Theoretical conformational analysis of leucine-enkephalin, N-terminal tridecapeptide dynorphin and their analogues Damirov Aslan Gasan ogly. Opioid peptides

Practical work on the section
"Reproduction of genetic information"

It is known that the modern course of general biology for schools contains insufficient materials for practical classes. In addition, the insufficiency or lack of material base, lack of equipment and supplies in school chemical and biological laboratories cause a difficult situation with laboratory and practical classes in the course of general biology. However, such a section of the course as "Reproduction of genetic information" provides enough opportunities for practical training in order to develop skills in processing and operating genetic information.

This work is a development of a practical lesson that can be used to conduct independent and control work on this topic with the involvement of materials on cell chemistry.

During the course, the following goals can be achieved.

1. Consolidation of knowledge on the structure and properties of the genetic code.

2. Consolidation of knowledge about the process of reduplication - DNA matrix copying and the principle of complementarity.

3. Consolidation of knowledge about transcription and translation of genetic information - the process of transmission.

4. Formulation of the fundamental principle of biology about the transfer of genetic information in the cell:
DNA ---> mRNA ---> protein.

5. Explanation of the possibility of transmitting information by RNA-containing viruses according to the scheme:
viral RNA ---> cDNA ---> mRNA ---> viral protein.

7. Acquaintance with the methods of modern biotechnology.

Of course, this is far from exhausting the objectives of the proposed task, but they cover the most important sections of the topic "Reproduction of genetic information".

To conduct a lesson, it is necessary to have a good knowledge of the material on the properties and structure of the genetic code, the processes of reproduction of genetic information (replication, transcription and translation), the principle of complementarity, the Chargaff rule, which should be repeated before work.

The transfer of genetic information always occurs in a certain way, which is reflected in the so-called "central dogma of biology", namely, only in the direction from DNA to mRNA and further to protein.

The first stage in the reproduction of genetic information, called transcription, occurs with the help of RNA polymerase, which builds a complementary copy of the gene in the form of mRNA.

In the second stage, which is called broadcast, information is translated from the language of nucleotides (RNA) into the language of amino acids (protein). Thus, there is a realization of genetic information for the construction of functional units - protein molecules with specific functions, which are also genetically fixed.

When RNA-containing viruses enter the cell, information can be transmitted along the chain: viral RNA ---> cDNA ---> DNA ---> mRNA ---> virus protein. This process is implemented using reverse transcriptase, which, at the first stage of reproducing the genetic information of the virus, builds coding DNA (cDNA) according to the viral RNA template. This cDNA is then inserted into the DNA of the host cell. However, this only happens when the resources of the cell into which the virus has entered are used.

Such a scheme for the transfer of genetic information is considered an atavism. This is due to the fact that RNA, apparently, in the course of chemical evolution began to play the role of an information molecule earlier than DNA. The main argument in favor of this statement is the presence of enzymatic activity in RNA molecules, discovered by Thomas Cech, and the ability of RNA molecules to reproduce themselves. The author of this discovery was awarded the Nobel Prize.

However, the ribozyme activity of RNA is tens of thousands of times lower than that of RNA polymerase, and only short RNA fragments, oligonucleotides up to 50–100 bases long, have it. On the other hand, there is an opinion that ribozyme activity is secondary and has nothing to do with chemical evolution.

A single genetic code is used to record genetic information. If the amino acid sequence of a protein becomes known in one laboratory, then the corresponding DNA (or RNA) nucleotide sequences can be written in another laboratory, and vice versa.

Several forms of work can be offered for class work based on filling in nucleotide maps and amino acid maps of the corresponding polypeptides (Appendices 1-4). This can be individual or group work. Group work can be thought of as the work of separate biotechnology laboratories, each of whose members performs a specific operation. Individual students or groups exchange cards, gradually filling them. A group of experts or one expert (it can be a teacher) at the end of the work checks the cards, revealing mutation errors.

The complexity of the work will depend on the ability to use educational material: tables of the genetic code, reduplication, transcription and translation schemes, complementarity tables, properties of the genetic code, etc. The lesson can be given the character of laboratory, practical, independent or control work.

To specify tasks, it is better to use maps of small polypeptides, for example, some peptide hormones. For this purpose, it is convenient to use oligopeptides of the hormones vasopressin and oxytocin, as well as methionine- and leucine-enkephalins - natural endorphins produced in the body of animals and humans (Appendices 1-4). Vasopressin and oxytocin have a wide spectrum of action, and endogenous morphine-like substances are attracting attention in connection with the problem of drug addiction and the explanation of the narcotic effect.

The cards may include material from the "Cell Chemistry" section, namely the formulas and properties of amino acids. Oligopeptides of vasopressin and oxytocin contain SH-containing amino acids (cysteine) that form disulfide bridges in the secondary structure of the peptide, which can be reflected in the degree of task complexity.

The maps include terminator codons, which must be written in the corresponding triplets in DNA or RNA chains. Also included is the initiator codon for the amino acid methionine, which in this case is at the beginning of the chain.

Nucleotides of the leading sequence after the initiator codon (and the corresponding amino acids) are not included in the content of the maps, since they are not of fundamental importance for the processing of genetic information and are removed from the amino acid sequence during processing (proteolysis).

The proposed work of students with cards and filling in tables for the translation of genetic information (reduplication, transcription, translation), writing formulas and symbols of amino acids can be calculated for 1-2 lessons, depending on the complexity and nature of the task.

At the end of the lesson, students are graded and the following conclusions are formulated.

Genetic information is universal. No life forms with other genetic codes have been found; the genetic code is the same for all organisms, and there is no other genetic code. This code has enough possibilities to describe the whole variety of protein molecules.

Conventional abbreviations are used on the maps: mRNA – informational RNA; cDNA, coding DNA strand; comp. DNA is a complementary strand of DNA. The amino acid codon is chosen arbitrarily, as one of the possible ones, which is allowed in the work of students.

For the lesson, card variants are used that do not have any one line, i.e. There are 5 options for each card. Accordingly, the work can be distributed to a specific number of students and groups. You can offer work on other maps for other peptides, the number of which is practically unlimited.

