Pathogenesis of itchy skin

Itching (pruritus) is a sensory sensation or nociception specific to the skin (and adjacent mucous membranes), 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 concerning the skin. It is an unpleasant sensation that is accompanied by a continuous need for a mechanical response to the skin. Chronic itching, like pain, can significantly affect the general condition of the patient and in extreme cases lead to the threat of suicide. However, itching and the subsequent scratching are perceived negatively in social terms and therefore, especially in the anogenital area, are often described by patients as a burning sensation or dryness. Itching, on the one hand, is a functional nociception that serves to remove harmful parasites and plant debris from the skin, on the other hand, it is a symptom of a disease that can lead to skin damage.

Itching is closely related to pain, but differs from it in the following points: both sensations are unpleasant, but pain implements the "avoidance" reflex, and itching, on the contrary, is an almost forced "processing" reflex, the implementation of which during scratching, rubbing leads to immediate (even if short-term) satisfying relief. Such a change in sensations 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 are included in the morphological picture of a number of dermatoses and can, for their part, again through a vicious circle, be involved in the pathogenesis of itching and skin disease.

The common structural basis of pain and itching 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 increases the sensation of pain; removal of the epidermis leads to the loss of the sensation of itching, the sensation of pain, however, remains; irritation with high-frequency currents produces pain with little itching irritation.

In mediating itching and pain, the free endings of type A delta fibers and type C fibers play a decisive role. If previously this was confirmed only by clinical observations, now there are also neurophysiological studies that support the theory that itching and pain fibers are a single whole with different activity thresholds.

The spectrum of perception of itching varies from a light tickling, warming-burning, cutting to dull, painful. Therefore, the reflex-like "processing reactions" are completely different: scratching, as in eczema, corresponds to an attempt to remove point sources of itching from the skin (a destructive act); gently rubbing, as in lichen planus; with a poorly localized or widespread source of itching (for example, mycosis fungoides or mechanical urticaria) or cooling (acute urticaria). Scratching is therefore not a self-evident consequence of itching. Probably, this difference in the perception of itching is balanced by the variety of causal mediators or their change.

In addition to the physical, chemical, biochemical, antimicrobial and immunological barrier functions of the skin, in its role as a boundary zone between the body and the environment, the innervation of the dermis and epidermis plays a decisive role in terms of sensation and the corresponding response. Today, it is no longer acceptable that there are separate specific receptors for different sensations. It is now 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 towards different chemicals is also clearly different. At present, there are no clearly defined chemicals that cause only itching or only pain; even histamine causes either itching or pain, depending on the dose.

Both light and electron microscopy are unable to completely and unambiguously differentiate epidermal sensory neurons. And only the immunohistochemistry technique in combination with immunoelectron microscopy and the use of antibodies to neuropeptides allowed further differentiation. Within the skin nerve fibers, it was possible to localize such substances as substance P, calcitonin gene peptide, neurotrophin and vasoactive intestinal peptide (VIP). It is also known that some fibers are supplied with a combination of such neuropeptides.

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

• Tactile receptors: (Merkel's discs, A-fibers, Meissner's tactile corpuscles, Vater-Pacini's lamellar corpuscles and Golgi-Mazzoni's corpuscles).
• Temperature receptors: (the superficial nerve network of the dermis contains receptors for the perception of cold - Krause's flasks, and for the perception of heat - Ruffini's corpuscles).
• Pain receptors are represented by free nerve endings.

Itching is transmitted predominantly via unmyelinated, slowly conducting C-fibers to 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 unmyelinated nerve fibers at the epidermal-dermal junction serve as nociceptors and are excited either directly or indirectly by the release of various mediators. Substances that cause itching include amines (histamine, serotonin), proteases (exogenous papain, kallikrein, trypsin), and various peptides (bradykinin, secretin), neuropeptides (substance P, vasoactive intestinal polypeptide), the thyroid hormone calcitonin, as well as arachidonic acid metabolites, interleukin-2, growth factors, and various biologically active substances of eosinophils and platelets. Prostaglandins and endorphins act as modulator of the peripheral and central nervous systems. Many of these substances are potential histamine liberators; others, such as papain and kallikrein, directly cause itching. Histamine is an important but not the only mediator of itching, which explains the sometimes unsatisfactory therapeutic response to antihistamines.

Nerve impulses that provide the sensation of itching are transmitted via afferent nerve fibers to the posterior horns of the spinal cord, where they are switched to neurons of the spinothalamic tract, through which they are transmitted to the thalamus and then to the sensory zone of the cerebral cortex.

Due to the cross-excitability of polymodal C-fibers, itch takes on different qualities. For example, mucanain, isolated from the pods of the plant Mycina pruriens, causes pure itch, while the typical histamine sensation consists of about 60% itch and 40% pain. In contrast, mustard oil causes pure burning pain. Stimulation of nociceptive receptors by bradykinin and, possibly, the acidic tissue environment in inflammatory dermatoses lead to the electrophoretic action of histamine being perceived as burning.

Individual mediators or a combination of them are able to activate individual receptors in the above-mentioned C-fibers, as a result of which a certain threshold of irritation is exceeded or a cascade is launched, which, during nerve stimulation, is processed in the central nervous system as an interpretive signal of itching.

