Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Seven patients with nodular prurigo, five patients with lichenified eczema and seven control volunteers were studied immunohistochemically using antisera to the pan-neuronal marker protein gene product 9.5 (PGP), and the neuropeptides calcitonin gene-related peptide (CGRP), substance P (SP), tyrosine hydroxylase (TH), vasoactive intestinal polypeptide (VIP) and the C-flanking region of neuropeptide Y (C-PON). PGP-, CGRP- and SP-immunoreactivities were also evaluated using image analysis quantification, and the data compared by statistical analysis. No significant changes were noted in the lichenified skin of patients with chronic eczema, compared with the control groups. In contrast, a significant increase in PGP immunoreactive nerve fibers was seen in lesional skin of all nodular prurigo cases studied, when compared with non-lesional skin from the same patient or from control subjects (P < 0.001). In one case massive neural hyperplasia was also identified. Staining for CGRP and SP showed a large increase of immunoreactive nerves in lesional skin of nodular prurigo patients, which closely paralleled that of PGP. Staining with VIP, C-PON and TH was similar in both lesional and non-lesional skin. These results indicate that neural changes in nodular prurigo are associated with an increase of sensory neuropeptides, which could be related to the intense pruritus which accompanies nodular prurigo. The absence of significant changes in lichenified skin suggests that the increase in CGRP- and SP-immunoreactive nerve fibres is a characteristic feature of nodular prurigo and may be important in its pathogenesis.
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PMID:Increased sensory neuropeptides in nodular prurigo: a quantitative immunohistochemical analysis. 141 54

Neuropeptides in primary afferent neurons have been found to be engaged in the immediate type of hypersensitivity. However, their role in the delayed form of hypersensitivity is not yet established. The hypothesis that substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP) are involved in delayed hypersensitivity was tested in oxazolone-induced, murine ear allergic contact dermatitis. Concentrations of immunoreactive SP, NKA, and CGRP were measured in extracts of the eczema ears (n = 26), whereas extracts of the opposite ears were used as controls. The SP, NKA, and CGRP contents in the treated ears were on the average 28% (p = 0.001), 32% (p = 0.004), and 15% (p = 0.016), respectively, lower than in the control ears. Lower peptide concentrations in the eczema ears indicate increased release of the peptides because the peptides are rapidly metabolized locally when released and only replenished by axonal transport from the cell bodies. Our results indicate that peptides released from primary afferent neurons play a role in the delayed type of hypersensitivity reactions.
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PMID:Tachykinins and calcitonin gene-related peptide in oxazolone-induced allergic contact dermatitis in mice. 169 38

The neuropeptides vasoactive intestinal polypeptide (VIP), substance P and somatostatin were studied in skin biopsies from patients with eczema, psoriasis and axillary hyperhidrosis. VIP concentrations were elevated in skin affected by eczema and psoriasis, whereas substance P and somatostatin levels did not differ from controls. There was a higher concentration of VIP, but not of substance P or somatostatin, in normal axillary skin when compared to adjacent trunk skin, with abundant VIP-containing fibres surrounding eccrine sweat glands. The VIP concentration was unchanged in skin affected by axillary hyperhidrosis. VIP may increase local blood flow in eczema and psoriasis, but does not appear to play a role in axillary hyperhidrosis.
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PMID:Neuropeptides in skin disease: increased VIP in eczema and psoriasis but not axillary hyperhidrosis. 171 21

