Expression of μ-Opiate Receptor in Human Epidermis and Keratinocytes

Bigliardi, Paul L.; Bigliardi-Qi, Mei; Buechner, Stanislaus; Rufli, T

doi:10.1046/j.1523-1747.1998.00259.x

Cited by 107 publications

(92 citation statements)

References 21 publications

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“…Figure 1a demonstrates the expression of µ-opiate receptor in the suprabasal layers of normal epidermis as it was shown before [3]. The µ-opiate receptor expression in epidermis of atopic dermatitis, shown in figure 1b, reveals a significant downregulation of this receptor.…”

Section: Resultsmentioning

confidence: 54%

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Changes of Epidermal Mu-Opiate Receptor Expression and Nerve Endings in Chronic Atopic Dermatitis

et al. 2005

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There is increasing evidence that neuropeptides such as a substance P, neurotrophins or β-endorphin, an endogenous agonist for µ-opioid receptor, are involved in the pathogenesis of atopic dermatitis in which mental stress and scratching deteriorate the disease. µ-Opioid receptor, a G-protein-coupled receptor, can be downregulated and internalized by agonists and other factors in vitro. In this study, we investigated the regulation of µ-opioid receptor and nerve endings in atopic dermatitis patients. Skin biopsies from atopic dermatitis patients revealed a significant downregulation of µ-opiate receptor expression in epidermis of atopic dermatitis. Permeabilization of the skin showed that the receptor in keratinocytes from atopic dermatitis is internalized. The mRNA expression pattern of the µ-opiate receptor is different in epidermis taken from patients with chronic atopic dermatitis compared to normal skin. In atopic dermatitis, the mRNA is concentrated in the subcorneal layers of the epidermis and in normal skin in the suprabasal layers. Staining of the nerve endings using protein gene product 9.5 shows a different pattern of epidermal nerve endings in normal skin compared to atopic dermatitis. In normal skin, the epidermal nerve endings are rather thick. However, in atopic dermatitis, the epidermal nerve endings are thin and run straight through the epidermis. Based on these observations and combining the ‘intensity’ and ‘pattern’ hypothesis, we propose a new theory especially for histamine-unrelated, peripheral induction of chronic pruritus. We suggest that ‘itch’ is elicited in the epidermal unmyelinated nerve C-fibers and ‘pain’ in the dermal unmyelinated nerve fibers. The downregulation of the opioid receptor in the epidermis contributes to the chronic itching. We call this new hypothesis the ‘layer hypothesis’.

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Section: Resultsmentioning

confidence: 54%

“…We have previously demonstrated that human epidermal keratinocytes express the µ-opiate receptor at both the mRNA and protein levels [3]. The µ-opiate receptor is expressed in all layers of the epidermis.…”

Section: Introductionmentioning

confidence: 99%

Changes of Epidermal Mu-Opiate Receptor Expression and Nerve Endings in Chronic Atopic Dermatitis

et al. 2005

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“…Immunohistochemistry studies in the skin have demonstrated the presence of multiple neuropeptides, neurotransmitters, and neurohormones in sensory nerves including substance P (SP), neurokinin A (NKA) (180), neurotensin, CGRP, VIP, pituitary adenylate cyclase activating polypeptide (PACAP) (549,809), peptide histidine-isoleucinamide (PHI), NPY (380), somatostatin (SST) (76), ␤-endorphin, enkephalin, galanin, dynorphin, secretoneurin, ACh, epinephrine, norepinephrine (NE), ␣-or ␥-melanocyte-stimulating hormone (MSH) (386, 497), and corticotropin-releasing hormone (CRH) (64,240,743,768,769,845). Colocalization of distinct neuropeptides can be observed in different tissues including the skin.…”

