|Year : 2016 | Volume
| Issue : 6 | Page : 484-490
Biomimetic proopiomelanocortin suppresses capsaicin-induced sensory irritation in humans
Sayed Ali Fatemi1, Abbas Jafarian-Dehkordi1, Valiollah Hajhashemi1, Ali Asilian-Mahabadi2
1 Department of Pharmacology & Toxicology and Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
2 Department of Dermatology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
|Date of Web Publication||8-Dec-2016|
Department of Pharmacology & Toxicology and Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan
Source of Support: None, Conflict of Interest: None
Sensitive skin is a frequently mentioned cosmetic complaint. Addition of a biomimetic of neuromediator has recently appeared as a promising new way to cure skin care product problems. This study was aimed to assess the inhibitory effect of a biomimetic lipopeptide derived from proopiomelanocortin (bPOMC) on capsaicin-induced sensory irritation in human volunteers and also to compare its protective effect with that of the well-known anti irritant strontium chloride. The effect of each test compound was studied on 28 selected healthy volunteers with sensitive skin in accordance with a double-blind vehicle-controlled protocol. From day 1 to day 13 each group was applied the test compound (bPOMC or strontium chloride) to one wing of the nose and the corresponding placebo (vehicle) to the other side twice daily. On days 0 and 14, acute skin irritation was induced by capsaicin solution and quantified using clinical stinging test assessments. Following the application of capsaicin solution, sensory irritation was evaluated using a 4-point numeric scale. The sensations perceived before and after treatment (on days 0 and 14) was calculated for the two zones (test materials and vehicle). Ultimately the percentage of variation between each sample and the placebo and also the inhibitory effect of bPOMC compared to that of strontium chloride were reported. Clinical results showed that after two weeks treatment, the levels of skin comfort reported in the group treated with bPOMC were significantly higher than those obtained in the placebo group and the inhibitory effect of bPOMC was about 47% higher than that of strontium chloride. The results of the present study support the hypothesis that biomimetic peptides may be effective on sensitive skin.
Keywords: Sensitive skin; Anti irritation; Contact dermatitis; Proopiomelanocortin; Biomimetic peptides; Neurocosmetics
|How to cite this article:|
Fatemi SA, Jafarian-Dehkordi A, Hajhashemi V, Asilian-Mahabadi A. Biomimetic proopiomelanocortin suppresses capsaicin-induced sensory irritation in humans. Res Pharma Sci 2016;11:484-90
|How to cite this URL:|
Fatemi SA, Jafarian-Dehkordi A, Hajhashemi V, Asilian-Mahabadi A. Biomimetic proopiomelanocortin suppresses capsaicin-induced sensory irritation in humans. Res Pharma Sci [serial online] 2016 [cited 2018 May 26];11:484-90. Available from: http://www.rpsjournal.net/text.asp?2016/11/6/484/194890
| Introduction|| |
The term sensitive skin generally assigns an excessive and undesirable sensitivity of the skin to usual or prolonged use of typical products such as health and beauty products  . Management of sensitive skin is usually burdensome for both the physician and the patient. It is required to find a composition of skin care products that does not cause discomfort  .
During recent years, manufacturers of personal care products have introduced a large diversity of formulations which are created for individuals with sensitive skin. These commercially available products contain different active ingredients such as various vitamins, minerals, antioxidants, anti-inflammatory agents, traditional herbs, and a variety of peptides  . Peptide cosmeceuticals are one of the new popular achievements to treat skin inflammation and pigmentation angiogenesis , . Synthetic biomimetic peptides replicate a small, active amino acid sequence of neuromodulators and make them available in the dermis  .Neuropeptides produced by nerve cells in addition to skin and immune cells constitute preferred messengers to maintain skin balance  . Cosmetics containing synthetically produced neuropeptides are commonly indicated as neurocosmetics. approach is based This new approach is based on the interrelation between the nerve system and the skin through special mediators. Neurocosmetic actives can play an important role in skin homeostasis by activating or inhibiting these messengers (8) . Skin responses to environmental changes assigned by biological, chemical, physical or electromagnetic factors are regulated by a skin neuroendocrine system that is able to initiate adaptation mechanisms through rapid (neural) or slow (humoral) pathways acting at local or systemic levels ,, .