Appendix 1

Methionine-enkephalin - a hormone of the nuclei of the cerebral cortex, an endogenous opioid peptide, consists of 5 amino acids

Amino acid

Comp. DNA

Annex 2

Leucine-enkephalin - a hormone of the nuclei of the cerebral cortex, an endogenous opioid peptide, consists of 5 amino acids

Chemical formula of the amino acid radical

Amino acid

Comp. DNA

Annex 3

Vasopressin - an antidiuretic hormone - produced by the pituitary gland, causes contraction of smooth muscles, reduces the excretion of water, consists of 9 amino acids with one disulfide bond

Chemical formula of the amino acid radical

Acetylcholine secreted from the terminals of somatic motor neurons (neuromuscular synapses), preganglionic fibers, postganglionic cholinergic (parasympathetic) fibers of the autonomic nervous system and axonal branches of many CNS neurons (basal ganglia, motor cortex). Synthesized from choline and acetyl-CoA by choline acetyltransferase, interacts with several types of cholinergic receptors. The short-term interaction of the ligand with the receptor is stopped by acetylcholinesterase, which hydrolyzes acetylcholine into choline and acetate.

Botulinum toxin Clostridium botulinum inhibits the secretion of acetylcholine.

Organophosphorus compounds(FOS) inhibit acetylcholinesterase, which leads to an increase in the amount of acetylcholine in the synaptic cleft. In case of FOS poisoning, pralidoxime promotes the separation of FOS from the enzyme, atropine protects cholinergic receptors from interaction with an excess amount of the neurotransmitter.

Pale toadstool toxins Amanita phalloides not only inhibit the activity of acetylcholinesterase, but also block cholinergic receptors.

Dopamine

Dopamine- a neurotransmitter in the endings of some axons of peripheral nerves and many CNS neurons (substance nigra, midbrain, hypothalamus). After secretion and interaction with receptors, dopamine is actively captured by the presynaptic terminal, where it is cleaved by monoamine oxidase. Dopamine metabolizes with the formation of a number of substances, incl. homovanillic acid.

Schizophrenia. In this disease, there is an increase in the number of D 2 dopamine receptors. Antipsychotics reduce the activity of the dopaminergic system to normal levels.

Chorea hereditary- impaired function of the neurons of the cortex and striatum - is also accompanied by increased reactivity of the dopaminergic system.

Parkinson's disease- a pathological decrease in the number of neurons in the substantia nigra and other areas of the brain with a decrease in the level of dopamine and methionine-enkephalin, the predominance of the effects of the cholinergic system. Application L-DOPA increases dopamine levels, amantadine stimulates dopamine secretion, bromocriptine activates dopamine receptors. Anticholinergic drugs reduce the activity of the cholinergic system in the brain.

Norepinephrine

Norepinephrine secreted from most postganglionic sympathetic fibers and is a neurotransmitter between many CNS neurons (eg, hypothalamus, locus ceruleus). It is formed from dopamine by hydrolysis with the help of dopamine- ?-hydroxylase. Norepinephrine is stored in synaptic vesicles, after release it interacts with adrenoreceptors, the reaction stops as a result of the capture of norepinephrine by the presynaptic part. The level of norepinephrine is determined by the activity of tyrosine hydroxylase and monoamine oxidase. Monoamine oxidase and catechol- O-methyltransferase converts noradrenaline to inactive metabolites (normetanephrine, 3-methoxy-4-hydroxy-phenylethylene glycol, 3-methoxy-4-hydroxymandelic acid).

Norepinephrine- a powerful vasoconstrictor, the effect occurs when the neurotransmitter interacts with the SMC of the wall of blood vessels.

Serotonin

Serotonin(5-hydroxytryptamine) is a neurotransmitter of many central neurons (eg, raphe nucleus, neurons of the ascending reticular activating system). The precursor is tryptophan, which is hydroxylated by tryptophan hydroxylase to 5-hydroxytryptophan, followed by decarboxylation by decarboxylase. L-amino acids. It is cleaved by monoamine oxidase to form 5-hydroxyindoacetic acid.

Depression characterized by a decrease in the amount of two neurotransmitters (norepinephrine and serotonin) and an increase in the expression of their receptors. Antidepressants decrease the number of these receptors.

manic syndrome. In this condition, the level of norepinephrine increases against the background of a decrease in the amount of serotonin and adrenoreceptors. Lithium reduces the secretion of norepinephrine, the formation of second messengers and increases the expression of adrenoreceptors.

Gamma aminobutyric acid

Gamma-aminobutyric acid(?-Aminobutyric acid) is an inhibitory neurotransmitter in the central nervous system (basal ganglia, cerebellum). It is formed from glutamic acid under the action of glutamic acid decarboxylase, is captured from the intercellular space by the presynaptic part and degrades under the influence of GABA transaminase.

Epilepsy- sudden synchronous bursts of activity of groups of neurons in different areas of the brain, associated with a decrease in inhibitory action ?-aminobutyric acid. Phenytoin stabilizes the plasma membrane of neurons and reduces excessive secretion of the neurotransmitter, phenobarbital increases the binding of GABA to receptors, valproic acid increases the content of the neurotransmitter.

Alarm state- psychotic reaction associated with a decrease in the inhibitory effect of GABA. Benzodiazepines stimulate the interaction of the neurotransmitter with the receptor and maintain the inhibitory effect g-aminobutyric acid.

beta endorphin

beta endorphin(?-Endorphin) - a neurotransmitter of the polypeptide nature of many CNS neurons (hypothalamus, cerebellar tonsil, thalamus, bluish place). Proopiomelanocortin is transported along axons and cleaved by peptidases into fragments, one of which is ?-endorphin. The neurotransmitter is secreted at the synapse, interacts with receptors on the postsynaptic membrane, and then is hydrolyzed by peptidases.

Substance P

Substance P- a peptide neurotransmitter in neurons of the central and peripheral nervous system (basal ganglia, hypothalamus, spinal nodes). The transmission of pain stimuli is realized with the help of substance P and opioid peptides.

