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To our understanding, this is the link I-Other governed by the archetype of the great mother, as termed by Jung. This bond I-Other, in the relational matrix of the Great Mother, will depend on the structure of our healthy primary narcissism as described by Freud, on the formation of a secure attachment as described by Bowlby, or on a good primal relationship according to Neumann.

The formation of a good self-image is dependent on a successful experience in this stage of life, colored of positive values, the matrix of a secure self-confidence. In this phase of life the body is the major via of the symbols for the structuring of our consciousness. The skin is the organ of utmost importance for this exchange between infant and the primary caregiver, through the touch.

The communication between the infant and the caregiver is based on the body, vision and touch are the main routes for this interaction. The similar and different, trying to find a new group, this time by choice, is when seeking what we call the psychological family. Structuring of consciousness at that stage, governed by the archetype of the Great Mother, requires physical closeness, affection, and protection in order to be well succeeded.

Perspective ARTICLE

This body contact will be mostly through the skin, the look and the affective tone of speech of the caregiver. Thus, activities such as baths, massages, comforting and proximity are fundamental. It is through this positive mirroring and emotional nourishment that the baby can build a positive self-image. The next step in the structuring of consciousness is governed by the archetype of the Father. It is associated to what Freud called Oedipus phase.

The body recognizes limits, the body starts to differentiate its own skin from someone else's skin. There is an important role of the skin in this structure, since it is what defines the body. In other words, it is the skin that will separate the inner and the outer, the I and the other.

During the alterity, structured by the archetypes of animus and anima , the I and the Other seek the symmetrical encounter. It is in the alterity that the search of ones profound identity and creativity occurs. And again, the skin plays a strong symbolic role. It is when you put yourself in the place of another, it is when we feel attracted by another partner. We use the term "it is a matter of skin" to speak of this type of attraction.

In old age, when the consciousness is structured by the archetype of wisdom, again the skin reflects its symbols. The wrinkles, the reduction of the tonus, the sensitive skin bring scars pointing to the final stage of our existence, preparing ourselves to death, an important and denied stage of life. The pruritus, itching sensation, can be present in physiological conditions, like when we are bitten by an insect, signaling a lesion. It is also present in the allergies, in sensitive skin and eczema, quite frequent in children with atopic dermatitis.

Atopic dermatitis alters the child's immune functioning with the onset of cutaneous lesions atopic eczema and respiratory symptoms asthma and bronchitis. These children have a lower threshold to the pruritus, i. With the act of scratching, the lesions worsen even further, causing much anguish to caregivers, who feel powerless in the face of the suffering and the fragility of the child. The act of scratching worsens existing lesions and generates new pruritic lesions; thus perpetuating the cycle "itching-scratch-itching", generating more pruritus in a vicious cycle that is extremely stressful.

The severity and progression of atopic dermatitis in the child has a close connection with the way the parents are capable of taking care of the child. Sometimes, the excess of concern leads to an anguish that disables them to help the child to calm down. Even with powerful anti-inflammatory drugs, such as steroids, chronic and intermittent crisis brings limitations to the contact and the development of the child with other children and at school. On the other hand, well oriented families, capable of dealing with such anguish, are able to calm the children.

They become more secure if touched, and massaged with oils in a way that soothes, moisturizes the skin, strengthen the immune system, minimize the itching and thus decrease the number and intensity of the crises. They become more adapted to everyday life along with other children, and do not stay in a "bubble" of overprotection. Feldman an american psychologist, Jungian analyst, studied atopic children and their families in different cultural contexts.

He compared the clinical outcome of children with atopic disease in countries of North America and Latin America. In the countries of Latin America, people touch each other more frequently in comparison with North America. There is more physical contact between children and adults in the latin families, when compared to the habits of north americans. In the United States, families "communicate the affection" more by words than by petting, they keep a greater distance between themselves, with less physical contact. These studies show that in the Latin countries, despite the worst financial conditions, fewer resources for health and education, the atopic children have less severe atopic dermatites and a better evolution of the disease after childhood.

Another example of the "nourishing touch" is in India, a country of extreme poverty: massages as the Shantala, practiced in babies seem to be of great value in the nutrition derived from contact with the intention to caress, soothe and relax. The researchers separated the preterm infants into two groups: one group of babies that were handled for the technical care "routine" changing diapers, cleaning, bathing and feeding and a second group which, in addition to receive the same care from the first, also received a massage, petting and "extra" attention.

Despite having the same food nutrition and being in the same ICU, the weight gain of caressed babies was higher and faster than those who did not receive the "extra" care. Skin: feel and touch. Caenorhabditis elegans and Drosophila melanogaster are living beings which have a relatively simple nervous system. In these organisms molecules required for the sensation of touch were identified and mechanisms by which these molecules control the sensitivity to mechanical stimuli, converting strength into cell signalling mecanotransduction was described LUMPKIN, This system involves mecanoceptores, neurons sensitive to forces that constantly bombard the surface of the body.

These signals were required for their movement, survival and reproduction, therefore, for the maintenance of the species. Studies on the mechanisms involving the tact and touch in mammals have demonstrated that keratinocytes, main cells on the surface of the epidermis, produce neurotransmitters which have the potential to tune the sensitivity of the touch by afferent pathways. Although the keratinocytes and sensory afferent fibers do not form synapses, its proximity may allow rapid paracrine signalling capacity of communication with neighboring cells through the secretion of bioactive compounds.

The touch is defined as the direct contact between two physical bodies. In the neurosciences, "touch" describes a special feeling by which the contact with the body of an organism is perceived by the conscious mind. Some types of touching involve an active behaviour - caress, touch or press - by which a part of the body is moved on another surface. Sensory and motor components of touching are connected and integrated in the brain. They are functionally important for deflagrating or to induce a behaviour, such as locomotion. Be a shift to depart from some potentially harmful stimulus e.

