Molecular characterization and distribution of the opioid growth factor receptor (OGFr) in mouse

Zagon, Ian S.; Verderame, Michael F.; Zimmer, Warren E.; McLaughlin, Patricia J.

doi:10.1016/s0169-328x(00)00232-1

Cited by 32 publications

(21 citation statements)

References 51 publications

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“…These findings have demonstrated that the δ-opioid receptor plays a significant role in the growth and maintenance of cells. In addition to the central nervous system and heart, δ-opioid receptors are abundantly expressed in the liver (8,9). It has been recently discovered that the δ-opioid receptor affects the generation and progression of hepatic tumors, viral hepatitis, liver cirrhosis and other diseases (10,11).…”

Section: Introductionmentioning

confidence: 99%

Activation of the δ-opioid receptor inhibits serum deprivation-induced apoptosis of human liver cells via the activation of PKC and the mitochondrial pathway

Wang¹

2011

Int J Mol Med

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Abstract. Apoptosis of human liver cells is commonly found in liver diseases and liver surgery and directly affects their prognosis. Recent studies have found that δ-opioid receptors, abundant in the membranes of hepatic cells, participate in the oncogenesis and progression of liver tumors, viral hepatitis, liver cirrhosis and other diseases. The purpose of this study was to analyze the effect of the activation of the δ-opioid receptor on liver cell apoptosis and explore its relationship with PKC and the mitochondrial pathway. Hepatic cells were serum-deprived to induce apoptosis in vitro. During the period of apoptosis, mitochondrial membrane potential decreased, protein levels of cytosolic cytochrome c increased and the expression of Bcl-2 decreased, indicating that apoptosis was specifically induced by the mitochondrial pathway. Importantly, activation of δ-opioid receptors reversed the apoptotic state of hepatic cells. Following δ-opioid receptor activation, the mitochondrial membrane potential remained stable, and the expression of cytosolic cytochrome c and Bax decreased. These data suggest that δ-opioid receptor activation specifically inhibits the mitochondrial apoptotic pathway. In addition, activation of the δ-opioid receptor apparently increased the levels of PKC; blocking the PKC pathway led to increased apoptosis of liver cells, which was not affected by the activation of δ-opioid receptor. Blocking the PKC pathway led to increased apoptosis of liver cells, which was associated with δ-opioid receptor activation. Therefore, the PKC pathway is involved in the anti-apoptotic effects of the δ-opioid receptor on liver cells.

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Section: Introductionmentioning

confidence: 99%

Activation of the δ-opioid receptor inhibits serum deprivation-induced apoptosis of human liver cells via the activation of PKC and the mitochondrial pathway

Wang¹

2011

Int J Mol Med

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“…OGF interacts with the OGF receptor to influence growth. This receptor has recently been cloned and sequenced in rat [18], mouse [19], and human [20], and its chromosomal location in humans identified as 20q13.3 [20]. The OGF receptor has no homology or motifs in common with classical opioid receptors.…”

Section: Introductionmentioning

confidence: 99%

Exposure to the Opioid Antagonist Naltrexone throughout Gestation Alters Postnatal Heart Development

McLaughlin

2002

Neonatology

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The influence of endogenous opioid blockade by naltrexone during prenatal life on postnatal heart development was studied in rats. Pregnant Sprague-Dawley rats received daily injections of 50 mg/kg naltrexone (NTX) or saline throughout gestation; offspring were cross-fostered at birth to mothers not receiving NTX. In general, NTX-treated offspring weighed more than controls throughout preweaning life, whereas heart weights were often increased from age-matched controls up to 35 days. Biochemical analyses of nucleic acids and protein demonstrated that DNA and protein content were increased throughout development in NTX-treated animals relative to controls. Morphometric analyses revealed increases in total area of the heart and myocardial area in NTX-exposed rats relative to control levels. These data suggest that endogenous opioids function to regulate cardiac growth during the prenatal period, and that disruption of this process has long-term implication for cardiac biology.

