β-Endorphin Stimulates Cytokeratin 16 Expression and Downregulates μ-Opiate Receptor Expression in Human Epidermis

Bigliardi-Qi, Mei; Bigliardi, Paul L.; Eberlé, Alex N.; Büchner, S.; Rufli, T

doi:10.1046/j.1523-1747.2000.00801.x

Cited by 64 publications

(68 citation statements)

References 18 publications

(15 reference statements)

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“…The same pattern was observed in psoriatic lesional skin, i.e. µ-opiate receptor expression was significantly downregulated and cytokeratin 16 expression upregulated [4]. These results suggest that the opiate receptor system in the epidermis is functionally active and the µ-opiate receptor is involved in the pathogenesis of psoriasis, especially in terms of keratinocyte differentiation.…”

Section: Introductionsupporting

confidence: 57%

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: Introductionsupporting

confidence: 57%

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

et al. 2005

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“…A study (3) has shown that ␤-endorphin induces a downregulation of MOR, and that is consistent with our finding of a reduction in MOR expression in the myenteric plexus in SCID mice in which visceral pain thresholds were normalized 12 wk postreconstitution. Interestingly, as the antinociceptive effect declined at 18 wk postreconstitution, ␤-endorphin expression also declined, and there was a corresponding upregulation of MOR (22).…”

supporting

confidence: 92%

Lymphocyte-mediated regulation of β-endorphin in the myenteric plexus

Verma-Gandhu¹,

Verdú²,

Cohen-Lyons³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Verma-Gandhu M, Verdu EF, Cohen-Lyons D, Collins SM. Lymphocyte-mediated regulation of ␤-endorphin in the myenteric plexus. Am J Physiol Gastrointest Liver Physiol 292: G344 -G348, 2007. First published September 7, 2006; doi:10.1152/ajpgi.00318.2006.-Lymphocytes are antinociceptive and can modulate visceral pain perception in mice. Previously, we have shown that adoptive transfer of CD4 ϩ T cells to severe combined immune-deficient (SCID) mice normalized immunodeficiency-related visceral hyperalgesia. Pain attenuation was associated with an increase in ␤-endorphin release by T cells and an upregulation of ␤-endorphin in the enteric nervous system. In this study, we investigated the relationship between T cells and opioid expression in the myenteric plexus. We examined opioid peptide and receptor expression in the myenteric plexus in the presence and absence of mucosal T cells. We found a positive association between T cells and ␤-endorphin expression; this was accompanied by a downregulation of the -opioid receptor (MOR). In vitro, T helper (Th) type 1 and type 2 cytokine stimulation of CD4 ϩ T cells or isolation of T cells from in vivo Th-polarized mice did not increase T cell release of ␤-endorphin or the induction of ␤-endorphin expression in the myenteric plexus. However, exogenous ␤-endorphin did upregulate ␤-endorphin expression, and both cycloheximide and naloxone methiodide inhibited peptide upregulation. Therefore, our results suggest that nonpolarized CD4 ϩ T cells release ␤-endorphin, which, through an interaction with MOR, stimulates an upregulation of ␤-endorphin expression in the myenteric plexus. Thus, we propose that the mechanism underlying lymphocyte modulation of visceral pain involves T cell modulation of opioid expression in the enteric nervous system. enteric nervous system; opioid; CD4 ϩ T cells MECHANISMS INVOLVED in the homeostatic regulation of visceral pain are not well understood. Visceral pain is traditionally examined in the context of inflammation; noxious inflammatory stimuli are commonly used to evaluate the effect of acute inflammation on visceral sensitivity. Several mediators released by acute inflammatory cells either directly or indirectly stimulate sensory afferent neurons in the gut and are thus are pronociceptive. Pronociceptive mediators are also released in a healthy gut; the intestine exists in a state of controlled inflammation due to continuous immune surveillance of luminal antigens (9), and the sensory apparatus is constantly exposed to inflammatory mediators, but in the absence of pain. An antinociceptive influence originating from the periphery is a plausible explanation for the absence of hyperalgesia or allodynia in a healthy gut. We consider the immune system to be a source of this antinociception. Recently, we have provided evidence for antinociception derived from mucosal T lymphocytes. We demonstrated increased visceral sensitivity in severe combined immune-deficient (SCID) mice compared with immunocompetent wildtype mice (22). Our results demonstrated a n...

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“…However, the dose of 2 to 8 mg/kg is in the range of effective antinociceptive doses for rats and therefore probably was too high to facilitate angiogenesis. The endogenous MOR and DOR agonist ␤-endorphin was reported to stimulate the expression of cytokeratin 16 (Bigliardi-Qi et al, 2000) and transforming growth factor ␤ type II (Bigliardi et al, 2003) in human skin organ cultures. Both, CK16 and TGF␤ type II receptor are not expressed in normal skin but appear in regenerating epithelial cells of the epidermis during wound healing.…”

Section: Subanalgesic Morphine To Accelerate Healing Processesmentioning

confidence: 99%

Opioids As Modulators of Cell Death and Survival—Unraveling Mechanisms and Revealing New Indications

2004

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β-Endorphin Stimulates Cytokeratin 16 Expression and Downregulates μ-Opiate Receptor Expression in Human Epidermis

Cited by 64 publications

References 18 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

Lymphocyte-mediated regulation of β-endorphin in the myenteric plexus

Opioids As Modulators of Cell Death and Survival—Unraveling Mechanisms and Revealing New Indications

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