The sensory modalities of touch are classically divided into four: tactile, thermal, itchy and painful. The presence of free nervous endings in the skin surface DELMAS et al, and the transmission of stimuli in specific ways suggested the existence of a fifth modality, the affective touch. The touch that creates a pleasant sensation, also called "positive touch" is transmitted through a specific type of touch C fiber. C fibers are divided into two types: C1 - those which work as low threshold mecanoceptors, and the C2 - which, in contrast, have a high threshold for outbreak of stimulus depolarization via ionic channels.

Type C2 fibres correlate with stimuli of pain or "harmful effects" nociceptors. This second group is also related to the itching and the pleasant sensation of touch, the affective aspect of a caress BOWLBY, The various subtypes of C fibers provide the substrate for a possible reinterpretation of the human somatosensory processing.

Angelo Ruffini in normal skin, typically are highly branched with abundant enlargements. Ruffini endings are usually enclosed by collagen capsules and are termed corpuscles Ruffini, ; Andres and von During, ; Halata and Munger, ; Munger and Ide, ; Sano, In the vibrissal follicle of the rat, Ruffini-like endings are not encapsulated; numerous endings spread broadly on the surface of the glassy membrane present a tree-like appearance. Ruffini-like endings are distributed widely in the mesenchymal sheath at the level of upper cavernous sinus. They are arranged without any space between them with little overlapping, such that they appear as a flattened collection of branches.

For most of the past 20 years, the identification of several mechanoreceptor types has been unclear. For instance Fundin et al. Ebara et al. In , Byers identified two types of mechanoreceptors in the periodontal ligament: large, complex Ruffini-like receptors and simple Ruffini-like receptors. Maeda et al. As a result of our recent investigations we have concluded that the two types of mechanoreceptors identified by Maeda et al. The parent afferent often branches once or twice. Sometimes, the branches are distributed far from each other, such that the total territory that an afferent can cover is a wider area than that of all the other types of mechanoreceptors unpublished data.

The morphology of Ruffini-like endings observed in the rat is different from that of the cat. Rat Ruffini-like endings are arranged similarly to the fingers of an open hand whose palm is pressed against a flat surface. The finger-like projections of these endings are splayed out over the surface of the glassy membrane. In contrast, Ruffini-like endings in the cat resemble a partially closed hand replete with curved fingers. In the cat, only the tips of the finger-like projections of Ruffini-like endings are applied to the glassy membrane.

Perhaps the differences in the shapes of Ruffini-like endings in whisking vs. Free nerve endings in the dermis, termed penicillate endings by Cauna , are fine-caliber axon terminals that originate primarily from unmyelinated nerve fibers but occasionally stem from small diameter, myelinated fibers. Numerous free nerve endings also occur within the epidermis Fig. In our preparations using immunohistochemistry, the parent afferents are observed to give rise to multiple branches composed of fine, varicose fibers.

Their axon terminals lack envelopment by terminal Schwann cell sheaths Cauna, ; instead, they are surrounded by keratinocytes Fig. Mechanoreceptors respond to mechanical stimulation, whereas free nerve endings typically respond to chemical stimulation as in pain or itching, or to temperature.

Recent studies of the primary sensory neurons, using a combination of gene targeting and immunostaining of stretch receptor molecules such as TRPV2 and TRPV4, suggest strongly that some free nerve endings are low-threshold mechanoreceptors Lawson et al. The axons of free nerve endings are considerably smaller in diameter than those of the typical mechanoreceptors described in sections on other types of endings. With respect to the vibrissae, free nerve endings are distributed widely throughout the entire depth of the follicle with the exception of the outer root sheath.

The densest distribution of unmyelinated fibers, including many free nerve endings, is seen within the inner conical body. Abundant unmyelinated nerve fibers surround the follicle at that level, with a few myelinated nerve fibers providing circumferential lanceolate endings Fig. These endings are of fine caliber, lose their myelin at the terminal point Fig. A dense innervation of free nerve endings is also observed in the intervibrissal skin Fig. Other types of mechanoreceptors intermingle with free nerve endings Fig.

Endings encapsulated by a collagenous capsule are termed corpuscles.

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Axon terminals of laminar corpuscles have multiple lamellae of terminal Schwann cell sheath, e. Murine or canine vibrissal follicles have simple corpuscles at the level of the cavernous sinus; the rat vibrissal follicle, however, does not have corpuscles Halata et al. A variety of other types of endings that do not occur within vibrissal follicles are not mentioned in this report, because as yet, there is little that can be said about the details of their specific morphologies and functional attributes.

When sufficient knowledge is provided about these mechanoreceptor types, it is expected that they will form the subject of a later entry. A large number of collaterals emitted by central processes may be the major factor in determining the tactile stimulation that is encoded even by the simplest mechanoreceptor, i. See also the chapter in this volume by Prof. Martin Deschenes. A useful approach to classify sensory receptors relies on a combination of morphological and physiological characteristics. For example, it is well known that conduction velocity correlates with the diameter of nerve fibers: Thicker myelinated fibers convey action potentials more quickly than thinner fibers.

In , Erlanger and Gasser proposed a system of classification that relied on physiological characteristics alone. Sano, ; Gardner and Johnson, Physiological classifications provide useful descriptions of the functional aspects of sensory nerve fibers. However, a classification system that relies only on fiber diameter does not necessarily correlate with conduction velocity because the diameters of the nerve fibers vary along their lengths Sano, and unpublished observations. Using intracellular recording, Tonomura et al.