Section: B Cutaneous Neuropeptides and Neuropeptide Receptor Biologymentioning

confidence: 99%

Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ

Roosterman¹,

Goerge

Schneider

et al. 2006

Physiological Reviews

548

521

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This review focuses on the role of the peripheral nervous system in cutaneous biology and disease. During the last few years, a modern concept of an interactive network between cutaneous nerves, the neuroendocrine axis, and the immune system has been established. We learned that neurocutaneous interactions influence a variety of physiological and pathophysiological functions, including cell growth, immunity, inflammation, pruritus, and wound healing. This interaction is mediated by primary afferent as well as autonomic nerves, which release neuromediators and activate specific receptors on many target cells in the skin. A dense network of sensory nerves releases neuropeptides, thereby modulating inflammation, cell growth, and the immune responses in the skin. Neurotrophic factors, in addition to regulating nerve growth, participate in many properties of skin function. The skin expresses a variety of neurohormone receptors coupled to heterotrimeric G proteins that are tightly involved in skin homeostasis and inflammation. This neurohormone-receptor interaction is modulated by endopeptidases, which are able to terminate neuropeptide-induced inflammatory or immune responses. Neuronal proteinase-activated receptors or transient receptor potential ion channels are recently described receptors that may have been important in regulating neurogenic inflammation, pain, and pruritus. Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin. A deeper understanding of cutaneous neuroimmunoendocrinology may help to develop new strategies for the treatment of several skin diseases.

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“…3,4) These reports indicate that the MOR agonists are useful analgesics in the periphery, especially against the inflammatory tissues.…”

mentioning

confidence: 99%

New .MU.-Opioid Receptor Agonists with Piperazine Moiety.

Komoto

Okada

Satô

et al. 2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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Recently, it has been reported that morphine, a representative m-opioid receptor (MOR) agonist, showed an analgesic activity in the periphery in mice.1) Additionally it has been recognized that tolerance to the peripheral analgesia was not developed after the repeated administration of morphine in mice.2) Furthermore, it has been reported that the MORs were increased around the inflammatory tissues in animals and humans.3,4) These reports indicate that the MOR agonists are useful analgesics in the periphery, especially against the inflammatory tissues.On the other hand, there are nonsteroidal antiinflammatory drugs (NSAIDs) as peripheral analgesics but they do not have an analgesic efficacy toward some serious peripheral inflammations.5) Therefore, we think that in the serious inflammation cases such as severe burns and grazes, MOR agonists can be effective medicines.As MOR agonists not having the morphinane structures, fentanyl, 6) loperamide 7) and diphenoxylate 8,9) are known. As for fentanyl, to improve the quality of life for cancer patients with pain, the plaster, 10) which has an analgesic activity that lasts for far seventy-two hours, has been developed so the patients do not need to go frequently to the hospital. Although loperamide and diphenoxylate are MOR agonists, they do not easily pass through the blood-brain barrier (BBB). Therefore, they are mainly used as antidiarrheals now.Recently, it has also been reported that when loperamide was administered to a burn on a rat as a peripheral percutaneous cream, it was effective and could not easily pass through the BBB so the manifestation of tolerance did not occur. 11)Therefore, our final objective is the synthesis of MOR agonists having peripheral analgesic activity, and as the first step, we intended to synthesize compounds having more potent activities than loperamide in the two in vitro tests mentioned in the above summary. The three compounds mentioned above have a piperidine moiety in their structures. Currently there is no compound having a piperazine moiety in the structure as a MOR agonist on the market. Therefore, we started to synthesize compounds having a piperazine moiety in their structures. In this paper, we describe the synthesis of the compounds and their affinities to the human MOR and dand k-opioid receptors (DOR and KOR) expressed in CHO cells and their agonist activities on MOR in guinea-pig ileum. ChemistryTo develop our new MOR agonists instead of the already known MOR agonists not having morphinane structures, we thought that our compounds had to have a structural feature. Therefore, based on the knowledge already known, we designed the piperazine (nϭ1) or homopiperazine (nϭ2) derivatives, which have side chains of fentanyl, diphenoxylate and loperamide on a nitrogen with another nitrogen directly connected to various aromatic rings including the heteroaromatic rings.Considering the novelty of our compounds, we first selected the heteroaryl groups as aryl groups. It has been well known that a halogen located in the a-or g-positio...

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Expression of μ-Opiate Receptor in Human Epidermis and Keratinocytes

Cited by 107 publications

References 21 publications

Changes of Epidermal Mu-Opiate Receptor Expression and Nerve Endings in Chronic Atopic Dermatitis

Changes of Epidermal Mu-Opiate Receptor Expression and Nerve Endings in Chronic Atopic Dermatitis

Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ

New .MU.-Opioid Receptor Agonists with Piperazine Moiety.

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