Pathogenesis of itchy skin

Pruritus is a sensory sensation or nociception that is specific to the skin (and located close to it mucous), which physiologically acts as a signal-warning system for tickling irritation, subthreshold pain sensations and in various qualitative and quantitative gradations accompanies numerous skin diseases.

Itching is one of the most common complaints about the skin. This is an unpleasant sensation, which is accompanied by a continuous need for a mechanical response to the skin irritation. Chronic itching, like pain, can significantly affect the general condition of the patient and in extreme cases lead to the threat of suicide. However, the itching and the subsequent combing are perceived negatively socially and, therefore, especially in the anogenital area, are often described by patients as burning or dry. Itching, on the one hand, is functional nociception, which serves to remove from the skin of parasites harmful to it, plant debris, on the other hand - it is a symptom of a disease that can lead to skin damage.

Itching is closely related to the pain sensation, but differs from it in the following points: both sensations are unpleasant, but pain realizes the reflex of "avoidance," and the itching, on the contrary, is almost a forced reflex of "processing", the execution of which during scratching, friction leads to instantaneous short-term) satisfactory relief. This change of feelings from unpleasant to pleasurable is one of the reasons why skin diseases are perceived as personal. In addition, the effects of scratching due to itching enter the morphological picture of a number of dermatoses and, for their part, again, through the vicious circle, become involved in the pathogenesis of pruritus and skin disease.

The general structural base of pain and pruritus is illustrated by numerous observations: the absence of these sensations, both congenital and acquired, almost always occurs in pairs. However, itching is not identical to mild pain, since both sensations have their own quality and their own intensity spectrum, do not pass into each other and are dissociable: heating the skin to 40C blocks itching, but it increases the pain sensation; removal of the epidermis leads to loss of sensation of itching, a sensation of pain however remains; irritation with high-frequency currents produces pain with a small itchy irritation.

In the mediation of pruritus and pain, free ends of type A and type C fibers play a decisive role. Earlier, this was confirmed only by clinical observations, but now there are neurophysiological studies supporting the theory that itch and pain fibers represent a single whole with different activity threshold.

The range of perception of itching varies from a mild tickling, heating-burning, cutting to a dull, painful. Therefore, the reflex-shaped "treatment reactions" are completely different: combing, as in eczema, corresponds to an attempt to remove point sources of pruritus from the skin (destructive act); gently rubbing, as with red flat lichen; with poorly localized or common source of pruritus (eg, fungal mycosis or mechanical urticaria) or cooling (acute urticaria). The scratches are therefore not a self-evident consequence of itching. Probably, this difference in the perception of itching is counterbalanced by the variety of causal mediators or their change.

In addition to the physical, chemical, biochemical, antimicrobial and immunological barrier functions of the skin, the innervation of the dermis and epidermis plays a decisive role in the sense of sensation and appropriate response in the context of its role as a boundary zone between the body and the environment. Today, it is unacceptable to say that there are separate specific receptors for different sensations. Currently, it is assumed that there are mixed receptors for the perception of heat, cold, pain, itching and touch. Some nociceptors react to chemical stimuli, but their behavior with respect to various chemicals is also clearly different. At present, there are no clearly defined chemicals that cause only itching or only pain, even histamine, depending on the dose, causes either itching or a painful sensation.

Both light and electron microscopy are unable to completely and unequivocally differentiate epidermal sensory neurons. And only the method of immunohistochemistry in combination with immunoelectronic microscopy and the use of antibodies on neuropeptides allowed further differentiation. Within the skin nerve fibers, substances such as substance P, gene-calcitonin peptide, neurotropin, and vasoactive intestinal peptide (VIP) could be localized. It is also known that some fibers are provided with a combination of such neuropeptides.

From the point of view of the physiology of the senses, the process of developing the itch as a symptom depends on the innervation of the skin. Various skin receptors conduct a sensation of itching mainly through polymodal C and A nerve fibers. Among the receptors of the skin are:

• Tactile receptors: (Merkel discs, A-fibers, Meissner's tactile bodies, Veter-Pacini plate-like bodies and Gol-Ji-Mazzoni bodies).
• Temperature receptors: (the superficial nerve network of the dermis contains receptors for the perception of cold - the Krause flask, and for the perception of heat - the calf Ruffini).
• Pain receptors are represented by free nerve endings.

