according to V.A.Mikhailovich and Yu.D.Ignatov, its applied value follows, which consists in the fact that it becomes possible to reduce the dosage of narcotic analgesics with the combined use of opiate and adrenopositive substances. According to the above authors, there is a general mechanism of presynaptic regulation of noradrenergic transmission of excitation in the CNS, which involves α2-adrenergic receptors and opiate receptors. Therefore, adrenopositive drugs and opiates, through independent binding sites, trigger a common mechanism that determines the correction of increased norepinephrine turnover during opiate withdrawal. In addition, in patients with tolerance to opiates and opioids, it is possible to prolong drug analgesia with adrenopositive substances.

Dopamine in the brain is involved in the formation of pleasure, motivation, motor function.

Dopamine is also involved in the regulation of pain, providing its modulation. Recent studies show that stimulation of dopaminergic structures of the brain (corpus striatum, nucleus accumbens, anterior tegmentum) or administration of dopamine reuptake blockers in the dopaminergic synapses of the brain increases the activity of the dopaminergic system, which reduces the manifestations of pain. On the contrary, a decrease in dopamine in dopaminergic structures is accompanied by an increase in pain sensitivity (hyperalgesia).

It was found that under pain and stress, the sympathetic-adrenal system is sharply activated, tropic hormones, β-lipotropin, β-endorphin and enkephalins, powerful analgesic polypeptides of the pituitary gland, are mobilized. Once in the cerebrospinal fluid, they affect the neurons of the thalamus, the central gray periaqueductal substance of the brain, 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, probably, the formation of serotonin in the large raphe nucleus increases, which also inhibits the implementation of substance P. The same pain relief mechanisms are activated during acupuncture stimulation of non-painful nerve fibers.

The important role of excitation of central a2-adrenergic receptors in the functioning of antinociception is evidenced by the high efficiency of using a2-adrenoceptor agonists (clophelin, sirdalud) in the treatment of pain.

In our laboratory of neurohumoral pain regulation, changes in the level of biogenic monoamines in the noci- and antinociceptive brain structures of rats in acute somatic pain were studied. It has been established, in particular, that in the acute period of the development of pain syndrome, the restructuring of noci- and antinociceptive interactions in the CNS is manifested by heterotopic changes in the adrenergic background with an emphasis on different functional elements. In the central link of the anti-nociceptive system - the central gray periaqueductal substance, a significant increase in all fractions of catecholamines (adrenaline, noradrenaline and, especially, dopamine) was revealed. In the center of nociception - the thalamus,

a diametrically opposite tendency to weaken catecholaminergic activity is formed. In nonspecific noci- and antinociceptive structures of the brain involved in the processes of modulation of pain and analgesic activity, as well as in the central gray periaqueductal substance, the total concentration of catecholamines increases, but this reaction is differentiated. In the somatosensory cortex, the level of dopamine rises sharply, while in the hypothalamus, the dopaminergic dominant is replaced by a noradrenergic one. At the segmental level of nociceptive impulse conduction in the acute period of somatic pain, against the background of a decrease in the concentrations of adrenaline and dopamine, a tendency to an increase in the norepinephrine fraction is formed.

It is important to note that during this period, in all the studied structures of the brain and spinal cord, an increase in the metabolism of serotonin is recorded, which, as is known, is a powerful modulator of catecholaminergic effects in the CNS, implemented at the level of α1- and α2-adrenergic receptors.

The experimental data obtained in our studies indicate that the central catecholaminergic mechanisms are necessary components of the complex processes of noci- and anti-nociception and their most important components: perception, transmission and modulation of the nociceptive flow at the segmental and suprasegmental levels.

Serotonergic mechanisms of pain relief

An analysis of changes in the level of serotonin in the blood plasma during tension headache indicates a decrease in its content and, conversely, treatment with antidepressants that inhibit its reuptake increases its level in the blood with the simultaneous disappearance of headache symptoms.

According to V.A.Mikhailovich and Yu.D.Ignatov, morphine causes a change in the metabolism of serotonin in the brain and an increase in the level of its metabolite -5-hydroxyindoleacetic acid. It is believed that morphine, on the one hand, directly activates serotonergic neurons, resulting in an increase in its output and metabolism, and on the other hand, under the influence of morphine, this effect may be associated with an increase in tryptophan levels.

Thus, it is concluded that serotonin is necessary for the manifestation of the central action of morphine, since a change in serotonergic mediation affects its analgesic, locomotor, euphoric and hypothermic effects.

Studies of the content of serotonin and the activity of monoamine oxidase in the blood plasma of patients suffering from chronic headaches in the head, neck and face showed an increase in the content of serotonin in the blood plasma and a decrease in the activity of monoamine oxidase.