Mast cells are involved in atopic disorders, often exacerbated by stress, and are located perivascularly close to sympathetic and sensory nerve endings. Mast cells are activated by electrical nerve stimulation and millimolar concentrations of neuropeptides, such as substance P (SP). Moreover, acute psychological stress induces CRH-dependent mast cell degranulation. Intradermal administration of rat/human CRH (0.1-10 microM) in the rat induced mast cell degranulation and increased capillary permeability in a dose-dependent fashion. The effect of CRH on Evans blue extravasation was stronger than equimolar concentrations of the mast cell secretagogue compound 48/80 or SP. The free acid analog of CRH, which does not interact with its receptors (CRHR), had no biological activity. Moreover, systemic administration of antalarmin, a nonpeptide CRHR1 antagonist, prevented vascular permeability only by CRH and not by compound 48/80 or SP. CRHR1 was also identified in cultured leukemic human mast cells using RT-PCR. The stimulatory effect of CRH, like that of compound 48/80 on skin vasodilation, could not be elicited in the mast cell deficient W/Wv mice but was present in their +/+ controls, as well as in C57BL/6J mice; histamine could still induce vasodilation in the W/Wv mice. Treatment of rats neonatally with capsaicin had no effect on either Evans blue extravasation or mast cell degranulation, indicating that the effect of exogenous CRH in the skin was not secondary to or dependent on the release of neuropeptides from sensory nerve endings. The effect of CRH on Evans blue extravasation and mast cell degranulation was inhibited by the mast cell stabilizer disodium cromoglycate (cromolyn), but not by the antisecretory molecule somatostatin. To investigate which vasodilatory molecules might be involved in the increase in vascular permeability, the CRH injection site was pretreated with the H1-receptor antagonist diphenhydramine, which largely inhibited the CRH effect, suggesting that histamine was involved in the CRH-induced vasodilation. The possibility that nitric oxide might also be involved was tested using pretreatment with a nitric oxide synthase inhibitor that, however, increased the effect of CRH. These findings indicate that CRH activates skin mast cells at least via a CRHR1-dependent mechanism leading to vasodilation and increased vascular permeability. The present results have implications for the pathophysiology and possible therapy of skin disorders, such as atopic dermatitis, eczema, psoriasis, and urticaria, which are exacerbated or precipitated by stress.
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PMID:Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects. 942 40

Neuropeptides mediate stress-induced cutaneous inflammation such as atopic dermatitis. The effect of substance P on proliferation and cytokine mRNA expression of peripheral blood mononuclear cells in response to Dermatophagoides farinae (Der f) was studied in atopic dermatitis patients with positive RAST scores to Der f. Upon stimulation with Der f peripheral blood mononuclear cells from patients proliferated in a B7-dependent (CD80- and CD86-dependent) manner, while those from the patients with negative scores, nonatopic eczematous dermatitis patients or normal individuals, did not. Based on the reactivity of normal individuals, atopic dermatitis patients with a stimulation index greater than 1.8 were tentatively defined as high responders, who comprised two-thirds of the patients. Proliferation in high responders was associated with upregulation of IL-2 mRNA expression and induction of IL-5 mRNA expression. Substance p at 10(-10) to 10(-8) M promoted the Der f-induced proliferation when added at the start of culture and upregulated IL-10 MRNA expression while downregulating IL-5 mRNA expression. Our results suggest that substance P modifies immune responses of atopic T cells to Der f by promoting proliferation and altering cytokine profiles, and thus modulates the clinical manifestations of atopic dermatitis.
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PMID:Regulation of peripheral blood mononuclear cell responses to Dermatophagoides farinae by substance P in patients with atopic dermatitis. 961 38