The role of hormones in the development of human skin and its importance to produce and release hormones are well known. Human skin cells produce insulin-like growth factors and binding proteins, proopiomelanocortin (POMC) derivatives, catecholamines, steroid hormones and vitamin D from cholesterol, eicosanoids from fatty acids, and retinoids from diet carotenoids. Hormones perform their biological effects on the skin via interaction with receptors for peptide hormones, neurotransmitters, steroid hormones and thyroid hormones [12, 13, 14] . The skin has established an independent and fully functional peripheral local stress response system equivalent to the hypothalamic-pituitary-adrenal axis  .
POMC peptides, at first detected as pituitary hormones, have been discovered in various tissues as well as the skin and are expressed by melanocytes, keratinocytes, microvascular endothelial cells, adnexal epithelial cells, mast cells, Langerhans cells, fibroblasts and also by immune cells such as monocytes and macrophages , . POMC is a precursor protein produces many biologically active peptides through a series of enzymatic steps in a tissue-specific manner, resulting the melanocyte-stimulating hormones (MSHs), corticotrophin (ACTH) and ß-endorphin , .
All of the melanocortins (α, ß, and γ-melanocyte-stimulating hormone and adrenocorticotropin) have melanotropic activity but can have many other effects on skin cells. Based on in vitro and in vivo findings melanocortins have been demonstrated to regulate immune and inflammatory responses, hair growth, exocrine gland activity and extracellular matrix composition ,,, .
Biomimetic POMC (bPOMC) is derived from POMC which is a natural precursor of different neuromediators with important roles in skin physiology. In vitro, POMC binds and activates the melanocortin-1 receptor (MC1-R) to cause a reduction in production of inflammatory cytokines such as interleukin-8 (IL-8), without influencing melanogenesis  . IL-8 is known to be a pro-inflammatory and chemotactic cytokines recently termed chemokines. IL-8 has been involved in the pathogenesis of some inflammatory skin diseases , . Interleukin-6 (IL-6) regulates POMC expression and ACTH production in normal pituitary cells , .
Capsaicin is the prominent pungent component in red chili peppers, which has been observed to cause release of neuropeptides from sensory nerve fibers in skin. Application of capsaicin to the skin causes an enhanced sensitivity to noxious stimuli. Capsaicin binds to a receptor called the vanilloid receptor subtype 1 (TRPV1) and activates the C nerve fibers and then causes the peripheral depletion of substance P, calcitonin gene related protein (CGRP) and vasoactive intestinal peptide, thereby resulting in some redness and local swelling , . Strontium salts have been demonstrated to inhibit irritation and inflammation when applied topically. So In the present study, we applied strontium chloride as positive control  . The objective of this study was to identify and assess the inhibitory effect of bPOMC on capsaicin-induced sensory irritation in humans.
| Materials and Methods|| |
This study was designed in accordance with a double-blind, vehicle-controlled protocols. A total of 56 healthy human volunteers (36 men and 20 women, aged 26-44 years) in 2 groups of 28 volunteers each were recruited and written consent was obtained from all subjects. Volunteers were factory workers recruited from the Goltash Company with a self-reported history of "sensitive skin" and were sensitive to a prescreening lactic acid facial challenge  . The study protocol was approved by the Ethics Committee of Isfahan University of Medical Sciences (ID No: IR.MUI.REC.93.3.378(.
The following chemicals were used: bPOMC (Neutrazen TM , Lucas Meyer Cosmetics Co., France), Capsaicin (Ferndale Laboratories, USA), Strontium chloride hexahydrate (Sigma Chemicals Co., USA). Two test samples, a 2.5% bPOMC and 5% strontium salt formulations were prepared using methylcellulose viscoelastic gel. The percentage of test materials was assigned in accordance to similar studies (5,8).
Volunteers came to the laboratory without applying any face cream and signed a consent form and an information sheet.
Induction of sensory irritation
Hydroalcoholic solution of capsaicin at 3×10 -4 % was applied to both cheek sites for 10 s and then every minute up to 5 min. After the application of capsaicin, sensory irritation (stinging + burning + itching) was evaluated using the following sensory irritation scale: 0 = absence of sensations, 1 = slight sensations, 2 = moderate sensations, and 3 = severe sensations. An overall reactivity score at day 0 was calculated as follows:
Total score = Ʃdi = 0.17 min - 5 min (1)
Treatment of sensory irritation
Each group received facial formulation (0.1 g) containing either active ingredient bPOMC or strontium chloride to right side and corresponding placebo (vehicle) to the left side, which was applied to the cleaned cheek sites, extending from the nasolabial fold to the outer cheek by circular movements twice a day for 14 days. Sensory irritation test was performed as mentioned above and the overall reactivity score was calculated on day 14  .