Multimodal Torus in the Weakly Electric Fish Eigenmannia

It should be noted that axons belonging to a particular type of mechanoreceptor do not always have fibers of the same diameter. Both types of mechanoreceptors are distributed within the vibrissal follicles as well as in other areas of the skin that lack vibrissae. Gardner and Johnson pointed out that these receptors respond to discrete stimuli and in doing so, reflect changes in temporal-spatial patterns of stimulation.

A number of researchers have determined that adaptation responses of mechanoreceptors can vary under certain conditions Zucker and Welker, ; Cash and Liden, ; Leiser and Moxon, ; Abraia and Ginty, Recently, Furuta et al. A receptive field is defined as a limited region on the skin surface which, through the mediation of mechanoreceptors, can evoke a response in a primary sensory neuron.

The standard classifications are no longer necessarily applicable to mechanoreceptors associated with the vibrissae. One reason is that each whisker has a different intrinsic curvature and emerges from the mystacial pad at a different angle Towal et al. Making detailed 3-dimensional analyses of the environmental structures and their movements in relation to the receptors, as well as quantifying the areas innervated by single neurons, is necessary to determine the sizes of receptive fields Tonomura et al. Increasing the relevancy of both previous and newer classifications applied to the various aspects of mechanoreceptors requires a much closer interaction between physiological and morphological approaches than hitherto employed.

Within a vibrissal follicle, multiple innervations of diverse mechanoreceptors that provide a variety of responses to stimulation are considered to play a key role in the highly sophisticated functions of the whisker sensory system. Furuta et al. In contrast to the Merkel endings, the club-like endings evoke rapidly adapting firing and occasionally evoke continuous firing to stimulation from most directions regardless of their location and orientation Furuta et al.

Ultrastructure of Merkel corpuscles and so‐called “transitional” cells in the white leghorn chicken

Their results also suggest that neurons having club-like endings can respond adaptably to even delicate vibrations of the hair shaft, evoking high-frequency action potentials. In contrast to the club-like endings, Ruffini-like endings display voluminous branching within their receptive fields Fig. Their findings and those of Gottschaldt et al. Club-like endings associated with the ringwulst represent an ideal model to investigate various mechanisms of mechanoreception regarding how movements of the ringwulst are related to whisker stimulation and the character of their central neurotransmission.

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  7. An interesting finding by Furuta et al. Intensive microscopic and electrophysiological examination and analysis can be expected to elucidate correlations of structure and function that will pave the way for a more complete understanding of mechanoreception, thereby greatly facilitating our understanding of touch.

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    The visual, auditory, gustatory and olfactory senses are each stimulated by a single element, for example, the retina responds to light, the cochlea to sounds, taste buds to molecules and olfactory receptors to odorants. This alternative pathway which is present in invertebrates remains to be tested in the skin. Catecholamines are deactivated by L-monoamine oxidase MAO and Catechol-O-methyltransferase COMT leading to the synthesis of homovanillic acid from dopamine or vanillylmandelic acid from norepinephrine or epinephrine.

    These findings are in agreement with our hypothesis that L-tyrosine and L-DOPA can have hormone- and neurotransmitter-like roles Slominski and Paus , ; Slominski et al. There are five subtypes of dopamine receptors, and they have been categorized into two families, i. After D2-like receptors were identified in the keratinocytes Fuziwara et al.

    Application of D2-like receptor agonists accelerated barrier recovery, whereas D2-like receptor antagonists delayed it. Actual receptor subtypes localize to different parts of the epidermis: D4 is localized in the uppermost part of the epidermis and D2 is localized in the basal layer of the epidermis where it plays a role in the regulation of cell proliferation Fuziwara et al. It remains to be tested whether dopamine is also regulating epidermal and follicular pigmentary systems as well as adnexal functions including hair follicle.

    Dopamine receptors on lymphocytes exert differential effects. Dopaminergic signaling through D2-like receptors of T lymphocytes showed an immunosti- mulatory effect Besser et al. Dopamine also inhibits prolifera- tion of human lymphocytes and causes apoptosis of peripheral blood mononuclear cells Bergquist et al. IL-6 and other cytokines stimulates a development of a subtype of T lymphocytes capable of producing IL and other cytokines , i.

    Th17 lymphocytes constitute relatively recently described branch of immune responses Harrington et al. Dopamine released by dendritic cells induces IL-6Th17 axis and upregulates synovial inflammation Nakano et al. The IL-6Th17 axis plays a role in the pathogenesis of inflammatory diseases including rheumatoid arthritis. It can therefore be deduced that dopamine may also have various differential modulatory roles in the skin immune system.

    The adrenergic receptors belong to the classic seven-transmembrane G-protein- coupled receptor GPCR family. These receptors respond to catecholamines and can be subdivided into subtypes of a and b families, based on their differential pharmacological responses and protein sequences Lands et al. More specif- ically, these receptors are defined, in part, by their endogenous ligand affinity to b receptors having a higher affinity to epinephrine when compared to norepinephrine, and to a receptors having a higher affinity for norepinephrine.

    Alpha adrenergic receptors can be further subdivided into a1 and a2, and b receptors can be further subdivided into b1, b2, and b3 subtypes. The a1 a1a, a1b, and a1d receptors couple to phospholipase C via Gqa and stimulate the formation of diacylglycerol and inositol trisphosphate Cotecchia The a2 a2a, a2b, and a2c receptors couple to Gia and inhibit the formation of cAMP, whereas b receptors are posi- tively coupled to the formation of cAMP via Gsa Hein Various receptors of both a and b subfamilies of adrenergic receptors are present on epidermal and dermal cells Grando et al.