Itching reflects a distinct quality of cutaneous nociception elicited by chemical or other stimuli to neuronal receptors at the superficial layers of the skin and muco-cutaneous orifices. Although recent experimental studies of the conduction and perception of itch have yielded deeper insight into the physiology of this sensory quality, little is known about the neuromechanisms involved in pruritus accompanying many inflammatory skin diseases, in particular, in atopic eczema. Previous case-control studies of our research group with patients suffering from atopic eczema (AE) revealed significantly diminished itch perception after iontophoretic application of different doses of histamine as well as substance P (i.c. injected). Further experiments using acetylcholine (ACh, i.c.) clearly demonstrated that ACh elicits pruritus instead of pain in patients with AE. The first part of the present review deals with the results of our most recent case-control studies on histamine-induced itch perception in atopics devoid of eczema as well as in patients with urticaria or psoriasis compared to atopics with or without manifest eczema. We demonstrated that both focal itch and perifocal alloknesis (i.e., itch elicited by a slight mechanical, otherwise non-itching stimulus) were significantly reduced in eczema-free atopics yet were normal in non-atopics suffering from urticaria or psoriasis. In further studies using ACh i.c. injected into the uninvolved skin of patients with AE, lichen ruber, psoriasis, type IV contact eczema, or non-specific nummular eczema (n = 10/each group), all the atopics and 6/10 psoriatics felt itch instead of burning pain, but none of the others did. Different doses of vasoactive intestinal peptide (VIP) i.c. applied to the controls and the atopics with or without eczema did not markedly increase the intensity of nociceptive sensations. However, ACh induced pain in the controls, pure pruritus in the atopics with acute eczema, and a 'mixture' of pain and itch in the atopics just free from eczema. Obviously, the quality of sensations evoked by ACh and VIP depends on the inflammatory or non-inflammatory state of the atopic skin. In a placebo-controlled, double blind study on histamine-induced focal itch and alloknesis with healthy subjects (n = 15) using naltrexone (opioid receptor antagonist) and cetirizine (H1-blocking agent), naltrexone was found to significantly reduce both itching and alloknesis. Cetirizine reduced focal itch but failed to influence the alloknesis phenomenon. The wheal and flare reaction was suppressed only by cetirizine. These different effects point to a mainly CNS-based activity of naltrexone but a peripheral level effect of cetirizine. Due to long-lasting experience with group sport as a supporting adjuvant for inpatients with AE, we evaluated, by clinical, psychometric, and physiological studies, the therapeutic efficacy of controlled physical exercise in addition to otherwise equal anti-eczematous therapy for both voluntary participants and non-participants in sports by performing several case-control studies, one followed-up to 6 months after the patients' discharge from the hospital. Regular moderate exercises neither deteriorated nor impeded the recovery from AE, ameliorated the participants' scratch controlling ability and significantly their depressed emotional mood. The non-participants failed to achieve these aims. Sweating-induced itch was inhibited in almost all participants if simple skin care (clearing by warm shower, ointment) and short-term rest were used by informed patients. In conclusion, there are several indications that itching is elicited in individuals inclined to cutaneous atopy, regardless of their eczematous or just eczema-free state, by a different physiological pathway from that in non-atopic individuals. Therefore, antipruritic agents influencing the centrally altered nociception of atopics are needed and may be expected in near future. (ABSTRACT TRUNCATED)
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PMID:Recent studies of cutaneous nociception in atopic and non-atopic subjects. 1009 77

The association between mast cells and sensory nerves and the distribution of the neuropeptides substance P (SP), vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP) were studied immunohistochemically in lesional and nonlesional skin of 26 atopic dermatitis (AD) and 23 nonatopic nummular eczema (NE) patients. Mast cell-nerve contacts were counted morphometrically and confirmed by confocal laser scanning microscopy. Neuropeptide positivity was assessed semiquantitatively. Dermal contacts between mast cells and nerves were increased in number in both lesional and nonlesional samples of AD and NE when compared to those in normal controls, although only the values in lesional AD reached statistical significance ( P<0.05). Nerve-mast cell contacts in the basement membrane zone were seen practically only in lesional NE. SP and CGRP fibres were prominently increased in lesional samples when compared to their nonlesional controls both in AD and NE in the epidermis and in the papillary dermis. In both AD and NE, only small differences were found regarding VIP positivity in lesional and nonlesional biopsies. The epidermis was devoid of VIP positivity. In conclusion, SP and CGRP but not VIP fibres were more frequent in lesional than in nonlesional papillary dermis of both AD and NE. Since mast cells are also increased in number in lesions of AD and NE, they are able to maintain neurogenic inflammation through activation by SP and CGRP. The increased SP/CGRP nerves in the epidermis of AD and NE lesions may stimulate keratinocytes to release cytokines which affect various cell types enhancing inflammation.
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PMID:Mast cells, nerves and neuropeptides in atopic dermatitis and nummular eczema. 1270 13