There is an interesting experimental observation when, with irritation of the nuclei of the suture, the blue spot, the central gray periaqueductal substance, deep analgesia develops due to the accumulation of serotonin and norepinephrine in the cerebrospinal fluid. Serotonin and substances that stimulate its synthesis increase opiate analgesia, while a decrease in serotonin

(introduction of parachloramphetamine, parachlorophenylalanine, fenfluramine) reduces morphine analgesia. According to A.B. Danilov and O.S. Davydov, a decrease in the content of serotonin in the CSO, the large nucleus, and the raphe nuclei reduces analgesia, since serotonin promotes the release of β-endorphins from the cells of the adeno-pituitary gland, therefore, it is believed that the effects of serotonin are mediated endogenous opioids.

Studies have shown that oral administration of the serotonin precursor L-tryptophan, as well as drugs that increase serotonin levels or block its reuptake, increase the pain threshold and reduce the perception of pain. In addition to reducing the perception of pain, an increase in brain serotonin, for example during acupuncture, also has an antidepressant effect.

According to J. Maye "tsr and V. Sang (1985), an excess of serotonin, especially in the medial thalamus, inhibits the cells of this zone that respond to pain. In the zone of the large suture, which is the most important area of ​​the descending analgesic pathways, the neurotransmitter serves as serotonin, which plays an exceptional role in the genesis, for example, of headache.It has been established that before a headache attack, the content of serotonin increases sharply in the blood plasma with the development of vasoconstriction.This leads to an increase in the excretion of serotonin unchanged in the urine, its breakdown under the influence of monoamine oxidase, and, consequently, to a decrease in the content of this monoamine in plasma, brain structures of the antinociceptive system and the appearance of pain.

In our studies on the problem of monoaminergic regulation of pain, we studied, in particular, the features of serotonin metabolism in the CNS in rats with acute somatic pain. It has been established that in the initial period of the development of acute pain syndrome in animals, the content of serotonin and its metabolite, 5-hydroxyindoleacetic acid, increases in the structures of the brain (cortex, hippocampus, thalamus, hypothalamus, central gray periaqueductal substance, medulla oblongata) and spinal cord. At the same time, the most significant increase in the concentration of monoamine and 5-hydroxyindoleacetic acid is observed in the structures responsible for conducting (spinal cord), transmission (reticular formation) and perception (cerebral cortex) of nociceptive impulses.

The fact of accumulation of serotonin in the thalamus during the acute period of pain stress, in our opinion, indirectly confirms the opinion of J. Maye "tsr and B. Santze%r about the modulating effect of this monoamine on the sensitivity of specific neurons that perceive and transform the nociceptive signal. At the same time The shift of serotonin metabolism in the direction of its increased utilization and conversion into 5-hydroxyindoleacetic acid, noted during this period in the central gray periaqueductal substance and hypothalamus, indicates the predominant activation of serotonergic mediation in these antinociceptive structures.

An analysis of the data obtained in these studies made it possible to conclude that serotonin plays a multifunctional role in the pain system both as a powerful modulator of nociceptive information in the CNS and as a leading mediator of antinociceptive reactions.

The synthesis of serotonin in the brain of women is 50% less than that of men. This explains the higher sensitivity of women to pain and its more frequent occurrence compared to men. In this regard, serotonin reuptake inhibitors in the presynaptic membrane have recently been used to treat chronic tension headaches. For this purpose, fluoxetine, paroxetine, sertalin are used.

Thus, there is no doubt that the serotonergic regulatory mechanism is a necessary component of a complex apparatus for controlling the processes of nociception and antinociception. The regulatory effects of serotonin are manifested at all levels of the functional system of pain, including the processes of occurrence, conduction, perception, modulation of the nociceptive flow and the formation of an antinociceptive component in the overall reaction of the body to pain.

Cholinergic mechanisms of pain relief

In recent years, the role of cholinergic mechanisms in the formation of pain has been widely and intensively studied. It is known that cholinergic substances excite the hippocampus, the administration of morphine with cholinergic drugs sharply enhances analgesia. In intact rats, activation of the cholinergic system and accumulation of acetylcholine have been found to promote analgesia.

The introduction of a cholinomimetic - prozerin, as well as M-cholinergic substances into the zone of the central gray periaqueductal substance enhances the analgesic effect, which is the result of the involvement of acetylcholine in the analgesia reaction at the level of the midbrain. Activation of the cholinergic system enhances, and its blockade weakens morphine anesthesia. It has been suggested that the binding of acetylcholine to certain central muscarinic receptors stimulates the release of opioid peptides involved in stress analgesia.

Recently, studies have appeared that show that the use of botulinum toxin type A (BTX-A) reduces the intensity of muscle pain. It is believed that such an analgesic effect is due to the effect on the neuromuscular synapse, where the release of acetylcholine is inhibited and, as a result, muscle relaxation is formed. In addition to reducing muscle hyperexcitability, botulinum toxin also has a direct antinociceptive effect by reducing neuronal activity, reducing the release of neuropeptides and peripheral sensitivity. It was also noted that the effect on pain intensity with the introduction of botulinum toxin begins after 3 days and reaches a maximum after 4 weeks. The duration of its analgesic action is up to 6 months.