Itching is mainly transmitted through the moth-free, slowly conducting C-fibers into the central nervous system. Itching is caused by mechanical, thermal, electrical or chemical stimulation of polymodal C-nerve fibers. The free nerve endings of these demyelinated nerve fibers on the border of the epidermis and the dermis serve as nociceptors and are excited either directly or indirectly by the release of various mediators. The substances that cause itching include amines (histamine, serotonin), proteases (exogenous papain, kallikrein, trypsin) and various peptides (bradykinin, secretin) and neuropeptides (substance P, vasoactive intestinal polypeptide), thyroid hormone calcitonin, and metabolites of arachidonic acid, interleukin-2, growth factors and various biologically active substances of eosinophils and platelets. Prostaglandins and endorphins act modulating on the peripheral and central nervous system. Many of these substances are potential histamine liberators; Others, like papain and kallikrein, directly cause itching. Histamine is an important but not the only mediator of itching, which sometimes explains the unsatisfactory therapeutic response to antihistamines.

Nerve impulses that provide the sensation of itching come along the afferent nerve fibers to the hindbusts of the spinal cord, where they switch to the neurons of the spinalotomy tract, through which they enter the thalamus and further into the sensory area of the cerebral cortex.

Due to the cross-reactivity of polymodal C-fibers, the itch acquires various qualities. For example, mukanain extracted from the pods of the plant Misyp pruriens, causes pure itching, and the typical sensation for histamine is approximately 60% of the itching and 40% of the pain. In contrast, mustard oil causes a sheer burning pain. Stimulation of nociceptive receptors by bradykinin and, possibly, an acidic tissue environment with inflammatory dermatoses lead to the fact that the electrophoretic action of histamine is perceived as burning.

Individual mediators or a combination of these can activate individual receptors in the above-mentioned C-fibers, as a result, a certain threshold of stimulation is exceeded or a cascade is triggered, which during the nervous stimulation is processed into the CNS by an interpretive itch signal.

A typical center of pruritus in the central nervous system has not yet been identified. By means of functional positron emission tomography with histamine itching caused by the skin, it was possible to prove as an indication of neuronal activation an increase in the blood flow velocity in the region of the cingulate gyrus. Some researchers point out that this region may be responsible for the sensory aspect of histamine-induced pruritus, while the premotor zone is probably responsible for preparing for combing.

Histamine is the most known substance studied in connection with itching. It is a component of mast cells, and when it is released as a result of their degranulation and binding by alpha receptors, there are three phenomena according to Lewis (1927): spotted erythema with dilated capillaries, reddening without increasing the tissue mass, blister development after 60-90 seconds, followed by the formation of a small anemic area, caused by edema and associated with the compression of capillaries.

The action of histamine can be completely or partially terminated by blockade of histamine receptors, using H1-antihistamines. Therefore, with the help of antihistamines, they have always tried to suppress the itching with various skin diseases and various internal diseases. It turned out that a number of forms of itching do not respond to antihistamines, so the search for other mediators has become even more necessary.

Another biogenic amine, serotonin, when injected or electrophoresis is also capable of causing itching and blistering. However, it is a weaker pruritogen than histamine. Serotonin does not accumulate in mast cells and can produce both algal and analgesic effects. It may play a special role in uremic or hepatitis itching. Studies have shown that capsaicin, although it reduces serotonin-induced blisters, can not affect the surrounding erythema. Proteinases are also pruritogenic. Trypsin and chymotrypsin cause itching, but its effect, however, stops with antihistamines, and it should be noted that modulation occurs through the release of histamine. Papain and kallikrein, on the contrary, do not cause their own, histamine-dependent effects.

Much attention has recently been paid to the interrelation between neuropeptides and pruritus. Substance P causes severe itching, in part by means of histamine. The therapeutic use of capsaicin further clarified this issue. Local application of capsaicin on the skin leads to the depletion of substance P by neuropeptides up to the damage of unmyelinated type C fibers. First, severe burning and pain occurs, and also itching, then perception or formation of substance P is blocked.