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“…The opioid growth factor‐receptor (OGFR or ζ‐opioid receptor) is a non‐canonical, peri‐nuclear opioid‐receptor that does not share structural homology with the canonical μ‐, κ‐, and δ‐opioid‐receptors (OPRM, OPRK, and OPRD, respectively) and binds the native opioid‐ligands less efficiently than the canonical opioid receptors . The opioid growth factor (OGF or met‐5 enkephalin; met5) is the native ligand for the OGFR . Met5 is derived from the pro‐hormone pro‐enkephalin (PENK) and to a lesser extent pro‐opiomelanocortin (POMC), which are first reduced by prohormone convertase (PCSK1 and PCSK2) and then carboxypeptidase E or D (CPE or CPD; enkephalin convertase) to form five copies of met5‐enkephalin .…”

mentioning

confidence: 99%

“…This led us to hypothesize that the opioid antagonists would function to stimulate bone formation by regulating MSC differentiation into osteoblasts. The opioid‐analogue antagonists, that include naloxone, have been observed to bind the OGFR with greater affinity than the canonical opioid‐receptors (OPRM, OPRK, or OPRD); however, it remains to be elucidated if opioid antagonism directly results in an osteogenic effect . Cheng et al found that met5 inhibited cell proliferation via activation of p21 by the OGFR .…”

mentioning

confidence: 99%

Antagonism of the Met5‐enkephalin‐opioid growth factor receptor‐signaling axis promotes MSC to differentiate into osteoblasts

Thakur

DeBoyace

Margulies

2015

Journal Orthopaedic Research

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Chronic opioid therapy is associated with bone loss. This led us to hypothesize that the opioid antagonists, that include naloxone, would stimulate bone formation by regulating MSC differentiation. The opioid growth factor receptor (OGFR) is a noncanonical opioid receptor that binds naloxone with high affinity whereas the native opioid growth factor, met5-enkephalin (met5), binds both the OGFR and the canonical delta opioid receptor (OPRD). Naloxone and an shRNA OGFR lentivirus were employed to disrupt the OGFR-signaling axis in cultured MSC. In parallel, naloxone was administered to bone marrow using a mouse unicortical defect model. OPRD, OGFR, and the met5-ligand were highly expressed in MSC and osteoblasts. A pulse-dose of naloxone increased mineral formation in MSC cultures in contrast to MSC treated with continuous naloxone or OGFR deficient MSC. Importantly, SMAD1 and SMAD8/9 expression increased after a pulse dose of naloxone whereas SMAD1, SMAD7, and ID1 were increased in the OGFR deficient MSC. Inhibited OGFR signaling decreased proliferation and increased p21 expression. The addition of naloxone to the unicortical defect resulted in increased bone formation within the defect. Our data suggest that novel mechanism through which signaling through the OGFR regulates osteogenesis via negative regulation of SMAD1 and p21. The opioid growth factor-receptor (OGFR or z-opioid receptor) is a non-canonical, peri-nuclear opioid-receptor that does not share structural homology with the canonical m-, k-, and d-opioid-receptors (OPRM, OPRK, and OPRD, respectively) and binds the native opioid-ligands less efficiently than the canonical opioid receptors.

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Molecular characterization and distribution of the opioid growth factor receptor (OGFr) in mouse

Cited by 32 publications

References 51 publications

Activation of the δ-opioid receptor inhibits serum deprivation-induced apoptosis of human liver cells via the activation of PKC and the mitochondrial pathway

Activation of the δ-opioid receptor inhibits serum deprivation-induced apoptosis of human liver cells via the activation of PKC and the mitochondrial pathway

Exposure to the Opioid Antagonist Naltrexone throughout Gestation Alters Postnatal Heart Development

Antagonism of the Met5‐enkephalin‐opioid growth factor receptor‐signaling axis promotes MSC to differentiate into osteoblasts

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