GABAergic mechanisms of pain relief

Gamma-aminobutyric acid (GABA) regulates pain sensitivity by suppressing emotional and behavioral reactions to pain. The CNS is dominated by two neurotransmitters involved in both the formation of pain and its modulation. These are glutamate and GABA. They account for 90% of all neurotransmitters.

terov and are found in all areas of the CNS, only on different neurons. GABA is formed from glutamate by activating the enzyme glutamate decarboxylase. Three groups of GABA were found: a, b, c. GABA-a is located mainly in the brain, and GABA-b in the dorsal horns of the spinal cord. GABA-a increases the permeability of the nerve cell membrane for chloride ions. GABA-b increases the permeability of the cell membrane for potassium ions, contributing to its hyperpolarization and the impossibility of transmitting a pain impulse.

GABA is released during pain in the posterior horns of the spinal cord simultaneously with glutamate. At the presynaptic nociceptive terminals, GABA suppresses the excessive release of glutamate and substance P, thus blocking the entry of pain impulses into the CNS. In the CNS, GABA suppresses neuronal firing in pain, chronic stress, depression, and fear.

GABA inhibits the formation of primary or localized pain, secondary or poorly localized pain, and thus prevents hyperalgesia and allodynia (pain on non-painful exposure).

The nociceptive effect is accompanied by an increase in the level of GABA and inhibition of its enzymatic inactivation in the structures of the forebrain. A decrease in the activity of the GABA-transferase enzyme in the brain and a decrease in inactivation as a result of this is considered as a protective mechanism aimed at enhancing the processes of inhibition. Pain, by activating GABA and GABAergic transmission, provides adaptation to pain stress.

In acute and chronic pain, activation of the synthesis and catabolism of GABA was initially detected, followed by a decrease in its enzymatic destruction and, as a result, an increase in the concentration of GABA in various brain structures. The administration of GABA-agonists and GABA-transaminase inhibitors to experimental animals in acute and chronic pain reduces behavioral and somatic status disorders in animals. A dependence of the GABAergic analgesic effect on the functional activity of other humoral antinociceptive mechanisms - opioid, adrenergic, cholinergic and serotonergic mechanisms was found.

It is known that the central gray periaqueductal substance has an inhibitory GABAergic effect on the neurons of the reticular formation and raphe nuclei of the brainstem, which are involved in the downward control of the pain flow at the spinal (segmental) level.

The relationship between GABA, opiates and opioids is interesting. It has been experimentally shown that under the influence of the latter, the release of GABA in the central gray periaqueductal substance and the dorsal nucleus of the raphe in rats increases.

GABA in high doses accelerates and prolongs the duration of morphine anesthesia. Conversely, GABA receptor blockers reduce the intensity of morphine analgesia and the effects of enkephalins. According to V.A. Mikhailovich and Yu.D. Ignatov, activation of GABA B and opiate receptors are relatively independent, while analgesia and tolerance to the analgesic effect of GABA agonists are realized with the involvement of the opioidergic system. At the segmental level

opioid and adrenergic mechanisms are involved in the formation of tolerance to the analgesic action of GABA-positive substances.

The introduction of GABA-positive drugs causes analgesia. For example, administration of GABA receptor agonists (baclofen, depakine) reduces chronic pain in animals and normalizes their behavior. Given this, it is considered appropriate to prescribe GABA-positive drugs (baclofen, depakine) with a narcotic analgesic such as promedol for chronic pain.

Cannabinoid pain relief system

In recent years, endogenous cannabinoids have become important in antinociception. Cannabinoids are substances found in cannabis or their synthetic counterparts. The implementation of their effects is carried out through interaction with cannabinoid CB1 and CB2 receptors. The highest concentration of CB1 receptors is in the CNS, especially in the frontal limbic structures of the brain. They are also found in the peripheral parts of the nervous system, in the pituitary gland, adrenal glands, heart, lungs, gastrointestinal tract, bladder, reproductive organs, and immune cells. Excitation of CB1 receptors on the nerve endings of the CNS and the periphery modulates the release of excitatory and inhibitory mediators, inhibiting or facilitating signal transmission. It has been shown that excitation of CB1-cannabinoid receptors inhibits the release of glutamate and, as a result, reduces the transmission of the pain impulse. This effect is especially important in conditions of hyperalgesia or allodynia. CB2 receptors are found on immunocompetent cells, their excitation causes immune suppression. The use of delta-9-tetrahydrocannabinol in people with induced pain is accompanied by a decrease in unpleasant effects, but does not affect its intensity and hyperalgesia. There is a decrease in the functional connection between the amygdala and the primary somatosensory cortex. The role of endogenous cannabinoids has recently been intensively studied. Thus, at the 6th Congress of the European Federation of the International Association for the Study of Pain, a special seminar was devoted to the endogenous cannabinoid system and its role in the mechanisms of anti- and nociception. It has been established that with chronic pain in the spinal cord and brain, the level of endogenous cannabinoids increases.