The sum of scores related to each volunteer at different test times was calculated for the two zones affected by test materials and vehicle both before and after the treatment. The variation of sensations perceived before and after treatment was calculated with the following formula:
where, TSD 0 is the total score on day 0, TSD 14 is the total score on day 14, P is the product zone, and V is the vehicle zone. The percentage of variations compared to the placebo was calculated as follows:
Abbreviations are as previously described.
Statistical analysis enables determination of the significance of differences observed for the effect of test materials vs placebo after 14 days of twice daily applications. The comparison involved the differences in the zone treated with the product and the zone treated with the placebo. Normal distribution of each quantitative variable was assessed by Kolmogorove-Smirnov test. The data was analyzed using Mann-Whitney U test for observed significance measuring between responses of the two groups. P values less than 0.05 were considered significant.
| Results|| |
Overall results are listed in [Table 1], [Table 2] and [Table 3] and illustrated in [Figure 1] and [Figure 2] . In this work, we investigated the effects of bPOMC (at 2.5%) on skin sensitivity in individuals exposed to stinging test compared to well-known anti-irritant compound strontium chloride (at 5%).
|Figure 1. Anti-irritant effects of bPOMC in methylcellulose viscoelastic gel on capsaicin-induced sensory irritation in human volunteers. (bPOMC) biomimetic pro-opiomelanocortin, Day 0 and Day 14 show the days of studies. All results are expressed as median (range). ∗∗ P < 0.01 compared with the vehicletreated group |
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|Figure 2. Anti-irritant effects of strontium chloride in methylcellulose viscoelastic gel on capsaicin-induced sensory irritation in human volunteers. (STC) strontium chloride, Day0 and Day14 show the days of studies. All results are expressed as median (range). ∗∗ P < 0.01 compared with the vehicle-treated group |
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|Table 1. Time course of sensory irritation after the application of a solution of capsaicin before and after 14 days of treatment with bPOMC in methylcellulose viscoelastic gel or the vehicle. (bPOMC) biomimetic proopiomelanocortin, (VbPOMC) vehicle on contralateral side of bPOMC zone. Each data point represents the median (range) irritation at each time for 28 subjects. **Significant difference (P < 0.01) was observed between formulations and vehicle |
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|Table 2. Time course of sensory irritation after the application of a solution of capsaicin before and after 14 days of treatment with strontium chloride in methylcellulose viscoelastic gel or vehicle. (STC) strontium chloride, (VSTC) vehicle on contralateral side of strontium chloride zone. Each data point represents the median (range) irritation at each time for 28 subjects. ∗∗Significant difference (P < 0.01) between formulations and vehicle |
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|Table 3. The percent reduction of total irritation score of bPOMC and strontium chloride in methylcellulose viscoelastic gel due to a solution of capsaicin. (bPOMC) biomimetic pro-opiomelanocortin, (STC) strontium chloride, (P) Significant difference between bPOMC or STC groups. All results are expressed as median (range). |
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The median of scores attributed by each volunteer at different test times was calculated for the test materials and vehicle zones both before and after the treatment and are shown in [Table 1] and [Table 2].
The median irritation sensation for bPOMC-treated zone was significantly (P < 0.01) less than that of the vehicle compared at 0.17, 2, and 3 min on day 0 and day 14 [Table 1].
The median irritation scores for strontium chloride was also significantly (P < 0.01) less than those of vehicle group, only at 0.17 min compared on day 0 and day 14 [Table 2].
[Figure 1] and [Figure 2] show the differences of total sensations perceived before and after the treatment. bPOMC thus limits irritation caused by a neurogenic substance, capsaicin, in comparison with strontium chloride and vehicle-treated groups. The bPOMC viscoelastic gel decreased the total irritation score on day 14 of the study compared to day 0 (4 for day 14 vs 8 for day 0; P < 0.01), and was superior to its own vehicle. The strontium chloride viscoelastic gel decreased the total irritation score on day 14 of the study compared to day 0 (4 for day 14 vs 7 for day 0; P < 0.01), and was superior to its own vehicle.