The typical itch center in the CNS has not yet been identified. Using functional positron emission tomography, increased blood flow velocity in the cingulate cortex has been demonstrated as a sign of neuronal activation in histamine-induced itch. Some researchers suggest that this region may be responsible for the sensory aspect of histamine-induced itch, while the premotor area is likely responsible for the preparation for scratching.

Histamine is the best known substance investigated in connection with pruritus. It is a component of mast cells, and when released by their degranulation and binding to alpha receptors, three phenomena occur, according to Lewis (1927): spotted erythema with capillary dilation, redness without increase in tissue mass, development of a wheal after 60-90 seconds, followed by the formation of a small anemic area caused by edema and associated compression of the capillaries.

The action of histamine can be completely or partially stopped by blocking histamine receptors using H1-antihistamines. Therefore, antihistamines have always been used to suppress itching in various skin diseases and a variety of internal diseases. At the same time, 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, is also capable of causing itching and wheals when injected or electrophoresed. However, it is a weaker pruritogen than histamine. Serotonin does not accumulate in mast cells and can produce both algesic and analgesic effects. It may play a special role in uremic or hepatic itching. Studies have shown that capsaicin, although it reduces serotonin-induced wheals, cannot affect the surrounding erythema. Proteinases are also pruritogenic. Trypsin and chymotrypsin cause itching, their effect, however, is abolished by the use of antihistamines, 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 relationship between neuropeptides and itching. Substance P causes intense itching, partly through histamine. Therapeutic use of capsaicin has further clarified this issue. Local application of capsaicin to the skin results in depletion of substance P by neuropeptides to the point of damaging unmyelinated C-type fibers. Initially, intense burning and pain occur, as well as itching, then the perception or production of substance P is blocked.

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

Prostaglandins and eicosanoids, which are found in large quantities in the skin as part of immunological and allergic reactions, apparently also play a role in itching. After injection, prostaglandins can cause mild itching, which is, however, much less than the itching caused by histamine, but which is apparently histamine-mediated or histamine itching can be intensified by prostaglandin E2. Leukotrienes, such as LTB4, cause erythema, but do not produce blisters after skin injection. Inhibitors of prostaglandin synthesis, such as acetylsalicylic acid or indomethacin, are unable to regulate this itching. On the other hand, acetylsalicylic acid plays a decisive role in the treatment of severe itching in the third trimester of pregnancy and is more effective than the H1-antagonist chlorpheniramine.

The role of cytokines and growth factors in terms of their possible association with itching is being clarified. In this regard, of particular importance is the study that was able to prove that the neurotropic factor neurotrophin-4 plays a role in the context of itching in atopic dermatitis.

Itching is the most common symptom in dermatology, which can occur in connection with 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-induced toxicoderma, lichen planus, eczema, urticaria, prurigo, Duhring's dermatosis herpetiformis, solar dermatitis.

In dermatoses, itching is a symptom and consequence of a skin disease. The corresponding dermatosis is diagnosed by typical rashes. Many skin diseases are accompanied by itching. Intense itching, leading to scratching and its effects, is observed in eczema, atopic dermatitis, some mycoses and parasitic skin diseases. In many dermatoses (lichen planus, urticaria), despite the intensity of itching, there are no effects of scratching, since the skin is rubbed, not scratched. Such patients have characteristic shiny nail plates. Crises of itching are typical for atopic dermatitis. In simple subacute prurigo, scratching causes a rash, after which the itching suddenly stops, only hemorrhagic crusts remain, but there are no traces of scratching. Itching is also a symptom of urticaria and is intensified by scratching, but excoriations do not occur.

Frequent hot baths or daily hot showers with low-fat soaps and especially bath additives can dry out the skin, often with barely visible flaking, and the skin reacts with intense itching. In older people, areas of the skin that are poor in sebaceous glands itch, especially the forearms and shins, especially in winter when the air humidity in the apartment is low due to heating.

Every patient suffering from itching should be checked for dermatozoonoses (scabies, insect bites, pediculosis). Scabies is the most common parasitic itchy skin disease. Itching with scabies is especially common at night. In case of itching of the scalp and ears, lice should be excluded; in case of itching in the pubic area, perineum, chest, armpits - pubic pediculosis; in case of itching in the lumbar region, shoulder blades, neck - pediculosis caused by body lice.

Itching is a constant companion of atopic dermatitis. Its intensity varies; it can be diffuse or localized, sometimes limited to the area of individual rashes. The latter occurs in elderly atopic patients with pruriginous changes. Itching can precede a relapse of atopic dermatitis. The effects of scratching caused by itching close the vicious circle, causing inflammation, leading to staphylococcal infection, and thus again to inflammation, which contributes to the persistence of the disease.

Skin itching with urticarial rashes, as well as atopic dermatitis, are caused by the classic mediator histamine. Many other skin diseases can also be accompanied by skin itching. The diagnosis of "pruritus sine materia" can be established when all diagnostic possibilities have been exhausted, and the somatic cause of prolonged itching is not established. Unconscious forced scratching leads to linear stripes on the skin. Sometimes dermatologists talk about "pruritus sine materia" when, upon examination, the skin is otherwise healthy. Itching as a symptom depends less on histamine, but rather on other mediators (serotonin, prostaglandin, and other vasoactive substances). Chronic itching without an obvious cause more often affects older people, especially men. In the differential diagnosis, pruritus senilis or general xerosis (dry skin) should be taken into account.

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