    As expected, a and b receptors are also expressed in dermal blood vessels. Keratinocytes express mainly b2 receptors and also a1 receptors Steinkraus et al. Catecholamines stimulate keratinocyte differ- entiation with increased expression of keratins 1, 10, involucrin, and transglu- taminase Mammone et al. Moreover, there is a local gradient of receptor expression with the highest level in basal keratinocytes and decreasing level toward the surface of the epidermis Schallreuter et al. This indicates a potential stimulatory functional role of catecholamines in the process of keratinocytes differentiation.

    Catecholamine-b2 adrenergic system has been implicated in the pathogenesis of atopic dermatitis, psoriasis, and vitiligo Sivamani et al. Expression of b2 receptors is increased in vitiligo and decreased in psoriasis Schallreuter et al. In vitiligo, there is an overproduction of 6-BH4 leading to a dysregulation of catecholamine biosynthesis with increased plasma and epidermal norepinephrine levels.

    This is associated with high numbers of b2 adrenoceptors in differentiating keratinocytes and with a defective calcium uptake in both keratinocytes and melanocytes Schallreuter et al. In atopic eczema, a point mutation in the beta 2- adrenoceptor gene could alter the structure and function of the receptor, thereby leading to a low density of receptors on both keratinocytes and peripheral blood lymphocytes Schallreuter et al. It is also known that catecholamines and b receptors have a role in wound healing although their exact role is far from being clarified Ghoghawala et al. The adrenergic beta-receptors not only affect keratinocytes proliferation and differentiation but also their immune activities.

    Activation of b receptors on keratinocytes affects expression of b-defensin 3 Martin-Ezquerra et al. Studies on cultured melanoma cell lines have shown that catecholamines can be an additional factor affecting melanogenesis Howe et al. Their role in the function of the pigmentary system has been well described in nonhuman systems reviewed by Slominski et al. Human melanocytes express a1 and b2 receptors Gillbro et al.

    The expression of b2 receptors on human melanocytes increases in response to UV irradiation Yang et al. UVB irradiation increases epinephrine release by cultured keratinocytes that in turn increases pigmentation in co-cultured melanocytes, which is an example of the interactions between these two cell types Sivamani et al. Adrenergic receptors are expressed also on immune cells of the dermis Steinkraus et al. Binding of adrenergic agonists to their receptors on lymphocytes has immunostimulatory effect and affects their homing. On the con- trary, stimulation of b receptor usually has immunosuppressive effects, but in other model systems can also cause immunostimulation, i.

    Mouse Langerhans cells express a1, b1, and b2 adrenergic receptors Seiffert et al. Agonists of b2 receptors on mast cells inhibit the release of preformed mediators such as histamine, and also newly synthesized mediators such as prostaglandin D2 from mast cells Okayama and Church They also inhibit release of inflam- matory cytokines from mast cells Bissonnette and Befus Ligation of b2 receptors activates epidermal growth factor EGF receptor and extracellular signal-regulated kinase ERK signaling that in turn stimulates fibro- blast migration.

    Binding of agonists to the b2 receptors can also activate protein A kinase PKA which can stimulate cell proliferation Pullar and Isseroff , attenuate collagen gel contraction, and alter actin cytoskeleton and focal adhesion distribution via PKA-dependent mechanisms Pullar and Isseroff A link between body stress response system that results in the release of epinephrine and activation of intracellular signaling that leads to DNA damage has been shown recently Hara et al.

    Specifically, in mouse and human fibroblasts binding of agonists to the b2 receptors led to Gs-protein-dependent activation of protein kinase A, followed by the recruitment of beta-arrestins. Then, b-arrestin 1 facilitated AKT- mediated activation of MDM2 and also promoted MDM2 protein binding to and degradation of p53 protein by acting as a molecular scaffold. The degradation of p53 resulted in the lack of protection and DNA damage Hara et al.

    In the skin there are several potential non-receptor-mediated effects, which are based on autoxidation of catecholamines in alkaline environment with a velocity increased by metal cations Lassalle et al. The potential phenotypic implications are predominantly based on the well-documented activity of L-DOPA which through its oxidation products and active melanogenesis can affect functions of immune cells Slominski and Goodman-Snitkoff ; Slominski et al. The possible mechanisms of action were discussed previ- ously Slominski et al.

    L-DOPA dramatically inhibits an in vitro phosphorylation of glycoproteins dependent on the presence of Mn ions indicating action of quinones generated through oxidation of DOPA Slominski and Friedrich It can also affect cellular metabolism in melanotic cells Scislowski et al. Memoli et al. Thus, taking into consideration similar chemical properties of DOPA and catecholamines products of DOPA enzymatic metabolism , and that their oxidation leads to the production of neuromelanin, one can safely conclude that non-receptor-mediated effects and mechanisms will be similar to that described for DOPA Slominski et al.

    Taking into consideration the above chemical properties of dopamine, epinephrine, or norepinephrine, one can expect that at micromolar or higher concentrations the predominant effects will be non-receptor-mediated mainly through their oxidation products and neuromelanin polymers generated during this process. It is also possible that some of the phenotypic effects at lower concentrations could also be influenced by oxidative effects. Dopamine, epinephrine, and norepinephrine are produced in the skin resident and nonresident cells.

    Their phenotypic effects are mediated through activation of dopaminergic and adrenergic receptors, the expression of which is cell-type and cell-context dependent. Their roles in epidermal, dermal, and adnexal as well as skin immune functions remain to be further investigated. It is likely that cutaneous catecholaminergic system will communicate with brain by activating sensory nerves, or, with other tissues, via entry into systemic circulation and by affecting immune cells circulating from the skin to other organs Fig.