The role of orexins in pain relief

Orexins play an important role in antinociception. They are neuropeptides of neurons of the lateral hypothalamic region, which is closely associated with most of the monoaminergic nuclei: noradrenergic tocus roeruleus, ventral dopaminergic tegmentum, and histaminergic tuberomammylar nuclei. Thus, orexin-containing neurons of the lateral hypothalamus innervate almost all areas of the brain, including the thalamus opticus, limbic system, tocus raeruleus, raphe nuclei, arcuate nucleus, tuberomammillary nucleus, and lateral mammillary nucleus.

Orexins consist of two structurally related peptides: orexin A and orexin B. Antinociception caused by

orexin, is modulated by stimulating histaminergic receptors at the supraspinal level. Experimental studies on mice have shown that the administration of orexin A and B significantly reduces pain behavioral responses under the action of thermal and mechanical factors. The same researchers showed a close relationship between the orexin and histamine systems of the spinal and supraspinal levels in the formation of pain sensitivity.

Thus, the arrival of pain impulses along the pain pathways stimulates the formation and release of many chemicals, under the action of which the effect of pain relief is formed at various levels of the pain system, i.e. in the very formation of pain, the mechanisms of its disappearance are laid.

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Degree of a person's response to pain varies greatly. This is partly due to the ability of the brain itself to suppress pain signals entering the nervous system by activating the so-called analgesia system (pain relief).

Pain relief system shown in the figure. It has three main components: (1) the gray matter areas of the midbrain and the upper part of the pons around the aqueduct and adjacent parts of the third and fourth ventricles of the brain. Neurons in these areas send signals to (2) the raphe nucleus major, which is a thin nucleus located in the midline of the lower part of the pons and the upper part of the medulla oblongata, and to the reticular paragiant cell nucleus, located laterally in the medulla oblongata. From these nuclei, second-order signals are transmitted down to the posterolateral columns of the spinal cord to (3) the pain-inhibiting complex located in the dorsal horns of the spinal cord. At this point, pain signals can block the pain until it is passed on to the brain.

Electrical stimulation gray matter around the midbrain aqueduct or the large raphe nucleus can suppress many of the strong pain signals entering the brain through the posterior roots of the spinal cord. Pain is also suppressed by stimulation of the higher regions of the brain that excite the gray matter around the plumbing. These include, for example, (1) the periventricular nuclei of the hypothalamus, adjacent to the third ventricle, and to a lesser extent (2) the medial forebrain bundle, also located in the hypothalamus.

In the anesthesia system some mediators are involved, especially enkephalin and serotonin. Many neurons in the periventricular nuclei and gray matter around the aqueduct secrete enkephalin. Consequently, the terminals of many fibers in the major raphe nucleus release enkephalin when stimulated.

The fibers coming out of this areas, send signals to the posterior horns of the spinal cord and release serotonin from their endings. Under the influence of serotonin, local spinal cord neurons also secrete enkephalin. It is believed that enkephalin causes presynaptic inhibition of type C and A pain fibers entering here at the site of their synaptic switching in the posterior horns and postsynaptic inhibition of the neurons associated with them.

Thus the system anesthesia can block pain signals in the region of their primary entry into the spinal cord. It also blocks many of the local spinal reflexes that occur in response to pain signals, especially the withdrawal reflexes.

Over 35 years ago, it was found that the introduction of a small amount of morphine into the periventricular nucleus adjacent to the third ventricle, or into the gray matter area around the aqueduct of the brain stem, causes pronounced analgesia. Subsequent studies have shown that morphine-like substances, mainly opiates, also act at many other levels of the analgesic system, including the dorsal horns of the spinal cord. Since the effect of most drugs on the excitability of neurons is through synaptic receptors, it was assumed that the receptors for some morphine-like neurotransmitters secreted in the brain under natural conditions are the morphine receptors of the analgesic system. In this regard, extensive research has been carried out regarding natural brain opiates. To date, about a dozen of these opiate-like substances (opiates) have been found in various parts of the nervous system; they are all degradation products of three large protein molecules: proopiomelanocortin, proenkephalin, and prodynorphin. The most important of the opiates include endorphin, met-enkephalin, leu-enkephalin and dynorphin.

Both enkephalin found in the brainstem and spinal cord, in areas corresponding to the previously described system of anesthesia, and endorphin is present in the hypothalamus and pituitary gland. Dynorphin is mostly found in the same areas where endorphins are, but in much smaller amounts.

Details opiate system of the brain are not yet fully understood, but activation of the analgesic system by nerve signals entering the gray matter around the aqueduct and periventricular areas, or inactivation of pain pathways by morphine-like drugs, can almost completely suppress many pain signals entering the nervous system through peripheral nerves.