Pathogenesis of atopic dermatitis involved the interactions of immune and neuroendocrine systems. Here we describe a mouse model for atopic dermatitis with concomitant neurogenic inflammation, by epicutaneous sensitization with a dust mite allergen. Allergen patching resulted in localized dermatitis characterized by pronounced epidermal hyperplasia and spongiosis, which was associated with infiltration of eosinophils and neutrophils, degranulated mast cells, CD4+ and CD8+ T cells, and dendritic cells. There was increased innervation of calcium gene related peptides and substance P in inflamed skins, interactions between nerve fibers and mast cells were seen, indicating the coexistence of neurogenic inflammation. Splenic T cells produced T helper 2-polarized cytokines in response to allergen stimulation in vitro, indicating systemic allergen sensitization. This is the first report of a mouse model of eczema, accompanied by neurogenic inflammation, which shows close resemblance to human allergic diseases. This work supports the notion that the skin is an important site for the initiation of primary allergen sensitization. Besides, this model may also be useful for study of other stress-associated neuroinflammatory skin disorders such as neurogenic pruritus and psoriasis.
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PMID:Mite allergen induces allergic dermatitis with concomitant neurogenic inflammation in mouse. 1288 Apr 20

Vernal keratoconjunctivitis (VKC) is an allergic eye disease that especially affects young boys. The most common symptoms are itching, photophobia, burning, and tearing. The most common signs are giant papillae, superficial keratitis, and conjunctival hyperaemia. Patients with VKC frequently have a family or medical history of atopic diseases, such as asthma, rhinitis, and eczema. However, VKC is not associated with a positive skin test or RAST in 42-47% of patients, confirming that it is not solely an IgE-mediated disease. On the basis of challenge studies as well as immunohistochemical and mediator studies, a Th2-driven mechanism with the involvement of mast cells, eosinophils, and lymphocytes has been suggested. Th2 lymphocytes are responsible for both hyperproduction of IgE (interleukin 4, IL-4) and for differentiation and activation of mast cells (IL-3) and eosinophils (IL-5). Other studies have demonstrated the involvement of neural factors such as substance P and NGF in the pathogenesis of VKC, and the overexpression of oestrogen and progesterone receptors in the conjunctiva of VKC patients has introduced the possible involvement of sex hormones. Thus, the pathogenesis of VKC is probably multifactorial, with the interaction of the immune, nervous, and endocrine systems. The clinical management of VKC requires a swift diagnosis, correct therapy, and evaluation of the prognosis. The diagnosis is generally based on the signs and symptoms of the disease, but in difficult cases can be aided by conjunctival scraping, demonstrating the presence of infiltrating eosinophils. Therapeutic options are many, in most cases topical, and should be chosen on the basis of the severity of the disease. The most effective drugs, steroids, should however be carefully administered, and only for brief periods, to avoid secondary development of glaucoma.A 2% solution of cyclosporine in olive oil or in castor oil should be considered as an alternative. The long-term prognosis of patients is generally good; however 6% of patients develop corneal damage, cataract, or glaucoma.
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PMID:Vernal keratoconjunctivitis. 1506 27

In the present study, eczema-induced alteration of sensorineural circuits of the spinal dorsal horn was investigated. Eczematous lesions resembling atopic dermatitis were induced by repeated application of diphenylcyclopropenone (DCP) onto murine right hind paws. Immunohistochemical labeling of calcitonin gene-related peptide and substance P was increased in the dorsal horn on the DCP-treated side. Expression of calcium binding proteins, calretinin and calbindin-D28K, normally widely seen in dorsal horn interneurons, was up-regulated on the DCP-treated side. E-Cadherin and alpha-N-catenin, synapse-related molecules, were intensely expressed in the spinal dorsal horn of the DCP-treated side. Interestingly, c-Fos positive cells were also significantly increased in laminae I and III of the DCP-treated side. These results suggest an enhanced release of neuropeptides from peripheral afferents and alterations in the sensorineural circuitry of the dorsal horn. These changes may account for the enhanced sensory sensitivity recognized in patients with chronic eczema and atopic dermatitis.
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PMID:Alteration of sensorineural circuits in spinal cord by chronic contact dermatitis. 1633 20


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