    Histamine is derived from the decarboxylation of histidine by the L-histidine decarboxylase. After release, histamine is degraded by histamine-N- methyltransferase in brain and at periphery or diamine oxidase in the periphery Fitzpatrick et al. Histamine is produced mainly by mast cells and basophils. Cross-linking of IgE antibodies attached to the cell membrane represents a main mechanism for histamine release. Histamine binds to four different types of seven-transmembrane receptors that signal through G-proteins.

    The H1 receptor is found on smooth muscle and endothelial cells and is responsible for smooth muscle contraction and decreased adhesion of endothelial cells. H2 receptor is located on vascular smooth muscles and parietal cells in the stomach and is responsible for vasodilatation and gastric acid secretion. H3 receptor is found in the central and peripheral nervous systems and is responsible for decreased secre- tion of several neurotransmitters including histamine, acetylocholine, serotonin, and norepinephrine.

    H4 receptor is found primarily on basophils and has a role in chemotaxis Fitzpatrick et al. In the epidermis, H1 and H2 receptors are expressed on keratinocytes Albanesi et al. Mediators released from mast cells inhibit keratinocyte growth in culture Huttunen et al. Activation of keratinocyte H2 receptors affects proliferation and differentia- tion via activation of the cyclic AMP pathway and also phospholipase C pathway with associated increase in intracellular calcium levels Koizumi and Ohkawara In mouse keratinocytes, H2 receptor signaling through the PLC second messenger system is inhibited during calcium-induced keratinocyte differentiation by an autocrine loop which involves downregulation of H2 receptor expression and inhibition of histamine metabolism Fitzsimons et al.

    H2, however, not H1, agonists stimulate intracellular calcium signaling in keratinocytes Koizumi and Ohkawara The effect of histamine acting through H2 receptor appears to be the opposite. IL, produced by Th17 cells infiltrating into the dermis a cytokine involved in various inflammatory skin diseases includ- ing psoriasis , stimulates keratinocytes to produce inflammatory mediators such as IL, TNF-a, IL-6, and IL-8 Carrier et al.

    Histamine promotes cutaneous antimicrobial defenses and wound repair by stimulating secretion of defensins Ishikawa et al. Histamine also enhances nerve growth factor production by inducing c- Fos expression in keratinocytes Kanda and Watanabe The activation of the H2 receptors on melanocytes stimulates melanogenesis Yoshida et al. Histaminergic system is upregulated in the B16F10 melanoma cells when compared to noncancerous melanocytes, which indicates that it might have a role in tumorigenesis Davis et al.

    Both Western blot and immunohistochemical studies showed much stronger histidine decarboxylase expression in melanoma cells as compared to normal melanocytes Haak-Frendscho et al. Moreover, H1 histamine recep- tor antagonists were shown to induce genotoxic and caspasedependent apoptosis in human melanoma cells, but not normal melanocytes Jangi et al. In the dermis, histamine receptors are expressed on fibroblasts, immunocytes, endothelial cells, blood vessels, smooth muscle, and nerve endings Fitzpatrick et al.

    In Th2 lymphocytes stimulation of H4 receptor led to the activation of transcription factor AP-1 followed by the release of IL, which is involved in the development of pruritus Gutzmer et al. On the other hand, activation of H4 histamine receptors expressed on monocytes activated intracellular calcium mobi- lization and inhibited the CCL2 chemokine production which reduced recruitment of monocytes Dijkstra et al. This effect, while observed in cultured eosinophils, may be of paramount importance in the skin Ling et al. Plasmacytoid dendritic cells migrate in response to H4 receptor agonist stimulation.

    Of note, H4 receptor is present in high levels on plasmacytoid dendritic cells in the lesional psoriatic skin Gschwandtner et al. Histamine is produced not only by mast cells but also by other cells of epidermis and dermis and acts locally in the epidermis and dermis by binding to H1-H4 receptors. It affects intracellular signaling cascades, cell proliferation, and melanogenesis. Histamine is upregulated in melanoma cells. It signals mainly via H4 receptor on the cells of the immune system and affects their migration and cytokine secretion patterns.

    Moreover, it modulates Th2-type immune responses and antimicrobial peptide expression. Thus, histamine is an important part of the neuro-immuno-endocrine system of the skin Slominski and Wortsman with local and systemic effects Figs. Serotonin 5-hydroxytryptamine, 5-TH is widely synthesized throughout the animal kingdom, plants, and unicellular organisms Azmitia , In plants, serotonin serves as a trophic factor and an antioxidant which is similar to the animal kingdom Azmitia In humans, serotonin was shown to be synthesized predominantly by intestinal enterochromafin cells with other sites of production represented by the central nervous system, pineal gland, retina, ovaries, placenta, thymus, pancreas, skin, breast, gestational tissues, blood vessels, rectal epithelium, bronchial epithelial cells, thyroid parafollicular cells, mast cells, and lymphocytes Nordlind et al.

    The first obligatory step in the synthesis of serotonin is the hydroxylation of L-tryptophan to produce 5-hydroxytryptophan TrpOH in a reaction catalyzed by tryptophan hydroxylase TPH Mockus and Vrana , a protein encoded by either TPH1 gene expressed ubiquitously Mockus and Vrana or TPH2 gene expressed predominantly in the brain Zhang et al. This reaction requires oxygen and cofactor 6BH4. In humans, L-tryptophan is present in blood plasma at steady-state level both in the free form approximately 1.

    Thus, fluctuations in free pool of tryptophan directly and immediately alter the level of serotonin synthesis Nordlind et al. Catabolism of serotonin is initiated by MAO with the production of 5-hydroxyindoleacetaldehyde, oxidized further by aldehyde dehydrogenase E. Alternatively, HIOMT activity may also lead to the production of methylated derivatives of serotonin. Fitzsimons et al. NAS can also be further metabolized to melato- nin Reiter In the skin, a number of NAS metabolites unrelated to melatonin were found, the nature and mechanism of generation of which remain to be defined Slominski et al.