Main questions

• 1. Definition of pain.
• 2. Classification of pain.
• 3. Causes of pain, factors that increase pain.
• 4. The concept of "total pain".
• 5. Pain assessment.
• 6. "Analgesic ladder" WHO.
• 7. Principles of chronic pain control.
• 8. Nursing care plan.
• 9. Education of patients receiving narcotic analgesics.
• 10. Non-pharmacological methods of pain relief.
• 11. Common mistakes of medical workers leading to poor pain relief.

The student must learn:

• assess pain;
• determine the causes of pain and the factors that provoke it;
• understand the principles of pharmacotherapy and management of chronic pain;
• provide education to patients receiving narcotic analgesics;
• within its competence, apply non-drug methods to eliminate and reduce pain;
• when controlling pain, make no mistakes leading to an unsatisfactory result.

It must be remembered that pain:

• - one of the main reasons for seeking medical help;
• - a symptom of many diseases and the action of external damaging factors;
• - biological defense mechanism;
• - warning signal about the danger to health and life;
• - includes objective and subjective mechanisms;
• - does not have objective measurement methods.

The current level of development of medicine makes it possible to control pain and relieve suffering in more than 90% of patients, however, the elimination of pain in cancer patients remains an urgent public health problem in our country and other countries of the world.

The World Health Organization estimates that "every day, at least 3.5 million people suffer from pain, whether or not they receive satisfactory treatment." Even in developed countries, 50-80% of patients do not receive satisfactory pain relief.

Pain is the most common manifestation of a malignant neoplasm.

Pain in 70-80% of patients in the late stage of the disease is the main symptom. Moderate and severe pain is experienced by 50-60% of patients, 30-40% - very severe or excruciating pain.

Reasons for this situation:

• a well-established tradition among medical personnel to administer painkillers “on demand” (“when it hurts” and “when the patient and his relatives insistently ask to reduce pain”), and not “by the hour” at certain intervals, preventing pain;
• insufficient knowledge of medical workers of existing methods of pain control in cancer patients;
• fears of medical workers, the patients themselves and their relatives that with a free opportunity to receive potent narcotic analgesics, patients will develop "addiction";
• legal and administrative restrictions on the access of cancer patients to appropriate drugs and especially to narcotic analgesics;
• lack of systematic training for medical students, physicians, nurses and other health care workers in pain relief for cancer patients.

Definitions of pain. The International Association for the Study of Pain defines pain How "unpleasant sensory and emotional experience, associated with actual or potential tissue damage, or described in terms of such damage. The inability to verbally express does not rule out the possibility that the person is in pain and needs appropriate pain management. Pain is always subjective.

Pain is an emotional reaction of the body to a damaging effect. Pain is what the person experiencing it says about it. It exists when the person experiencing it himself speaks about it.

Pain is anything that causes anxiety to the patient.

Pain classification

By localization:

• somatic superficial(in case of damage to the skin);
• somatic deep(with damage to muscles and bones);
• visceral(with damage to internal organs).

At the site of damage to the structures of the nervous system:

• with damage to peripheral nerves - neuropathic pain;
• damage to the structures of the central nervous system - central pain.

If the pain does not coincide with the site of injury, the following are distinguished:

• projected pain(for example, when squeezing the spinal roots, pain is projected into the areas of the body innervated by them);
• referred pain arises as a result of damage to internal organs and is localized in the superficial areas of the body remote from the injury site.

By intensity and duration:

• acute pain - new, recent pain, inextricably linked to the injury that caused it and, as a rule, is a symptom of some disease, disappears when the injury is repaired;
• chronic pain - The International Association for the Study of Pain defines chronic pain as pain lasting more than three months and lasting beyond the normal tissue healing period.

Causes of pain

The main causes of the onset and intensification of pain:

• connection with the tumor process (primary causes of pain);
• complications associated with tumor growth and its spread (secondary causes of pain);
• paraneoplastic syndromes (manifestations of a malignant tumor caused not by its local growth and metastasis, but by the body's reaction to a malignant tumor or the production of biologically active substances by a malignant tumor);
• complications of antitumor treatment (surgical, radiation and medicinal);
• environmental factors, social, psychological and spiritual problems (external factors), etc.

Increase sensitivity to pain:

• insomnia;
• depression and fear;
• thirst;
• infections;
• malnutrition;
• cooling;
• lack of knowledge;
• careless handling;
• violation of the technology of care and manipulation;
• lack of communication and information about the upcoming treatment.

Increased pain is affected by:

• the presence of severe symptoms, side effects of treatment;
• depression caused by the loss of social position, prestige associated with work and a decrease in material standards; loss of role in the family; chronic feeling of fatigue and insomnia; a feeling of helplessness; change in appearance and body defects;
• anger caused by organizational defects in health care and this medical institution, stopping visits from friends, work colleagues, relatives, inaccessibility of doctors, nurses and their silence, lack of results from treatment;
• anxiety, fear of death and hospitalization, concern for the future of one's family;
• sleep and rest disorders (noise, bright light, manifestations of inattention, violations of the medical and protective regime, lack of communication, understanding, poorly organized work of the staff).