Substance P(from English pain, pain) - a neuropeptide from the tachykinin family, produced by both neurons and non-nerve cells and functioning as a neurotransmitter (basal ganglia, hypothalamus, spinal cord, where substance P transmits excitation from the central process of a sensitive neuron to a neuron of the spinothalamic tract; through opioid receptors, enkephalin from the intercalary neuron inhibits the secretion of substance P from the sensitive neuron and the conduction of pain signals). Substance P also enhances the permeability of the vascular wall of the skin, vasodilates or vasoconstrictes the SMCs of the arterioles of the brain, stimulates the secretion of the salivary glands and reduces the SMCs of the airways and gastrointestinal tract. Substance P also functions as an inflammatory mediator.

Methionine enkephalin and leucine enkephalin

Methionine-enkephalin and leucine-enkephalin- small peptides (5 amino acid residues) present in many CNS neurons (pallidus, thalamus, caudate nucleus, central gray matter). Like endorphins, they are formed from pro-opiomelanocortin. After secretion, they interact with peptidergic (opioid) receptors.

Dynorphins

This group of neurotransmitters consists of 7 peptides of similar amino acid sequence, which are present in neurons of the same anatomical regions as enkephalinergic neurons. Formed from prodynorphin, inactivated by hydrolysis.

Glycine, glutamic and aspartic acids

These amino acids are neurotransmitters in some synapses (glycine in the interneurons of the spinal cord, glutamic acid in the neurons of the cerebellum and spinal cord, aspartic acid in the neurons of the cortex). Glutamic and aspartic acids cause excitatory responses, and glycine - inhibitory.

Orlov R.S., Nozdrachev A.D. normal physiology. - M.: GEOTAR-Media, 2009. 688 p. Chapter6. Synapses. - Neurotransmitters. pp. 87-88 +CD-ROM.

parkinson James (Parkinson James), English surgeon (1755-1824); in 1817 he published a book on shaking paralysis.

DOPA(dihydroxyphenylalanine). This amino acid is isolated from Vicia faba L, is active and used as an antiparkinsonian agent, its L-form - levodopa ( L-DOPA, levodopa, 3-hydroxy- L-tyrosine, L-dihydroxyphenylalanine). DOPA? decarboxylase (gene DDC, 107930, 7p11, EC 4.1.1.28) catalyzes decarboxylation L?DOPA; the enzyme is involved in the synthesis of dopamine, as well as serotonin (from 5-hydroxytryptophan).

For centuries, opiates, specifically morphine, have been used as pain relievers. In 1680, Thomas Sydenham wrote: "Among all the medicines that the Almighty has given to man in order to relieve his suffering, there is none more universal and more effective than opium." But why do vertebrate brains contain receptors for alkaloids from poppy seeds? Neuropharmacologists have suggested that opiate receptors are not designed to interact with plant alkaloids, but to perceive endogenous regulators of pain sensation. According to this view, morphine has a pharmacological effect only because it mimics substances that exist in the animal body. This issue was finally resolved in 1975, when John Hughes isolated two opiate-like peptides from pig brain. These similar pentapeptides, called methionine-enkephalin and leucine-enkephalin, are present in large quantities in some nerve endings. They appear to be involved in the integration of sensory information related to pain.

A year later, Roger Guillemin isolated longer peptides, endorphins, from the intermediate lobe of the pituitary gland. Endorphins have almost the same ability to relieve the sensation of pain as morphine (at the same concentration). The introduction of endorphins into the ventricles of the brain of laboratory animals has

Rice. 35.16. Amino acid sequences of methionine-enkephalin (A), leucine-enkephalin (B) and P - endorphin (C). The blue color shows their common tetrapeptide sequence.

remarkable action. So, P-endorphin induces deep analgesia of the whole body for several hours, and during this period the body temperature decreases. Moreover, the animals develop a stupor, and they lie sprawled. After a few hours, the effect of endorphins disappears, and the animals behave normally again. It also turned out to be a surprising fact that the effect of endorphins disappears a few seconds after the administration of naloxone (Fig. 35.17), a well-known antagonist of morphine. Judging by the behavioral responses induced by endorphins, these peptides under normal conditions are involved in the regulation of emotional responses. Many of the methods needed to test this hypothesis have already been developed. Thus, to determine extremely small amounts of peptides, such as endorphins, radioimmunoassay is used, which combines the sensitivity of radioisotope methods with the specificity of the immune response. Here we are faced with the birth of a new and promising field of neuroscience and neuropsychiatry.

Endorphins are formed from lipotropins in brain tissue and in the intermediate lobe of the pituitary gland. A common type of structure for these compounds is a tetra-peptide sequence at the N-terminus. Beta-endorphin is formed from beta-lipotropin by proteolysis. Beta-lipotropin is formed from the prohormone precursor proopicortin (molecular weight 29 kDa, 134 amino acid residues).

In the anterior pituitary, the precursor molecule is cleaved into ACTH and β-lipotropin, which are secreted into the plasma. A small part (about 15%) of b-lipotropin is cleaved to form b-endorphin. The biosynthesis of proopicortin in the anterior pituitary gland is regulated by corticoliberin of the hypothalamus. Three different opioid peptide precursor proteins are known: proenkephalin, proopiomelanocortin, and prodynorphin.

Natural opioid peptides were isolated for the first time in 1976 from the brain of mammals. These were the so-called enkephalins - leucine-enkephalin and methionine-enkephalin, differing only in the terminal C-residue.