Clinical results showed that after a 14-day treatment, the levels of skin comfort reported in the group treated with bPOMC were significantly (87%) higher than those obtained in the vehicle group [Table 3]. T he differences of sensations distinguished before and after 14 days of treatment by strontium chloride was significantly better than vehicle (40%) [Table 3].
The data demonstrate that both bPOMC and strontium chloride caused inhibition of the uncomfortable sensations caused by the application of a 3×10 -4 % solution of capsaicin on the wings of the nose. The results suggest that bPOMC is more effective than strontium chloride.
| Discussion|| |
The field of biomimetic neurocosmetics has recently appeared as an encouraging new way to overcome cosmetic problems through an action on the cutaneous nervous system. But not much work has been done in this field and their benefits have not been conclusively demonstrated. Our research for the first time measured the efficacy of bPOMC on capsaicin-induced sensory irritation in humans. Considering the sensory irritation is a subjective symptom, there is a high degree of variation between individuals. To quantify this subjective data, we utilized a 0-3 grade scale to evaluate the sensations after 0.17 min, and then every minute up to 5 min post-application of test materials. We supposed this scale could better quantify small changes in subjective responses (33-35).
Evidences suggest that various neuropeptides and neurohormones play a significant immunoregulatory role and the complex cascade of interacting mediators is involved in the physiopathology of sensitive skin ,. The physiopathology of sensitive skin includes a nonspecific reaction related to cutaneous sensory innervation through unmyelinated (C) or myelinated (Aδ) fibers responding to a range of chemicals and physiologic stimulants . Response to noxious stimuli, substance P and CGRP lead to vasodilatation and mast cell degranulation activating a process called neurogenic inflammation [9,37]. Classical pathways are then triggered causing a nonspecific inflammation as a result of released eicosanoids and cytokines such as prostaglandin-E2, prostaglandin-F2, tumor necrosis factor-alpha (TNF-α), interleukin-1α (IL-1α), and IL-8 . Melanocortin MC1 and MC3 receptors, mediate the anti-inflammatory effects of melanocortin peptides. Targeting these receptors could lead to development of new anti-inflammatory therapeutic agents. Furthermore, POMC activities consist of antagonism and down-regulation of adhesion molecules and reduced inflammation by modulation of IL-10 production ,.
Skin is a target organ for corticotropin-releasing hormone (CRH) and POMC peptides. Thus, the skin neuroendocrine system mediated via production of CRH hormone and POMC peptides might interact with the skin immune system and organize the skin stress response system against local stress ,. POMC peptides exert their effects via five subtypes of heterodimeric G protein-coupled receptors with seven transmembrane domains assigned as melanocortin receptors (MC-1R through MC-5R),.
bPOMC is an innovative tri-peptide of a greater category named biomimetic peptides, linked to a lipid for optimal penetration and efficacy. Biomimetic molecules are designed to mimic natural products while increasing specificity and efficacy. Biological processes in the body are being closely monitored and active molecules are being studied in search for synthetic and better analogues. The relatively recent appearance of peptides in skin care products can be explained by the need for more effective actives, for lower dosages, and for purer and better defined compounds. At the present time, such actives are being increasingly included into formulation to provide worldwide cosmetic products ,.
Our results show that bPOMC calms and soothes irritated skin and helps to maintain and restore a normal skin sensitivity threshold. bPOMC is a favorable anti-inflammatory agent without influencing melanogenesis. According to previous studies we hypothesized that biomimetic peptides exert their powerful efficacy on the reduction of capsaicin-induced inflammation, through the reduction of the consequences of substance P release and inhibit the release of IL-1-induced IL-8 production ,.
According to the studies conducted by Hahn, strontium salts can effectively suppress sensory irritation caused by chemical irritants . Papoiu et al. showed that the strontium chloride formulation was superior to hydrocortisone on the peak of skin itch intensity . So the strontium chloride was considered as positive control.
