Deletion of δ-opioid receptor in mice alters skin differentiation and delays wound healing

Bigliardi-Qi, Mei; Gavériaux‐Ruff, Claire; Zhou, Hayan; Hell, Clarisse; Bady, Pierre; Rufli, T; Kieffer, Brigitte L.; Bigliardi, Paul L.

doi:10.1111/j.1432-0436.2006.00065.x

Cited by 65 publications

(75 citation statements)

References 31 publications

(32 reference statements)

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“…Thus, in addition to the analgesic, anxiolytic, d-Opioid Receptor Pharmacology and antidepressant actions (Ribeiro et al, 2005;Hsu et al, 2015) that were mentioned in previous sections, opioids also promote cell survival (Hayashi et al, 2002;Ma et al, 2005), cardioprotection (Ikeda et al, 2006;Tsutsumi et al, 2010;Headrick et al, 2015), neuroprotection (He et al, 2013b;Liu et al, 2015), modulation of the immune/inflammatory response (Neptune and Bourne, 1997;Hedin et al, 1999;Sharp, 2006;Wang et al, 2014), and wound healing (Bigliardi-Qi et al, 2006;Iaizzo et al, 2012;Bigliardi et al, 2015). At the cellular level, a majority of these responses are mediated by an evolutionarily conserved set of kinase cascades whose activation has been traditionally associated with receptor tyrosine kinases (RTKs) (Takeda et al, 2011).…”

Section: B D-opioid Receptors and Mitogen-activated Protein Kinase Smentioning

confidence: 95%

“…Consistent with these observations, organotypic skin cultures containing DOPr-overexpressing keratinocytes displayed KRT10 repression and reduced epidermal thickness . Conversely, DOPrdeficient mice exhibited markedly increased expression of KRT10, hypertrophic wound edges, and delayed wound healing (Bigliardi-Qi et al, 2006;Bigliardi et al, 2009). Although the therapeutic potential of this type of response is undeniable, DOPr effects in the human skin were opposite to those described just above , underscoring the need for a better understanding of the human neuroendocrine skin system (Slominski, 2015) before any treatment strategy in wound healing can be envisioned.…”

Section: B D-opioid Receptors and Mitogen-activated Protein Kinase Smentioning

confidence: 99%

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Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

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Section: B D-opioid Receptors and Mitogen-activated Protein Kinase Smentioning

confidence: 95%

Section: B D-opioid Receptors and Mitogen-activated Protein Kinase Smentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

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“…The G protein-coupled delta opioid receptor (DOR) not only plays a critical role in opioidmediated pain control, drug tolerance and addiction [1], but it is also associated with neuronal differentiation, cell survival, neuroprotection, and neurogenesis [2][3][4][5][6]. Nerve growth factor (NGF), which is the prototype of neurotrophins, plays a critical role in the development and maintenance of the central and peripheral nervous systems [7].…”

Section: Introductionmentioning

confidence: 99%

NGF/PI3K signaling-mediated epigenetic regulation of delta opioid receptor gene expression

Chen

Law

Loh

2008

Biochemical and Biophysical Research Communications

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The G protein-coupled delta opioid receptor gene (dor) has been associated with neuronal survival, differentiation, and neuroprotection. Our previous study identified PI3K/Akt/NF-κB signaling is a main downstream signaling pathway in nerve growth factor (NGF)-induced temporal expression of the dor gene in the PC12 cell model. It is still unknown how NGF/PI3K signaling regulates the expression of the dor gene in the nucleus. In the current study, we investigated how PI3K signaling affected epigenetic modifications of histone H3 Lys 9 (H3K9) in the 5′-UTR region of the rat dor gene locus. NGF treatment resulted in the global reversal of H3K9 trimethylation in cells. Moreover, the locus-specific reversal of H3K9 trimethylation and acetylation of H3K9 were dependent upon NGF/PI3K signaling and temporally well correlated with NGF-induced gene expression. These results indicate the importance of epigenetic modifications of H3K9, particularly the reversal of trimethylated H3K9, in the regulation of NGF/ PI3K-dependent genes during neuronal differentiation. KeywordsAkt; Chromatin remodeling; Delta opioid receptor; Histone modification; Lysine trimethylation; NF-κB; NGF; PI3KThe G protein-coupled delta opioid receptor (DOR) not only plays a critical role in opioidmediated pain control, drug tolerance and addiction [1], but it is also associated with neuronal differentiation, cell survival, neuroprotection, and neurogenesis [2][3][4][5][6]. Nerve growth factor (NGF), which is the prototype of neurotrophins, plays a critical role in the development and maintenance of the central and peripheral nervous systems [7]. The rat adrenal pheochromocytoma PC12 cell line is a well-established NGF-responsive model for the study of gene expression during neuronal differentiation and development [8]. NGF temporally induces the expression of the dor gene in PC12 cells [9][10][11]. Neurotrophins regulate the expression of many neuronal genes during neuronal development. Moreover, the dor gene is expressed both spatially and temporally in specific developmental stages [12,13]. Token together, elucidating the molecular mechanisms of NGF-induced dor gene expression might shed light on the general mechanism of neurotrophin-mediated gene expression during neuronal differentiation and development. One possible mechanism for NGF-induced gene expression in the nucleus is that the NGF signal leads to the regulation of locus-specific modifications of histone tails, which subsequently bind to the promoter of an NGF-induced gene to initiate transcription and elongation. Such epigenetic modifications of histone tails can be a critical step for NGFinduced late phase gene expression. To test this idea, we examined the global and locusspecific effects of NGF signaling on modifications of histone H3. We also analyzed the status of H3 trimethylation in the rat dor promoter region in living cells using chromatin immunoprecipitation (ChIP) assays. We provide several lines of evidence showing that NGF treatment results in modifications of H3 Lys 9 (H...