In the early 1970s, various laboratories around the world discovered that brain cells have receptors that bind morphine, and only in this bound form does it become active. There was no reason to assume that the brain specially prepared such receptors for such a rare ingredient as morphine. There was a suspicion that the function of these receptors was not to bind morphine, but some substance close to it, produced by the body itself. In 1976, Dr. Hughes in Scotland extracted this mysterious substance from the brain of a guinea pig, which immediately experienced a sharp decrease in pain sensitivity. Hughes named the substance enkephalin, which means "from the brain" in Greek. And Professor Cho Hao Lee in San Francisco extracted from the brain of a camel, and more specifically from the camel pituitary gland, another internal drug that turned out to be 50 times stronger than the known morphine. Cho called it endorphin - "internal morphine". In the same 1976, two more internal drugs were isolated from the blood of animals, which were similar to morphine in composition, but, unlike plant morphine, did not depress breathing and did not lead to drug addiction. And, finally, Dr. Pless synthesized endorphin in Switzerland, that is, he made it in a laboratory, in a test tube, knowing exactly the chemical composition and structure of this mysterious substance. Other opioid peptides, endorphins, have also been isolated from mammalian pituitary and hypothalamic tissue extracts. All of them usually contain an enkephalin residue in the N-terminal region. All endogenous opioid peptides are synthesized in the body as large precursor proteins by proteolysis. The spatial structure of enkephalins is similar to that of morphine. Enkephalins and endorphins have an analgesic effect, reduce the motor activity of the gastrointestinal tract, and affect the emotional state.

· MSH - melanocyte-stimulating hormone;

· LPG - lipotropic hormone;

· KPPP - corticotropin-like intermediate peptide;

· ACTH - adrenocorticotropic hormone.

Secretion regulation

All POMC cleavage products are produced in equimolar amounts and secreted into the blood at the same time. Thus, it is impossible to increase the secretion of adrenocorticotropic hormone without a concomitant increase in the secretion of beta-lipotropic hormone. The production of POMC is regulated by factors that are formed in the hypothalamus and the paraventricular nucleus of the brain: corticoliberin, arginine vasopressin - activate the synthesis of ACTH, cortisol - the main inhibitor of the synthesis of corticoliberin and the formation of POMC, therefore, corticoliberin, arginine vasopressin, cortisol will affect the synthesis and secretion of β-endorphin.

The synthesis of β-endorphin decreases in endocrine, infectious and viral diseases, chronic fatigue syndrome, and synthesis can be enhanced with the help of physical activity.

Transport and peripheral metabolism

Endorphins are synthesized "for the future" and released into the blood in certain portions due to the emptying of secretory vesicles. Their level in the blood increases with an increase in the frequency of hormone release from glandular cells. Once in the blood, hormones bind to plasma proteins. Usually, only 5-10% of hormone molecules are in the blood in a free state, and only they can interact with receptors.

The degradation of peptide hormones often begins already in the blood or on the walls of blood vessels, this process is especially intense in the kidneys. Protein-peptide hormones are hydrolyzed by proteinases, namely exo- (at the ends of the chain) and endopeptidases. Proteolysis results in the formation of many fragments, some of which may be biologically active. Many protein-peptide hormones are removed from the circulation system by binding to membrane receptors and subsequent endocytosis of the hormone-receptor complex. The degradation of such complexes occurs in lysosomes; the end product of degradation is amino acids, which are again used as substrates in anabolic and catabolic processes.

biological significance

The main target of endorphins is the so-called opioid system (its main purpose is protection from stress damage, pain relief and coordination of the work of organ and tissue systems at the level of the body as a whole) of the body, and opioid receptors in particular. Endorphin is responsible for regulating the activity of all internal glands, for the functioning of the immune system, for the level of pressure, and endorphin also affects the nervous system. Specific morphine receptors have been found in the brain. These receptors are concentrated on synaptic membranes. The limbic system is the richest in them, on which the emotional response depends. Subsequently, endogenous peptides were isolated from the brain tissue, imitating various effects of morphine upon injection. These peptides, which have the ability to specifically bind to opiate receptors, are called endorphins and enkephalins.

Because Since opiate hormone receptors are located on the outer surface of the plasma membrane, the hormone does not penetrate into the cell. Hormones (the first messengers of the signal) transmit a signal through the second messenger, the role of which is performed by cAMP, cGMP, inosotol triphosphate, Ca ions. After the attachment of the hormone to the receptor, a chain of events follows that changes the metabolism of the cell.

Physiologically, endorphins and enkephalins have the strongest analgesic, anti-shock and anti-stress effect, they reduce appetite and reduce the sensitivity of certain parts of the central nervous system. Endorphins normalize blood pressure, respiratory rate, accelerate the healing of damaged tissues, the formation of callus in fractures.

Endorphins often occur in conjunction with the release of adrenaline. With long workouts, adrenaline is released in the body, muscle pain increases and endorphins begin to be produced, which reduce pain, increase the reaction and speed of adaptation of the body to stress.

What do the endorphin systems influence?

- analgesic effects

- slowing down breathing, palpitations - anti-stress effects

- strengthening of immunity

- regulation of renal blood flow

- regulation of intestinal activity

- participation in the processes of excitation and inhibition in the nervous system

- participation in the processes of development of associative-dissociative connections in the nervous system - regulation of the intensity of metabolism

- feeling of euphoria

- accelerate the healing of damaged tissues

-formation of bone callus in fractures

In addition, endorphins are associated with thermoregulation, memory, lipolysis, reproduction, pleasure, fat breakdown in the body, antidiuresis, suppression of hyperventilation in response to an increase in carbon dioxide, and inhibition of thyrotropin and gonadotropin synthesis.

Pathology

The lack of endorphin is noted in depression, in a situation of constant emotional stress, it exacerbates chronic diseases, and can cause chronic fatigue syndrome. Hence the accompanying depression of mood and increased susceptibility to infectious diseases.

Endorphin production is reduced in some pathologies. Due to the lack of endorphins in the body, the risk of chronic diseases, the so-called "lifestyle diseases", which have recently been the main cause of death, increases. Lifestyle diseases are diabetes, cardiovascular disease, chronic respiratory disease, cancer and obesity.

The lack of endorphins is expressed in apathy, a very bad mood and ultimately leads a person to depression. Everyone wants to know how to enjoy life. The feeling of pleasure in a person appears with an increase in the level of endorphins, which are produced by the brain and this chemical compound is similar to the drug morphine. Therefore, endorphin received such a name - endogenous morphine, that is, produced by the body itself.

The most severe manifestation is anhedonia, a disease in which a person is not able to experience pleasure.

Neurohormones

Neurohormones are substances with high physiological activity that are produced in the neurosecretory cells of the nervous system (neurons).