    Serotonin can be transported through the plasma membrane in either direction; however, under most conditions, its reuptake is favored Nordlind et al. Plasma serotonin is also cleared by the liver and lung endothelial cells and further catabolized to 5-HIAA. Thus, the TPH1 gene is expressed in human skin under normal and pathological conditions as well as in a wide array of normal and transformed human epidermal, dermal, and adnexal skin cells with some cells expressing the aberrant TPH1 transcript Slominski et al.

    As to the TPH2 gene, it is expressed in the retinal pigment epithelium Zmijewski et al. Although the TPH gene is expressed almost in all types of human skin cells, the highest expression was found in normal and malignant melanocytes that also accumulated significant amounts of serotonin Figs. Interestingly, the enzymatic conversion of tryptophan to TrpOH in melanoma cells occurs at high levels, comparable to those in the brain Slominski et al.

    TPH and TPH1 were also detected in the mouse and hamster skin, and in cultured mouse follicular melanocytes and melanoma cells Slominski et al. Interestingly, the TPH1 gene expression changes during murine hair cycle Slominski et al. In addition, TPH and serotonin are strongly expressed in rodent masts cells. Interestingly, nonenzymatic production of TrpOH through H2O2 and UVA radiation indicates that a free-radical-mediated oxidation of L-tryptophan is also possible in the skin Schallreuter et al. In human skin biopsies immunoreactivity of TPH and serotonin was found in normal epidermal melanocytes and malignant melanomas Figs.

    These findings are consistent with the immunodetection of serotonin in perivascular human mast cells of adrenal cortex Lefebvre et al. Serotonin was also detected by immunocytochemistry in dermal Merkel cells in rat and pig skin at the epidermal rete ridges and upper hair follicles adjacent to nerve terminals Nordlind et al. Cutaneous serotonin content can be affected by inflamma- tory processes Lonne-Rahm et al.

    For example, human skin affected by psoriasis or chronic eczema showed elevated expression of serotonin in the epidermal and adnexal structures Nordlind et al. For technical details of the assays, see Slominski et al. MAO metabolism of serotonin was also detected in guinea pig skin Tachibana et al.

    In hamster skin, we characterized two N-acetyltransferase activities including NAT-1 with substrate specificity toward arylamines, and NAT-2 showing substrate specificity toward both arylamines and arylalkylamines such as serotonin, tryptamine, and methoxytryptamine Gaudet et al. Furthermore, we demonstrated that at least part of this activity in hamster, rat, and human skin represented native AANAT Slominski et al. It was immunolocalized in the epidermis ES , hair follicle ORS , eccrine glands EG , showing the highest expression in melanocytes arrows Panels a and b.

    Immunocytochemical localization of melatonin-like immunoreactivity is shown in Panel d on the right upper E, BV, and MC. For technical details, see Slominski et al. Reproduced with permission from the publisher Slominski et al. Most interestingly, acetylation of serotonin, but not of tryptamine, was dependent on the phase of hair cycle, skin anatomic location, and the presence of pathology melanoma.

    NAS was further metabolized to several products the chemical nature of which remains to be defined in a hair cycle- dependent fashion Slominski et al. In humans, both skin racial pigmen- tation and cutaneous pathology determine the reaction rate and specificity of serotonin acetylation Slominski et al. Serotonin regulates a wide range of physiological processes at the central and peripheral levels acting as a neurotransmitter, hormone, cytokine, biological modi- fier, growth factor, morphogen, and antioxidant or pro-oxidant Azmitia , The above functions are mediated through receptor-dependent and receptor-independent mechanisms Hoyer et al.

    Most of these receptors are metabotropic, with the exception of 5-HT3, which is ionotropic and primarily gates sodium and potassium ions.

    The 5-HT5 receptor 5A and 5B is considered to be an orphan receptor. Serotonin receptor function can be modulated by RNA editing, endogenous lipids that act as allosteric modulators, and serotonin moduline tetrapeptide, 5-HT-moduline that is produced by proteolytic modification of chromogranin. The receptors heterogeneity and functional diversity are also amplified by the process of alternative splicing and differential subunit incorporation into the receptor complex.

    The regulation of 5-HT receptor activity is also affected by serotonin transporters, which remove serotonin from the extracellular environment or, under certain conditions, pump it out of the cell. In human skin and skin cells, we identified expression of genes coding 5-HT receptors, including HTR1A, 1B, 2A, 2B, 2C, and 7 genes, and it was shown that the pattern of expression was cell type specific and modified by skin pathology Slominski et al. In mouse and hamster skin, expression of the HTR2B and HTR7 genes was demonstrated, which was dependent on the phase of hair cycle mouse and type of tissue or cells Slominski et al.

    We should also mention that Kaneko et al. However, these findings have to be considered with caution, since other researchers demonstrated that 5-HT2A antagonists inhibited UVR-induced skin carcinogenesis Sreevidya et al. Furthermore, 5-HT2A protein was detected by immunocytochemistry in dermal lymphocytes, fibrocytes, vasculature, and sensory nerve endings, abating the epidermis Nordlind et al. Furthermore, 5-HT1A and 5-HT2A were detected in the majority of benign tumors such as compound nevi, dysplastic nevi, and also in malignant melanomas Nordlind et al. By the use of immunocytochemistry, 5-HT2C was detected in epidermal Langerhans cells and melanocytes, 5-HT3 in the basal epidermal keratinocytes, and 5-HT7 in dermal vasculature Nordlind et al.