It must be remembered that medical personnel can also be one of the risk factors for provoking, intensifying or stabilizing pain. It has been found that nurses often overestimate pain relief after taking analgesics and underestimate the level of pain they experience.

Physical, mental, spiritual and social factors, contributing to the emergence, maintenance and intensification of pain is included in the concept of "total pain". It is necessary to look for factors that provoke the appearance of increased pain and take actions aimed at eliminating them. Ensuring the control of symptoms and the elimination of factors that cause them, ensuring a good quality of life are of great importance in reducing pain in patients in the advanced stage of the disease.

The presence of pain, as a rule, is a rather late symptom of a malignant neoplasm and is not typical for the initial stages of the disease. The speed of development of this painful symptom depends on the location of the tumor: in a limited cavity, loose or dense tissues, hollow and well-stretched organs, but the very fact of the presence of pain in an oncological patient with a high degree of probability indicates that the neoplasm has a significant degree of spread.

Pain in patients with neoplasms of the kidneys, mammary and thyroid glands, pelvic organs, and liver indicates that the tumor has reached a significant size, stretches and grows into the organ capsule and grows into neighboring organs and tissues. Lung cancer is manifested by pain syndrome more often when the tumor is located subpleurally, when pleural sheets are involved in the process.

Pain syndrome is most often detected in malignant tumors of the digestive system, which is associated with a violation of the passage of food and concomitant inflammatory changes in the mucosa. Intense pain is characteristic of the defeat of the pancreatic tumor process (primary pancreatic cancer or when a tumor invades from nearby organs).

Headaches can occur even with minor primary and metastatic brain tumors.

Severe pain syndrome is often associated with metastatic lesions of organs and tissues, even with a small size of the primary tumor. For example, severe pain in patients with a prostate tumor most often indicates a metastatic lesion of the spine.

The task of the nurse, together with the doctor, is to determine the main cause of the occurrence of t intensification and persistence of pain, develop a plan to eliminate it.

The nurse should know:

• 1) factors affecting the occurrence and sensation of pain;
• 2) available methods for assessing pain in humans;
• 3) methods, the use of which by a nurse should contribute to the elimination or reduction of pain and feelings of fear.

A WHO expert group dealing with the problem of pain management in cancer patients has identified three main areas of "comprehensive approach to the problem of pain relief in cancer patients":

• assessment of the nature of pain;
• therapeutic strategy;
• permanent care.

Assessment of the nature of pain includes an assessment of the physical, psychological, spiritual, social, economic and interpersonal components that make up the "total" pain experienced by the patient. The responsibility for the evaluation lies with the doctor and nurse.

Measures aimed at eliminating or reducing pain should be preceded by an analysis of the pain assessment by the patients themselves. This is necessary in order to have an idea of ​​​​the individual threshold of sensitivity to pain in a particular patient. The response to pain varies from patient to patient., it can change in the patient at different periods of the disease. It is necessary to follow the recommendations of WHO experts on assessing the nature of pain in cancer patients. Ignorance or neglect of their implementation is the main reason for the incorrect assessment of the nature of pain and inadequate control of it.

You must:

• 1) trust the patient's complaints of pain,
• 2) assess the severity of pain, experienced by the patient.

Pain assessment includes:

• localization of pain;
• intensity and duration of pain;
• the nature of the pain;
• factors contributing to the appearance and intensification of pain;
• a history of pain;
• human response to pain.

To determine the severity of pain, experienced by the patient, need to find out:

• whether the pain leads to a limitation of activity, daily activities of the patient;
• whether it causes sleep disturbances and how many hours he sleeps without pain;
• whether prescribed medications and ancillary non-pharmacological methods of pain relief relieve pain;
• degree of pain relief;
• whether the pain that the patient feels at the moment is similar in severity to that which he experienced in the past (toothache, muscle pain or cramps, postoperative pain, renal colic, labor pains).

With the help of mediators of the nociceptive system, information is transmitted from cell to cell.

§ Substance P (from the English pain - "pain") - the main one.

§ Neurotensin.

§ Bradykinin.

§ Cholecystokinin.

§ Glutamate.

22. - Theories of pain. The mechanism of pain occurrence according to the theory of gate control. Functioning mechanisms of the antinoceptive system.

Theories of pain.

Specificity theory claims that pain is a separate sensory system in which any damaging stimulus activates special pain receptors (nociceptors) that transmit pain impulses along special nerve pathways to the spinal cord and pain centers of the brain, causing a defensive response aimed at moving away from the stimulus .