According to the mechanism of action, they have much in common with neurotransmitters, but neurohormones, unlike them, enter the blood and other biological fluids of the body (lymph, cerebrospinal fluid and tissue fluid) and have a long-term remote regulatory effect.

According to the chemical structure, neurohormones are peptides (contain amino acids) or catecholamines (biogenic amines), their obligatory fragment is 3,4-dihydroxyphenylalanine (catechol).

Neurohormones maintain water-salt homeostasis, regulate smooth muscle tone and metabolic processes, and also participate in the regulation of the endocrine glands. In general, the function of these substances is to maintain the protective and adaptive functions of the body.

The synthesis of neurohormones occurs in the neurosecretory cells of the hypothalamus (dopamine, vasopressin, oxytocin, norepinephrine, serotonin and releasing factors), spinal cord, pineal gland, adrenal glands (chromaffin tissue of the medulla). They are also synthesized in the ganglia, paraganglia and nerve trunks of the autonomic nervous system ( synthesis of adrenaline and norepinephrine).

The process of biosynthesis of peptide neurohormones occurs in the body of the neuron, in a structure called the endoplasmic reticulum; then in the Golgi complex they are packed into granules and from there they are transported along the axon to the nerve endings.

Neurophysiology of sleep

Neurophysiological mechanisms of sleep and its age-related features

Sleep is a physiological state, which is characterized by the loss of active mental connections of the subject with the world around him. Sleep is vital for higher animals and humans. For a long time, it was believed that sleep is a rest necessary to restore the energy of brain cells after active wakefulness. However, it turned out that brain activity during sleep is often higher than during wakefulness. It was found that the activity of neurons in a number of brain structures during sleep increases significantly; sleep is an active physiological process.

sleep stages

Reflex reactions during sleep are reduced. A sleeping person does not respond to many external influences, unless they are of excessive strength.

Sleep theories:

humoral theory, considers substances that appear in the blood during prolonged wakefulness as the cause of sleep. The proof of this theory is an experiment in which an awake dog was transfused with the blood of an animal deprived of sleep during the day. The recipient animal immediately fell asleep. But humoral factors cannot be considered as the absolute cause of sleep. This is evidenced by observations of the behavior of two pairs of unseparated twins. In them, the division of the nervous system occurred completely, and the circulatory systems had many anastomoses. These twins could sleep at different times: one girl, for example, could sleep, while the other was awake.

Subcortical and cortical theories of sleep. With various tumor or infectious lesions of subcortical, especially stem, brain formations, patients have various sleep disorders - from insomnia to prolonged lethargic sleep, which indicates the presence of subcortical sleep centers. When the posterior structures of the subthalamus and hypothalamus were stimulated, the animals fell asleep, and after the stimulation ceased, they woke up, which indicates the presence of sleep centers in these structures.

Chemical theory. According to this theory, easily oxidized products accumulate in the cells of the body during wakefulness, as a result, oxygen deficiency occurs, and a person falls asleep. We fall asleep not because we are poisoned or tired, but in order not to be poisoned and not tired.

Sleep functions

o provides rest for the body.

o plays an important role in metabolic processes. During non-REM sleep, growth hormone is released. REM sleep: restoration of plasticity of neurons, and their enrichment with oxygen; biosynthesis of proteins and RNA of neurons.

o contributes to the processing and storage of information. Sleep (especially slow sleep) facilitates the consolidation of the studied material, REM sleep implements subconscious models of expected events. The latter circumstance can serve as one of the reasons for the deja vu phenomenon.

o this is an adaptation of the body to a change in illumination (day-night).

o restores immunity by activating T-lymphocytes that fight colds and viral diseases.

Varieties of sleep

Upon further detailed research, it turned out that in terms of its physiological manifestations, sleep is heterogeneous and has two varieties: slow (calm or orthodox) and fast (active or paradoxical).

With slow sleep, there is a decrease in the frequency of breathing and heart rate, muscle relaxation and slowing of eye movements. As NREM sleep deepens, the total number of movements of the sleeper becomes minimal. At this time, it is difficult to wake him up. Non-REM sleep usually takes 75 - 80%.

With REM sleep, physiological functions, on the contrary, are activated: breathing and heart rate become more frequent, the motor activity of the sleeper increases, the movements of the eyeballs become fast (in connection with which this type of sleep was called "fast"). Rapid eye movements indicate that the sleeper at this moment is dreaming. And if you wake him up 10 - 15 minutes after the end of rapid eye movements, he will talk about what he saw in a dream. When awakening during non-REM sleep, a person, as a rule, does not remember dreams. Despite the relatively greater activation of physiological functions in REM sleep, the muscles of the body during this period are relaxed, and it is much more difficult to wake the sleeper. REM sleep is essential for the life of the body. If a person is artificially deprived of REM sleep (to be awakened during periods of rapid eye movements), then, despite the quite sufficient total duration of sleep, after five to seven days he will develop mental disorders.

The alternation of fast and slow sleep is typical for healthy people, while the person feels well-rested and alert.

There is another classification of sleep stages:

1. Equalizing phase: characterized by an effect on both strong and weak stimuli.

2. Paradoxical phase: strong stimuli cause weaker responses than weak stimuli.

3. Ultradoxal phase: a positive stimulus inhibits, and a negative stimulus causes a conditioned reflex.

4. Narcotic phase: a general decrease in conditioned reflex activity with a much stronger decrease in reflexes to weak stimuli than to strong ones.

5. Inhibitory phase: complete inhibition of conditioned reflexes

Age features:

Children's sleep is superficial and sensitive. They sleep several times a day.

In newborns, sleep takes up most of the day, and activated sleep, or twitching sleep (analogous to REM sleep in adults), makes up the majority of sleep. In the first months after birth, the time of wakefulness increases rapidly, the proportion of REM sleep decreases, and slow-wave sleep increases.