    Diverse expression of 5-HT receptors was also found in immune cells that were dependent on cell type and their level of activation. Also Merkel, Langerhans and mast cells, lymphocytes and macrophages Nordlind et al. Their role is substantiated by observations which showed that serotonin uptake inhibitors could induce spontane- ous bruising, pruritus, urticaria, angioedema, erythema multiforme, the StevenJohnson syndrome, toxic epidermal necrolysis, erythema nodosum, alope- cia, hypertrichosis, leukocytoclastic vasculitis, and acneiform eruption reviewed by Nordlind et al.

    This can also be associated with flares of psoriasis vulgaris and development of delayed hypersensitivity. Under in vitro conditions, serotonin exerted variable effects on skin cells depending on the context Nordlind et al. It stimulated proliferation of dermal fibroblasts Slominski et al. Serotonin also stimulated growth of epidermal melanocytes in the absence of growth factors, while inhibiting their proliferation in media supplemented with serum Slominski et al. The former effect could be linked with the stimulation of intracellular cAMP accumulation, while the latter could represent serotonin antagonism with serum growth factors Slominski et al.

    NAS, the product of serotonin metabolism, showed no effect on the proliferation of fibroblasts and melanocytes Slominski et al. Interestingly, serotonin content within mast cell granules steadily decreased throughout anagen and increased during catagen and telogen phases of hair cycle Hasse et al. Serotonin shows vasoactive and immunomodulatory effects.

    For example, it plays a role in the Arthus reaction Tachibana et al. Serotonin participates in the activation of T cells and natural killer cells by macrophages, initiation of delayed-type hypersensitivity responses, production of chemotactic factors, and the modification of innate immune responses Benton et al.

    In allergic contact dermatitis and psoriasis, the number of cells expressing both 5-HT1A and tryptase diminishes, whereas the number of dermal cells expressing 5-HT2A and CD3 increases, including atopic dermatitis Lonne-Rahm et al. Similar pattern is found in the murine epidermis affected by contact eczema. Furthermore, both eczematous and psoriatic human skin shows increased number of mononuclear cells expressing 5- HTT reviewed by Nordlind et al. In addition, serotonin can act as a chemoattractant for eosinophils, probably by binding to 5-HT2A receptors.

    It is involved in the mast cell recruitment to the site of tissue injury through the activation of 5-HT1A, however, without inducing their degranulation Nordlind et al. Regulatory function of 5-HT1A in inflammatory responses is emphasized by the suppression of the severity of contact allergy in rats, after topical or oral administration of its agonist, buspirone Nordlind et al.

    Another 5- HT1A agonist, tandospirone, attenuates itching in patients with atopic dermatitis Nordlind et al. On the other hand, treatment with 5-HT2A antagonists reduced the severity of contact allergic reactions in mice and one of them, spiperone, was effective when applied either systemically or topically. Further- more, 5-HT2 receptor antagonist, ketanserin, inhibited the established but not challenge-induced phases of allergic contact dermatitis Nordlind et al.

    Serotonin is also involved in the pathogenesis of cholestatic and uremic pruritus, urticaria, and itch reaction reviewed by Slominski et al. Intradermal injection of serotonin into rat elicited enhanced c-fos-like immunoreactivity in superficial lamina at the lateral aspect of the dorsal horn, in a manner similar to the immuno- reactivity evoked by capsaicin. Although neither 5-HT2 nor 5-HT3 appears to be involved in itch responses caused by chronic allergic skin dermatitis in rats, acute scratching is mediated by skin 5-HT2 receptors, and intradermal injection of serotonin induced itching in normal, but not inflamed skin reviewed by Nordlind et al.

    In human skin, 5-HT2A and 5- HT3 are localized on sensory nerve ending in the dermis or located close to or entering the epidermis, and their activation may explain pruritic responses to intradermally injected serotonin Nordlind et al. Specifically, an antagonist of 5-HT3, ondansetron, can reduce the severity of pruritus, while paroxetine is used in the treatment of pruritus and its antipruritic action is connected with downregulation of 5-HT3 expression Nordlind et al.

    The cutaneous serotoninergic system may play a role in body reception of and reaction to light Slominski et al. For example, it has been reported that UVA-induced well-being can be linked to increased serum serotonin and decreased melatonin levels after a single radiation exposure Gambichler et al.

    It has also been proposed that 5-HT2A plays a role in the transduction of UVR energy into biological responses by serving as the receptor for cis-urocanic acid cis- UCA , generated through photoisomerization of the trans-UCA in the stratum corneum after absorption of UVR Walterscheid et al. Cis-UCA acts as a powerful local and systemic immunosuppressor Garssen et al.

    Thus, there is sufficient information to support involvement of the local serotoninergic system in cutaneous responses to the UV light; however, the mechanism may be more complex than originally anticipated. It may include activation of 5-HT receptor signaling on either nerve ending or skin cells secondary to UVR-induced local production of serotonin or alternative ligands for HT receptors with a consequent regulation of local homeo- stasis and immune system. Such signals will be projected to the brain via the ascending nerve routes. Furthermore, release of serotonin into circulation may generate endocrine effects.

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    The mammalian skin cells have the capability to produce and metabolize serotonin. The serotonin receptors are also expressed on sensory nerve endings, which transmit to the brain information on changes in skin homeostasis induced by either intrinsic or environmental factors Slominski ; Slominski and Wortsman Finally, the cutane- ous serotoninergic system may be involved in the transformation of light energy of solar radiation into local and systemic biological responses, with the latter mediated via transmission to brain, endocrine effects, or regulation of systemic responses as shown on Figs.