The basis for the creation of the theory of specificity was the teaching of the French philosopher and physiologist R. Descartes on the reflex. In the 20th century, the validity of the concept of pain as a specific projection sensory system was confirmed by numerous studies and discoveries in anatomy and experimental physiology. Pain-conducting nerve fibers and pain-conducting pathways in the spinal cord, pain centers in various parts of the brain, pain mediators (bradykinin, substance P, VIP, etc.) were found.

According to the theory of specificity, the psychological sensation of pain, its perception and experience are recognized as adequate and proportional to physical trauma and peripheral damage. In practical medical practice, this provision led to the fact that patients suffering from pain and not having obvious signs of organic pathology began to be considered "hypochondriacs", "neurotic" and, at best, were referred for treatment to a psychiatrist or psychotherapist.

intensity theory claims that the sensation of pain occurs when any receptor is irritated by an excessive stimulus (noise, light).

Gate control theory(Melzack and Wall, 1965). The flow of pain impulses from the periphery goes to the posterior horn of the spinal cord along large myelinated (A-delta) and small unmyelinated (C-fibers) nerve fibers. Both types of fibers form synapses with second-order (T) neurons ("transmission/projection"). When T neurons are activated, they deliver nociceptive information to the brain.

Peripheral nerve fibers also form synapses with gelatinous substance (GS) interneurons, which, when stimulated, depress T-neurons. A-delta fibers stimulate, and C-fibers inhibit the ventricular interneurons, respectively reducing and increasing the central transmission of nociceptive incoming signals.

In addition, stimulation of GS interneurons to suppress the activity of T-neurons occurs through descending pathways originating in the central nervous system (this occurs when activated by various factors). The balance between excitatory and depressing signals determines the degree of transmission of nociceptive information to the brain (“+” - excitatory signal; “-” - depressing signal).

Rice. 8.2. Scheme of the "gate control" theory according to R. Melzack, 1999 (explanation in the text).

Note. ZhS - gelatinous substance of the posterior horns of the spinal cord, T - transmissible neurons.

The main scientific and medical significance of the "entrance gate" theory was the recognition of the spinal cord and brain as an active system that filters, selects and acts on input sensory signals. The theory approved the central nervous system as the leading link in pain processes.

Theory " generator of pathologically enhanced excitation» in the central nervous system emphasizes the importance of central mechanisms in the pathogenesis of pain and determines the role of peripheral factors.

Pathologically increased excitation generator(GPUV, generator) is an aggregate of hyperactive neurons that produces an excessive uncontrolled stream of impulses.

HPUV is formed in the damaged nervous system from primary and secondary altered neurons and represents a new pathological integration, unusual for the activity of the normal nervous system, that occurs at the level of interneuronal relations. A feature of the generator is its ability to develop self-sustaining activity. GPUV can be formed in almost all parts of the CNS, its formation and activity are typical pathological processes.

When creating a generator, various pain syndromes appear in the pain sensitivity system: pain syndrome of spinal origin (generator in the dorsal horns of the spinal cord), trigeminal neuralgia (generator in the caudal nucleus of the trigeminal nerve), thalamic pain syndrome (generator in the nuclei of the thalamus).

Neuromas, nerve damage, displacement of the intervertebral discs cause pain and lead to pathological central processes. In the CNS, a "generator of pathologically enhanced excitation" is formed, as a result, the value of peripheral factors decreases. Therefore, with severe phantom neuralgic and lumbar pain after removal of nerve neuromas, disc herniations, etc. elimination of peripheral factors may not lead to cessation of pain.

The emergence of a generator begins either with primary hyperactivation of neurons, or with primary violation of their inhibition. During primary hyperactivation of neurons, inhibitory mechanisms are preserved, but they are functionally insufficient. In this case, there is a secondary insufficiency of inhibition, which increases with the development of the generator, with the predominance of excitation. With primary insufficiency of inhibitory mechanisms, disinhibition and secondary hyperactivation of neurons appear.

Primary hyperactivation of neurons occurs as a result of enhanced and prolonged excitatory effects: during synaptic stimulation, under the action of excitatory amino acids, K +, etc. The role of synaptic stimulation is clearly visible in the example of the formation of a generator in the nociceptive system. Chronically irritated receptors in tissues, ectopic foci in damaged nerves, neuroma (chaotically overgrown afferent fibers) are a source of constant impulses. Under the influence of this impulse, a generator is formed in the central apparatus of the nociceptive system.

The primary impairment of neuronal inhibition is formed under the action of substances that selectively damage inhibitory processes. This effect occurs under the action of tetanus toxin, which disrupts the release of inhibitory mediators by presynaptic endings; under the action of strychnine, which blocks glycine receptors on postsynaptic neurons of the spinal cord, where glycine has an inhibitory effect; under the action of certain convulsants that disrupt postsynaptic inhibition.

Since the activity of generator mechanisms is determined by multiple interactions, it can be influenced by the simultaneous use of antidepressants, irritation of trigger points with electric current, physiotherapy, etc.