Sleep hygiene:

Sleep should have sufficient duration and depth for age. A longer time is supposed to sleep for children with poor health, recovering from acute infectious diseases, increased excitability of the nervous system, and children who quickly get tired. Before going to bed, exciting games, enhanced mental work should be excluded. Dinner should be light, no later than 2-1.5 hours before bedtime. Favorable for sleep:

fresh, cool indoor air (15-16)

The bed should not be soft or hard.

clean, soft, wrinkle-free bed linen

It is better to lie on the right side or back, which provides freer breathing, does not complicate the work of the heart.

Children should be taught to get up and go to bed at the same time. The child quite easily forms conditioned reflexes to the situation of sleep. The conditioned stimulus in this case is the time of going to bed.

Neurophysiology of the ANS

The concept of the autonomic nervous system was first introduced in 1801 by the French physician A. Besha. This department of the central nervous system provides the vegetative functions of the body and includes three components:

1) sympathetic;

2) parasympathetic;

3) metasympathetic.

Vegetative functions include those functions that provide metabolism in our body (digestion, blood circulation, respiration, excretion, etc.). They also include ensuring the growth and development of the body, reproduction, preparing the body for adverse effects. The vegetative system regulates the activity of internal organs, blood vessels, sweat glands and other similar functions. It regulates metabolism, excitability and autonomy of internal organs, as well as the physiological state of tissues and individual organs (including the brain and spinal cord), adapting their activity to environmental conditions.

The sympathetic department of the nervous system ensures the mobilization of the body's resources (energy and intellectual) to perform urgent work. It is clear that this can lead to imbalances in the body. Restoring balance and constancy of the internal environment of the body is the task of the nervous parasympathetic system. the shifts caused by the influence of the sympathetic department restore and maintain homeostasis. In this sense, the activity of these departments of the nervous autonomic system in a number of reactions manifests itself as antagonistic.

Under homeostasis in physiology is understood as maintaining the constancy of the parameters of the internal environment in the body. These include maintaining a constant blood composition, body temperature, etc.

The centers of the autonomic nervous system are located in the brain stem and spinal cord. The centers of the parasympathetic nervous system are located in the brain stem and in the sacral spinal cord. In the midbrain there are centers that regulate the expansion of the pupil and the accommodation of the eye. In the medulla oblongata there are centers of the nervous parasympathetic system, from which fibers depart as part of the vagus, facial and glossopharyngeal nerves. These centers are involved in the implementation of a number of functions, including regulating the activity of a number of internal organs (heart, stomach, intestines, liver, etc.), are "triggering" for the release of saliva, lacrimal fluid, etc. All these functions carried out according to the reflex principle (according to the type of response to a stimulus). Some of these reflexes will be described below.

In the sacral segments of the spinal cord, there are also centers of the nervous parasympathetic autonomic system. The fibers from them go as part of the pelvic nerves, which innervate the pelvic organs (large intestine, bladder, genitals, etc.).

The centers of the sympathetic nervous system are located in the thoracic and lumbar segments of the spinal cord. Vegetative fibers from these centers depart as part of the anterior roots of the spinal cord along with the motor nerves.

All the centers of the sympathetic and nervous parasympathetic systems listed above are subordinate to the higher autonomic center - the hypothalamus. The hypothalamus, in turn, is influenced by a number of other centers of the brain. All these centers form the limbic system. A complete description of the system will be given in the relevant topic, and now we will consider the "work" of the peripheral parts of the nervous autonomic system.

On both sides of the spine from the ventral side are two trunks of the sympathetic nervous system. They are also called sympathetic chains. The chain consists of individual ganglia connected to each other and the spinal cord by numerous nerve fibers. Each fiber that comes to the ganglion innervates up to several dozen neurons in the ganglion (divergence). Thanks to such a device, sympathetic influences usually have a spilled, generalized character. In turn, nerves depart from these ganglia, which are directed to the walls of blood vessels, sweat glands and internal organs. In addition to the ganglia of the border trunk, at some distance from them are the so-called prevertebral ganglia. The largest of them are the solar plexus and mesenteric nodes.

The adrenal glands play an important role in the activity of the sympathetic nervous system. They are formed in humans during the prenatal period due to the migration of neuroblasts (not yet differentiated neurons) from the neural tube to the kidney region. There, these cells form a special organ on the tops of both kidneys - the adrenal glands. The adrenal glands are innervated by sympathetic nerves. In addition, they can be activated by adrenocorticotropic hormone, which is released in response to stress from the pituitary gland and reaches the adrenal glands along with the blood. Under the action of this hormone, a mixture of adrenaline and adrenaline is released into the blood from the adrenal glands, which are carried through the bloodstream and cause a number of sympathetic reactions (increased rhythm of heart contractions, sweating, increased blood supply to the muscles, reddening of the skin, and much more).

Axons of sympathetic neurons in peripheral synapses secrete the mediator adrenaline. Molecules of adrenaline and norepinephrine interact with the corresponding receptors. Two types of such receptors are known: alpha and beta adrenoreceptors. Some internal organs have only one of these receptors, while others have both. So, in the walls of blood vessels there are both alpha- and beta-adrenergic receptors. The connection of the sympathetic mediator with the alpha-adrenergic receptor causes narrowing of the arterioles, and the connection with the beta-adrenergic receptor causes the expansion of the arterioles. In the intestine, where both types of adrenergic receptors are present, the mediator inhibits its activity. In the heart muscle and the walls of the bronchi there are only beta-adrenergic receptors - a sympathetic mediator causes the expansion of the bronchi and an increase in heart rate.

The ganglia of the parasympathetic division of the autonomic nervous system, in contrast to the sympathetic ones, are located in the walls of the internal organs or near them. The nerve fiber (axon of a neuron) from the corresponding parasympathetic center in the brain stem or sacral spinal cord reaches the innervated organ without interruption, and ends on the neurons of the parasympathetic ganglion. The next parasympathetic neuron is located either inside the organ, or in close proximity to it. Intraorganic fibers and ganglia form plexuses rich in neurons in the walls of many internal organs of the heart, lungs, esophagus, stomach, etc., as well as in the glands of external and internal secretion. The anatomical design of the parasympathetic part of the vegetative nervous system indicates that its influence on the organs is more local than that of the nervous sympathetic system.