    Chapter 3 Melatoninergic System in the Skin. Melatonin production is highly conserved in nature through different species including bacteria, unicellular eukaryotes, algae, plants invertebrates, and vertebrates Hardeland et al. In mammals, melatonin is produced in the pineal gland Reiter as well as in brain, retina, Harderian gland, ciliary body, lens, thymus, airway epithelium, bone marrow, immune cells, gonads, placenta, gastrointestinal tract, and skin Bubenik ; Carrillo-Vico et al. Circulating melatonin predominantly derives from the pineal gland by diffusion into the circulation, although entry from other extra-pineal sites of production is also possible.

    In the pineal gland melatonin production is controlled by the suprachiasmatic nucleus through nocturnal sympathetic release of norepinephrine that acting via adrenergic receptors activates cAMP-dependent signal transduction cascades leading to the stimulation of AANAT and ultimate production of melatonin Klein ; Reiter ; Yu and Reiter NAS can also be produced by the action of arylamine N-acetyltransferases Fitzsimons et al. In addition, the existence of low flux rate alternative pathways has been proposed that involves O-methylation of serotonin with subsequent N-acety- lation, or O-methylation of tryptophan followed by consecutive decarboxylation and N-acetylation.

    Transcripts of AANAT and of HIOMT genes were detected in normal and pathological skin biopsies, and in most skin cells cultured in vitro including normal keratinocytes neonatal and adult, epidermal and follicular , immortalized HaCaT keratinocytes, fibroblasts dermal and hair follicle papilla , normal melanocytes, several melanoma cell lines, and squamous cell carcinoma cells Slominski et al.

    The acetylation of serotonin was also dependent on local cellular environment. Thus, when AANAT activity was calculated for two substrates, tryptamine and serotonin, the activity ratios were close to 1 for all melanoma lines and for keratinocytes. On the other hand, these ratios ranged from 2.

    These findings suggest a role for both skin racial pigmentation and type of cutane- ous pathology such as melanoma in this regulation Slominski et al. Both of them may be important determinants of reaction rate and specificity of serotonin acetylation. Using immunocytochemistry AANAT antigen was detected in suprabasal differentiating keratinocytes in human scalp epidermis. However, melanocytes also exhibited immunoreactivity for this enzyme Fig.

    High expression of the antigen was also seen in the outer peripheral epithelial layers of the anagen hair follicles Fig. The expression was further found in sensory nerve endings abutting the epidermal layers Slominski et al. Melatonin-like immunoreactivity in human skin was detected on differentiating keratinocytes in spinous and granular layers of the epidermis Fig. The antigen was not expressed in keratinocytes of basal and suprabasal layers of the epidermis, while being found in singly scattered melanocytes.

    Melatonin immunoreactivity was also detected throughout the hair follicle epithelium, in blood vessels, and cutaneous mast cells Slominski et al. These findings showed that human skin, in addition to the pineal gland and retina, possesses the intrinsic capability to synthesize melatonin Abe et al. Importantly, this cutaneous melatoninergic pathway operates in a compartment-specific manner since it is localized mainly to the epidermal, adnexal, and dermal cell populations Fig. Similar capability to produce melatonin was demonstrated in rodent skin Slominski et al.

    For example, in hamster skin fragments maintained ex vivo serotonin was transformed into melatonin with NAS as the intermediate product Slominski et al. This transformation was time- and dose- dependent, and was stimulated by forskolinindicating involvement of cAMP signal in this process Slominski et al. These findings have been confirmed in follow-up studies Slominski et al.

    Specifically, biochemical assays in mouse, rat, and hamster skin clearly demonstrated that skin of all of these species can transform serotonin to NAS, the obligatory precursor for melatonin Semak et al. Additionally, murine skin in organ culture and mouse vibrissae hair follicles can produce melatonin and its synthesis was enhanced by the addition of norepinephrine Kobayashi et al. Melatonin can be degraded via indolic and kynuric pathways. In the liver, the intrinsic clearance for melatonin hydroxylation by high- and low-affinity components indicated that both mitochondrial and microsomal cytochrome Ps metabolize melatonin princi- pally by 6-hydroxylation, with O-demethylation representing minor metabolism Ma et al.

    In the kynuric pathway, melatonin can be converted either enzymatically or non-enzymatically to N1-acetyl-N2-formylmethoxykynuramine AFMK , in a process that encompasses generation of 3-hydroxymelatonin, 2-hydroxymelatonin, melatonin 2-indolinone, 3-hydroxymelatonin, 2-indolinone, and melatonin dioxe- tane as intermediate products Hardeland et al. AFMK synthesis involves enzymes or pseudoenzymes such as cyto- chrome c, horseradish peroxidase, indoleamine dioxygenase, myeloperoxidase, oxoferryl hemoglobin, or hemin as well as nonenzymatic pathway that may be activated in the presence of reactive oxygen species ROS or UVB Fischer et al.

    Melatonin metabolites 5-methoxytryptamine 5-MTT and 5-methoxytryptophol 5-MTOL have been detected in cultured mammalian skin fragments and mela- noma cells Slominski et al. It was shown that cutaneous degradation of melatonin may also include pathways known to be operative in the liver and kidney Grace et al. This shows that indolic degradative pathway is operating in the skin Fischer et al. However, experiments with cultured human immortalized keratinocytes have shown that melatonin is mostly metabolized to 2-hydroxymelatonin and AFMK by the kynuric pathway or through direct non- enzymatic action of UVB Fischer et al.

    Based on the above, together with the known mechanism for melatonin degradation or transformation in peripheral organs, we proposed that in the skin melatonin can be metabolized via alternative pathways including nonenzymatic reactions Fig.