In the present study, the inhibitory effect of bPOMC was significantly 47% higher than that of strontium chloride, a well-known anti-inflammatory salt (P < 0.05). This finding suggests that bPOMC may reduce sensitive skin symptoms related to cutaneous neurogenic inflammation. So the addition of biomimetic peptides to formulations of topical products can significantly reduce the signs and symptoms of irritant contact dermatitis, which is a significant problem for many people using cosmetics and topical formulations ,. Comprehensive studies available on epidemiology of sensitive skin reveal that the hyper-reactivity of the skin is more frequently observed in women than men . So the most limitation in this study was to choose the volunteer panel composed of a bigger population of women.
| Conclusion|| |
It seems that in near future biomimetic peptides will represent a new class of inhibitors of sensory irritation and irritant contact dermatitis. Our study indicates that the addition of bPOMC to personal care products significantly reduces the sensory irritation caused by capsaicin in a comparison with strontium chloride. These clinical data can be partially explained by the in vitro findings showing the anti-inflammatory effect of biomimetic peptides. In the light of the revealed anti-irritation efficacy of bPOMC, further studies investigating the antipruritic effect of biomimetic-based formulations in acute and chronic itch conditions would be timely.
| Acknowledgements|| |
The content of this paper is extracted from the Ph.D thesis NO: 393378 submitted by Sayed Ali Fatemi which was financially supported by the Research Department of Isfahan University of Medical Sciences, Isfahan, I.R. Iran. We thank Zahra Banaei-Esfahani for statistical analysis of the data and for recruitment of volunteers for the study.
| References|| |
Farage M, Katsarou A, Maibach H. Sensory, clinical and physiological factors in sensitive skin: a review. Contact Dermatitis. 2006;55(1):1-14.
Pons-Guiraud A. Sensitive skin: a complex and multifactorial syndrome. J Cosmet Dermatol. 2004;3(3):145-148.
Kligman A, Sadiq I, Zhen Y, Crosby M. Experimental studies on the nature of sensitive skin. Skin Res Technol. 2006;12(4):217-222.
Lupo M, Cole A. Cosmeceutical peptides. Dermatol Ther. 2007;20(5):343-349.
Zhang L, Falla TJ. Cosmeceuticals and peptides. Clin Dermatol. 2009;27(5):485-494.
Xie Y, Rizzi SC, Dawson R, Lynam E, Richards S, Leavesley DI, et al
. Development of a three-dimensional human skin equivalent wound model for investigating novel wound healing therapies. Tissue Eng Part C Methods. 2010;16(5):1111-1123.
Fuller RW, Conradson TB, Dixon CM, Crossman DC, Barnes PJ. Sensory neuropeptide effects in human skin. Br J Pharmacol. 1987;92(4):781-788.
Lintner K, Mas-Chamberlin C, Mondon P, Peschard O, Lamy L. Cosmeceuticals and active ingredients. Clin Dermatol. 2009;27(5):461-468.
Slominski A, Wortsman J, Paus R, Elias PM, Tobin DJ, Feingold KR. Skin as an endocrine organ: implications for its function. Drug Discov Today Dis Mech. 2008;5(2):137-144.
Elias PM. Stratum corneum defensive functions: an integrated view. J Invest Dermatol. 2005;125(2):183-200.
Slominski A, Wortsman J. Neuroendocrinology of the skin. Endocr Rev. 2000;21(5):457-487.
Zouboulis CC. Human skin: an independent peripheral endocrine organ. Horm Res. 2000;54(5-6):230-242.
Raffin-Sanson ML, de Keyzer Y, Bertagna X. Proopiomelanocortin, a polypeptide precursor with multiple functions: from physiology to pathological conditions. Eur J Endocrinol. 2003;149(2):79-90.
Luger TA, Scholzen T, Brzoska T, Becher E, Slominski A, Paus R. Cutaneous immunomodulation and coordination of skin stress responses by alpha-melanocyte-stimulating hormone. Ann N Y Acad Sci. 1998;840:381-394.
Arck PC, Slominski A, Theoharides TC, Peters EM, Paus R. Neuroimmunology of stress: skin takes center stage. ýJ Invest Dermatol. 2006;126(8):1697-1704.
Roosterman D, Goerge T, Schneider SW, Bunnett NW, Steinhoff M. Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol Rev. 2006;86(4):1309-1379.
Slominski A. Neuroendocrine system of the skin. Dermatology. 2005;211(3):199-208.
Millington GW. Proopiomelanocortin (POMC): the cutaneous roles of its melanocortin products and receptors. Clin Exp Dermatol. 2006;31(3):407-412.
Slominski A, Wortsman J, Luger T, Paus R, Solomon S. Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress. Physiol Rev. 2000;80(3):979-1020.
Bohm M, Luger TA. The role of melanocortins in skin homeostasis. Horm Res. 2000;54(5-6):287-293.