The mediator in the peripheral synapses of the nervous parasympathetic system is acetylcholine, to which there are two types of receptors: M- and H-cholinergic receptors. This division is based on the fact that M-cholinergic receptors lose their sensitivity to acetylcholine under the influence of atropine (isolated from the fungus of the genus Muscaris), H-cholinergic receptors - under the influence of nicotine.

Influence of the sympathetic and parasympathetic autonomic system on body functions. In most organs, excitation of the sympathetic and nervous parasympathetic autonomic systems produces opposite effects. However, it must be kept in mind that these interactions are not simple. For example, parasympathetic nerves cause relaxation of the sphincters of the bladder and, at the same time, contraction of its muscles. Sympathetic nerves contract the sphincter and simultaneously relax the muscles. Another example: stimulation of the sympathetic nerves increases the rhythm and force of heart contractions, and irritation of the vagus (parasympathetic) nerve reduces the rhythm and force of heart contractions. Moreover, studies have shown that between these parts of the nervous autonomic system there is not only antagonism (multidirectional), but also synergism (unidirectional). An increase in the tone of one section of the nervous autonomic system, as a rule, leads to an increase in the tone of another section. Moreover, it turned out that there are organs and tissues with only one type of innervation. For example, the vessels of the skin, the adrenal medulla, the uterus, skeletal muscles, and some others have only sympathetic innervation, while the salivary glands are innervated only by parasympathetic fibers.

Vegetative reflexes. These reflexes are numerous. They are involved in many regulation of the human body. In the implementation of vegetative reflexes, influences are transmitted along the corresponding nerves (sympathetic or parasympathetic) from the central nervous system. In medical practice, the greatest importance is attached to viscero-visceral (from one internal organ to another), viscero-dermal (from internal organs to the skin) and dermo-visceral (from the skin to internal organs) reflexes.

Among the viscero-visceral include reflex changes in cardiac activity, vascular tone, blood filling of the spleen with an increase or decrease in pressure in the aorta, carotid sinus or pulmonary vessels. For example, due to the inclusion of such a reflex, cardiac arrest occurs when the abdominal organs are irritated. Viscero-dermal reflexes occur when internal organs are irritated and are manifested in a change in the sensitivity of the corresponding skin areas (in accordance with which organ is irritated), sweating, and vascular reactions. Dermo-visceral reflexes are manifested in the fact that when certain areas of the skin are irritated, the functioning of the corresponding internal organs changes. Actually, the use of warming or cooling certain areas of the skin for therapeutic purposes is based on the mechanism of these reflexes, for example, for pain in the internal organs.

Vegetative reflexes are often used by doctors to judge the functional state of the nervous autonomic system. For example, in the clinic, reflex changes in blood vessels are often studied during mechanical skin irritation (for example, when a blunt object is passed over the skin). In a healthy person, this causes a short-term blanching of the irritated skin area (white dermographism, derma-skin). With high excitability of the nervous autonomic system, a red strip appears at the site of skin irritation, bordered by pale stripes of narrowed vessels (red dermographism), and with even higher sensitivity, skin edema in this place. Often in the clinic, functional autonomic tests are used to judge the state of the nervous autonomic system. For example, orthostatic reaction: when moving from a lying position to a standing position, there is an increase in blood pressure and an increase in heart rate. The nature of the change in blood pressure and cardiac activity during this test can serve as a diagnostic sign of a disease in the blood pressure control system. Another example is the ocular-cardiac reaction (Ashner's reflex): when pressing on the eyeballs, a short-term decrease in heart rate occurs.

Vegetative centers. In the medulla oblongata are nerve centers that inhibit the activity of the heart (nucleus of the vagus nerve). In the reticular formation of the medulla oblongata there is a vasomotor center, consisting of two zones: pressor and depressor. Excitation of the pressor zone leads to vasoconstriction, and excitation of the depressor zone leads to their expansion. The vasomotor center and nuclei of the vagus nerve constantly send impulses, thanks to which a constant tone is maintained: the arteries and arterioles are constantly somewhat narrowed, and cardiac activity is slowed down.

In the medulla oblongata is the respiratory center, which, in turn, consists of the centers of inhalation and exhalation. At the level of the bridge, there is a respiratory center (pneumotaxic center) of a higher level, which adapts breathing to changes in physical activity. Breathing in a person can also be controlled voluntarily from the side of the cerebral cortex, for example, during speech.

In the medulla oblongata there are centers that stimulate the secretion of the salivary, lacrimal and gastric glands, the secretion of bile from the gallbladder, and the secretion of the pancreas. In the midbrain, under the anterior tubercles of the quadrigemina, there are parasympathetic centers of accommodation of the eye and pupillary reflex. All the centers of the sympathetic and parasympathetic systems listed above are subordinate to the higher autonomic center - the hypothalamus.

The role of the hypothalamus in the regulation of autonomic functions. Influence on sympathetic and parasympathetic regulation allows the hypothalamus to influence the autonomic functions of the body through humoral and nervous pathways. Previously, it was already understood that irritation of the nuclei of the anterior group is accompanied by parasympathetic effects. Irritation of the nuclei of the posterior group causes sympathetic effects in the functioning of the organs. Stimulation of the nuclei of the middle group leads to a decrease in the influence of the sympathetic division of the autonomic nervous system. The specified distribution of functions of the hypothalamus is not absolute. All structures of the hypothalamus are capable of inducing sympathetic and parasympathetic effects to varying degrees. Consequently, there are functional complementary, mutually compensating relationships between the structures of the hypothalamus.

In general, due to the large number of connections, polyfunctionality of structures, the hypothalamus performs an integrating function of autonomic, somatic and endocrine regulation, which is also manifested in the organization of a number of specific functions by its nuclei. So, in the hypothalamus there are centers of homeostasis, thermoregulation, hunger and satiety, thirst and its satisfaction, sexual behavior, fear, rage, regulation of the wakefulness-sleep cycle. All these centers realize their functions by activating or inhibiting the autonomic part of the nervous system, the endocrine system, the structures of the brainstem and the forebrain.

The hypothalamus, in turn, is influenced by a number of higher centers of the brain, including the cortex.