Clearing the nature of pruritus was promoted by the action of opioids. Morphine eliminates pain, but on the other hand it causes itching. Although opioids, such as morphine, cause itching, releasing histamine from mast cells, antihistamines are unable to interrupt it through a receptor blockade.

Prostaglandins and eicosanoids, which are found in the skin in large quantities within the framework of immunological and allergic reactions, obviously also play some role in itching. After injection, prostaglandins can cause mild itching, which, however, is significantly less than the pruritus caused by histamine, but which is obviously histamine mediated or histamine itching can be enhanced by prostaglandin E2. Leukotrienes, for example of the LTB4 type, cause erythema, but after the skin injection they do not give blisters. Prostaglandin synthesis inhibitors, such as acetylsalicylic acid or indomethacin, are not able to regulate this itch. On the other hand, acetylsalicylic acid in the treatment of severe itching in the third trimester of pregnancy plays a decisive role and is more effective than the H1 antagonist chlorpheniramine.

The role of cytokines and growth factors in the aspect of their possible co-infection with pruritus is elucidated. In this regard, a special study is of great importance, which could prove that the neurotropic factor neurotropin-4 plays a role in the itching of atopic dermatitis.

Itching is the most common symptom in dermatology, which can occur due to a number of skin diseases or without a clinically visible skin disease: xeroderma (dry skin), dermatozoonoses (scabies, pediculosis, insect bites), atopic dermatitis, contact dermatitis, drug toxemia, red flat lichen, eczema, urticaria, prurigo, herpetiform dermatosis of Dühring, sunny dermatitis.

With dermatosis, itching is a symptom and consequence of skin disease. The corresponding dermatosis is diagnosed by typical rashes. Many skin diseases are accompanied by itching. Intensive itching, leading to combs and their effects, is observed with eczema, atopic dermatitis, some fungal infections and parasitic skin diseases. With many dermatoses (red flat lichen, urticaria), despite the intensity of itching, there are no combing effects, since the skin is rubbed and not combed. Such patients have characteristic shiny nail plates. Atopic dermatitis is typical of pruritus crises. With a simple subacute prurigo, combings cause rashes, after which the itch suddenly stops, only hemorrhagic crusts remain, but there are no traces of scratching. Itching is also a symptom of urticaria and is enhanced by scratching, but excoriation is not found.

Frequent hot baths or daily use of a hot shower with the use of degreased soap and especially bath additives can lead to drying of the skin, often with barely visible peeling, and the skin reacts with a strong itch. In elderly people, skin areas, poor in the sebaceous glands, especially the forearms and lower legs, itch, mainly in winter, when due to heating the humidity of the air in the apartment is low.

Every patient suffering from itching should be tested for dermatozoonosis (scabies, insect bites, pediculosis). Scabies are the most frequent parasitic itchy skin disease. Itching often occurs at night especially during scabies. In case of itching of the scalp and ears, lice should be avoided; with itching in the area of the pubis, perineum, chest, axillary cavities - pubic pediculosis; with itching in the lumbar region, scapula, neck - pediculosis caused by lice.

Itching is the eternal companion of atopic dermatitis. Its intensity is different; it is diffuse and localized, partly limited to a zone of individual rashes. The latter occurs in elderly atopics with pruriginosis changes. Itching may precede a recurrence of atopic dermatitis. The pruritic effects of scratching close the vicious circle, causing inflammation leading to staphylococcal infection, and thereby again to inflammation, which contributes to the persistence of the disease.

Skin itch with urticaria eruptions, as well as atopic dermatitis, causes the classical mediator histamine. Many other skin diseases can also be accompanied by pruritus. The diagnosis of "pruritus sine materia" can be established when all diagnostic possibilities are exhausted, and the somatic cause of prolonged pruritus is not established. Unconscious forced scratching leads to linear strips on the skin. Sometimes dermatologists talk about "pruritus sine materia", when on examination the skin is otherwise healthy. Itching as a symptom is less dependent on histamines, more likely from other mediators (serotonin, prostaglandin and other vasoactive substances). Chronic itch without obvious cause affects more often elderly people, especially men. When a differential diagnosis should be considered pruritus senilis or general xerosis (dry skin).

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