The concept of the antinociceptive system. Its levels, mediators.

Antinociceptive system

The complex of the nociceptive system is equally balanced in the body by the complex of the antinociceptive system, which provides control over the activity of the structures involved in the perception, conduction and analysis of pain signals.

It has now been established that pain signals coming from the periphery stimulate the activity of various parts of the central nervous system (periaductal gray matter, raphe nuclei of the brainstem, nuclei of the reticular formation, nucleus of the thalamus, internal capsule, cerebellum, interneurons of the posterior horns of the spinal cord, etc. ) providing downward inhibitory action on the transmission of nociceptive afferentation in the dorsal horns of the spinal cord.

The main neurons of the antinoceceptive system are localized in the periaqueductal gray matter (the Sylvian aqueduct connects the III and IV ventricles). Their axons form descending pathways to the medulla oblongata and spinal cord and ascending pathways to the reticular formation, thalamus, hypothalamus, limbic system, basal ganglia, and cortex.

The mediators of these neurons are pentapeptides: methenkephalin and leuenkephalin. Enkephalins excite opiate receptors. Opiate receptors are excited not only by mediators-enkephalins, but also by other components of the antinoceceptive system - brain hormones - endorphins (beta-endorphin, dynorphin).

In the mechanisms of the development of analgesia, the greatest importance is attached to the serotonergic, noradrenergic, GABAergic and opioidergic systems of the brain.

The main of them, the opioidergic system, is formed by neurons, the body and processes of which contain opioid peptides (beta-endorphin, met-enkephalin, leu-enkephalin, dynorphin).

By binding to certain groups of specific opioid receptors (mu-, delta- and kappa-opioid receptors), 90% of which are located in the dorsal horns of the spinal cord, they contribute to the release of various chemicals (gamma-aminobutyric acid) that inhibit the transmission of pain impulses.

Enkephalins and endorphins excite opiate receptors. In enkephalinergic synapses, opiate receptors are located on the postsynaptic membrane, but the same membrane is presynaptic for other synapses. Opiate receptors are associated with adenylate cyclase and cause its inhibition by disrupting cAMP synthesis in neurons. As a result, calcium entry and release of mediators, including pain mediators (substance P, cholecystokinin, somatostatin, glutamic acid) are reduced.

The mediators of the antinoceceptive system also include catecholamines. They excite inhibitory a 2 -adrenergic receptors, thereby carrying out postsynaptic inhibition of pain.

Types of cellular inhibition

· presynaptic aimed at inhibition of mediator release due to hyperpolarization of the entire neuron.

· postsynaptic– hyperpolarization of the next neuron.

Speaking about the antinociceptive system, the first component should be:

1. gelatinous substance spinal cord (in the sensitive nuclei of the trigeminus, apparently, there is something similar).

2. Descending hypothalamic-spinal tracts(the possibility of pain relief by hypnosis, suggestion and self-hypnosis). Inhibitory mediators are also released from axons in the spinal cord or on the trigeminus nuclei.

The natural pain-relieving system is just as important for normal functioning as the pain-signaling system. Thanks to her, minor injuries such as a bruised finger or a sprain cause severe pain only for a short time - from a few minutes to several hours, without making us suffer for days and weeks, which would happen in conditions of persisting pain until complete healing.

Thus, physiological nociception includes four main processes:

1. transduction- a process in which the damaging effect is transformed into electrical activity in free non-encapsulated nerve endings (nociceptors). Their activation occurs either as a result of direct mechanical or thermal stimuli, or under the influence of endogenous tissue and plasma algogens formed during trauma or inflammation (histamine, serotonin, prostaglandins, prostacyclins, cytokines, K + and H + ions, bradykinin).

2. transmission- conduction of the resulting impulses through the system of sensory nerve fibers and pathways to the central nervous system (thin myelinated A-delta and thin unmyelinated C-afferents in the axons of the spinal ganglia and posterior spinal roots, spinothalamic, spinomesencephalic and spinoreticular pathways coming from the neurons of the posterior horns of the spinal brain to the formations of the thalamus and the limbic-reticular complex, thalamocortical pathways to the somatosensory and frontal areas of the cerebral cortex).

3. Modulation- the process of changing nociceptive information by descending, antinociceptive influences of the central nervous system, the target of which is mainly the neurons of the dorsal horns of the spinal cord (opioidergic and monoamine neurochemical antinociceptive systems and the gate control system).

4. Perception- subjective emotional sensation perceived as pain and formed under the influence of background genetically determined properties of the central nervous system and situationally changing stimuli from the periphery.

23. - Extreme conditions. Differences of syncope, collapse, shock and coma. general pathogenesis of shock.

extreme conditions- conditions accompanied by gross disorders of metabolism and vital functions and representing an immediate danger to life.

Extreme conditions are often associated with the action of superstrong pathogenic factors.