Thus, The autonomic nervous system has a number of anatomical and physiological features that determine the mechanisms of its work:

Anatomical properties

1. Three-component arrangement of nerve centers. The lowest level of the sympathetic section is represented by the lateral horns from the VII cervical to III-IV lumbar vertebrae, and the parasympathetic - by the sacral segments and the brain stem. The higher subcortical centers are located on the border of the nuclei of the hypothalamus (the sympathetic division is the posterior group, and the parasympathetic division is the anterior one). The cortical level lies in the region of the sixth-eighth Brodmann fields (motosensory zone), in which point localization of incoming nerve impulses is achieved. Due to the presence of such a structure of the autonomic nervous system, the work of internal organs does not reach the threshold of our consciousness.

2. The presence of autonomic ganglia. In the sympathetic department, they are located either on both sides along the spine (sympathetic nerve chain), or are part of the plexus. Thus, the arch has a short preganglionic and a long postganglionic path. The neurons of the parasympathetic division are located in the ganglion, located near the working organ or in its wall, so the arc has a long preganglionic and short postganglionic path.

Physiological properties

1. Features of the functioning of the autonomic ganglia. The presence of the phenomenon of multiplication (the simultaneous occurrence of two opposite processes - divergence and convergence). Divergence is the divergence of nerve impulses from the body of one neuron to several postganglionic fibers of another. Convergence - convergence on the body of each postganglionic neuron of impulses from several preganglionic ones. This ensures the reliability of the transmission of information from the central nervous system to the working body. An increase in the duration of the postsynaptic potential, the presence of trace hyperpolarization and synaptic delay contribute to the transmission of excitation at a speed of 1.5–3.0 m/s. However, the impulses are partially extinguished or completely blocked in the autonomic ganglia. Thus, they regulate the flow of information from the CNS. Due to this property, they are called nerve centers placed on the periphery, and the autonomic nervous system is called autonomous.

2. Features of nerve fibers. Preganglionic nerve fibers belong to group B and conduct excitation at a speed of 3-18 m/s, postganglionic nerve fibers belong to group C. They conduct excitation at a speed of 0.5–3.0 m/s. Since the efferent pathway of the sympathetic division is represented by preganglionic fibers, and the parasympathetic pathway is represented by postganglionic fibers, the speed of impulse transmission is higher in the parasympathetic nervous system.

In general, the sympathetic nervous system performs an adaptive-trophic function, being included in the work during physical exertion, emotional reactions, stress, pain, blood loss. It provides adaptation of the organism to the changing conditions of the environment of existence.

The parasympathetic nervous system is an antagonist of the sympathetic and performs homeostatic and protective functions, regulates the emptying of hollow organs. The homeostatic role is restorative and operates at rest. This manifests itself in the form of a decrease in the frequency and strength of heart contractions, stimulation of the activity of the gastrointestinal tract with a decrease in blood glucose levels, etc.

Ministry of Health of the Republic of Belarus

EE "Gomel State Medical University"

Department of Biological Chemistry

Endorphins

Prepared by a student of l-206 group Kurmaz V.A.

Checked Myshkovets N.S.

Gomel 2013

General information-3

Biological significance-6

Pathology-7

Literature-9

General information

Endorphins(endogenous morphines (on behalf of the ancient Greek god Morpheus - "one who forms dreams") - a group of polypeptide chemical compounds similar in structure to opiates (morphine-like compounds), which are naturally produced in the neurons of the brain and have the ability to reduce pain similarly to opiates and influence on the emotional state.Endorphins are formed from lipotropins in brain tissue and in the intermediate pituitary gland.The common type of structure for these compounds is a tetra-peptide sequence at the N-terminus.Beta-endorphin is formed from beta-lipotropin by proteolysis.Beta-lipotropin is formed from a precursor -prohormone proopicortine (molecular weight 29 kDa, 134 amino acid residues).In the anterior pituitary gland, the precursor molecule is cleaved into ACTH and b-lipotropin, which are secreted into plasma.A small part (about 15%) of b-lipotropin is cleaved to form b-endorphin. The biosynthesis of proopicortin in the anterior pituitary gland is regulated by the cortico liberin of the hypothalamus. Three different opioid peptide precursor proteins are known: proenkephalin, proopiomelanocortin, and prodynorphin.

N-Tyr-Gli-Gli-Fen- Met-OH methionine-enkephalin

N-Tyr-Gli-Gli-Fen- Leu-OH leucine-enkephalin

N-Tyr-Gli-Gli-Fen- Met-Tre-Ser-Glu-Liz-Ser-Gln-Tre-Pro-Lay-Val-Tre-Ley-Fen-Liz-Asn-Ala-Ile-Val-Liz-Asn-Ala-Gis-Liz-Liz- Gly-Gln-OH beta-endorphin

MSH - melanocyte-stimulating hormone;

LPG - lipotropic hormone;

KPPP - corticotropin-like intermediate peptide;

ACTH - adrenocorticotropic hormone.

Secretion regulation

The synthesis of β-endorphin decreases in endocrine, infectious and viral diseases, chronic fatigue syndrome, and synthesis can be enhanced with the help of physical activity.

Transport and peripheral metabolism

biological significance

What do the endorphin systems influence?

Anti-pain effects

Deceleration of breathing, palpitations - anti-stress effects

Strengthening immunity

Regulation of renal blood flow

regulation of bowel activity

Participation in the processes of excitation and inhibition in the nervous system

Participation in the processes of development of associative-dissociative connections in the nervous system - regulation of metabolic intensity

Feeling of euphoria

Accelerate the healing of damaged tissues

Bone formation in fractures

Pathology

The most severe manifestation is anhedonia, a disease in which a person is not able to experience pleasure.

Literature

Endocrinology and metabolism / Under. ed. P. Feliga et al. M.: Medicine, 1985.

Berezov, T.T. Biological chemistry / T.T. Berezov, B.F. Korovkin. – M.: Medicine,

Rosen V. B. Fundamentals of endocrinology. Moscow: Higher school, 1984.

http://dic.academic.ru/

Portal for the student. Self-training

Practical work on the section "Reproduction of genetic information"