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“…Several endogenous opioids (enkephalins, endorphins, dynorphins, endomorphins) and classical (μ/MOR/Oprm1, δ/DOR/Oprd1, κ/KOR/Oprk1) opioid receptors, as well as the nuclear-associated, non-classical OGFr are present and functioning in skin [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. Enkephalins such as [Met 5 ] and [Leu 5 ]-enkephalin and the synthetic d-Ala-d-Leu-enkephalin have been reported to inhibit cell differentiation dose-dependently in human keratinocytes in vitro, while β-endorphin had no effect [38].…”

Section: Opioids Opioid Receptors Opioid Antagonists and Skinmentioning

confidence: 99%

“…Enkephalins such as [Met 5 ] and [Leu 5 ]-enkephalin and the synthetic d-Ala-d-Leu-enkephalin have been reported to inhibit cell differentiation dose-dependently in human keratinocytes in vitro, while β-endorphin had no effect [38]. Deletion of the classical opioid receptors in mice resulted in a phenotype of thinner epidermis and higher expression of differentiation markers, whereas a burn wound healed significantly slower in these KO mice relative to wildtype mice [31,32]. Naloxone and naltrexone (NTX) are general opioid antagonists that are devoid of intrinsic biological actions [39] and block the interaction of three opioid peptide families (prodynorphin, proopiomelanocortin, proenkephalin) and classical (μ, δ, κ) as well as non-classical (OGFr) opioid receptors.…”

Section: Opioids Opioid Receptors Opioid Antagonists and Skinmentioning

confidence: 99%

Opioid Antagonists Enhance Diabetic Wound Closure: A New Therapy

McLaughlin¹

2014

Transl Med (sunnyvale)

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A major complication of type 1 or type 2 diabetes involves proper healing of cutaneous wounds. Diabetic wounds heal slowly and treatments do not mediate the underlying pathophysiology. Enkephalins are reported to be elevated in diabetes and one enkephalin, opioid growth factor (OGF), serves as an inhibitory growth factor that delays cell replication. OGF interacts with its receptor, OGFr, to mediate cellular homeostasis, including wound repair. Blockade of the inhibitory function of OGF using the antagonist naltrexone (NTX) accelerates cell proliferation in a receptormediated, non-toxic manner. Topical application of NTX to full-thickness cutaneous wounds in type 1 diabetic rats and type 2 diabetic mice accelerated three phases of wound closure that are normally [defective, retarded] in diabetes including initial re-epithelialization, new blood vessel formation, and establishment of granulation tissue and integrity of the skin. These data support observations that a novel biological pathway is impaired under diabetic conditions and can be corrected by topical NTX to accelerate diabetic wound healing.

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Deletion of δ-opioid receptor in mice alters skin differentiation and delays wound healing

Cited by 65 publications

References 31 publications

Molecular Pharmacology ofδ-Opioid Receptors

Molecular Pharmacology ofδ-Opioid Receptors

NGF/PI3K signaling-mediated epigenetic regulation of delta opioid receptor gene expression

Opioid Antagonists Enhance Diabetic Wound Closure: A New Therapy

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