Altemus M, Rao B, Dhabhar FS, Ding W, Granstein RD. Stress-induced changes in skin barrier function in healthy women. J Invest Dermatol. 2001;117(2):309-317.
Slominski A, Wortsman J, Tuckey RC, Paus R. Differential expression of HPA axis homolog in the skin. Mol Cell Endocrinol. 2007;265-266:143-149.
Böhm M, Luger TA, et al. Cutaneous neuromodulation: the proopiomelanocortin system. Exp Clin Endocrinol Diabetes. 1999;107:225-228.
Luger TA. Neuromediators - a crucial component of the skin immune system. J Dermatol Sci. 2002;30(2):87-93.
Kondo S, Kono T, Sauder DN, McKenzie RC. IL-8 gene expression and production in human keratinocytes and their modulation by UVB. J Invest Dermatol. 1993;101(5):690-694.
Böhm M, Schulte U, Kalden H, Luger TA. Alpha-melanocyte-stimulating hormone modulates activation of NF-êB and AP-1 and secretion of interleukin-8 in human dermal fibroblasts. Ann N.Y Acad Sci. 2006;885:277-286.
Clausen BE, Girard-Madoux M. IL-10 control of dendritic cells in the skin. Oncoimmunology. 2013;2(3):e23186.
Laouini D, Alenius H, Bryce P, Oettgen H, Tsitsikov E, Geha R. IL-10 is critical for Th2 responses in a murine model of allergic dermatitis. J Clin Invest. 2003;112(7):1058-1066.
Nakagawa H, Hiura A. Capsaicin, transient receptor potential (TRP) protein subfamilies and the particular relationship between capsaicin receptors and small primary sensory neurons. Anat Sci Int. 2006;81(3):135-155.
Bode AM, Dong Z. The two faces of capsaicin. Cancer Res. 2011;71(8):2809-2814.
Schliemann S, Antonov D, Manegold N, Elsner P. The lactic acid stinging test predicts susceptibility to cumulative irritation caused by two lipophilic irritants. Contact Dermatitis. 2010;63(6):347-356.
Papoiu AD, Valdes-Rodriguez R, Nattkemper LA, Chan YH, Hahn GS, Yosipovitch G. A novel topical formulation containing strontium chloride significantly reduces the intensity and duration of cowhage-induced itch. Acta Derm Venereol. 2013;93(5):520-526.
Willis CM, Shaw S, De Lacharriere O, Baverel M, Reiche L, Jourdain R, et al.
Sensitive skin: an epidemiological study. Br J Dermatol. 2001;145(2):258-263.
Diogo L, Papoila AL. Is it possible to characterize objectively sensitive skin? Skin Res Technol. 2010;16(1):30-37.
Dieamant Gde C, Velazquez Pereda Mdel C, Eberlin S, Nogueira C, Werka RM, Queiroz ML. Neuroimmunomodulatory compound for sensitive skin care: in vitro and clinical assessment. J Cosmet Dermat. 2008;7(2):112-119.
Primavera G, Berardesca E. Sensitive skin: mechanisms and diagnosis. Int J Cosmet Sci. 2005; 27(1):1-10.
Misery L, Myon E, Martin N, Consoli S, Boussetta S, Nocera T, et al
. Sensitive skin: psychological effects and seasonal changes. J Eur Acad Dermatol Venereol. 2007;21(5):620-628.
Peters EM, Ericson ME, Hosoi J, Seiffert K, Hordinsky MK, Ansel JC, et al.
Neuropeptide control mechanisms in cutaneous biology: physiological and clinical significance. J Invest Dermatol. 2006; 126(9):1937-1947.
Luger TA, Lotti T. Neuropeptides: Role in inflammatory skin diseases. J Eur Acad Dermatol Venereol. 1998;10(3):207-211.
Kono M, Nagata H, Umemura S, Kawana S, Osamura RY. In situ expression of corticotropin-releasing hormone (CRH) and proopiomelanocortin (POMC) genes in human skin. FASEB J. 2001;15(12):2297-2299.
Luger TA, Scholzen T, Grabbe S. The role of á-melanocyte-stimulating hormone in cutaneous biology. J Investig Dermatol Symp Proc. 1997;2(1):87-93.
Catania A, Gatti S, Colombo G, Lipton JM. Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol Rev. 2004;56(1):1-29.
Hahn GS. Strontium is a potent and selective inhibitor of sensory irritation. Dermatol Surg. 1999;25(9):689-694.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]