Agonist regulation of the expression of the delta opioid receptor in NG108‐15 cells

Kim, Dong Sun; Chin, Hemin; Klee, Werner A.

doi:10.1016/0014-5793(95)01233-6

Cited by 18 publications

(4 citation statements)

References 20 publications

(22 reference statements)

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“…However, internalization and downregulation during the first 24 h of treatment in this study did not serve as an adequate stimulus for regulation of -opioid receptor mRNA, since changes were not observed until 3 days later. Our data agree with a previous cell culture study (Kim et al, 1995) in which etorphine-induced downregulation of ␦-opioid receptor density occured within 1 day, but a decrease in ␦-receptor mRNA levels requires 3-5 days.…”

Section: Discussionsupporting

confidence: 93%

In vivo regulation of ?-opioid receptor density and gene expression in CXBK and outbred Swiss Webster mice

Duttaroy

Yoburn

2000

Synapse

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Chronic in vivo treatment with the opioid agonist etorphine downregulates -opioid receptor density, produces tolerance, and regulates gene expression in the mouse. After cessation of treatment, there is an increase in -opioid receptor mRNA level associated with the recovery of -opioid receptors. However, the effect of etorphine on the regulation of mRNA during treatment is currently not known. In this study, etorphine-induced changes in -opioid receptor density, mRNA, and opioid analgesic potency were determined in two mouse strains that differ in basal -opioid receptor density in brain. CXBK mice (-opioid receptor deficient) and outbred Swiss Webster mice were implanted s.c. with placebo pellets (controls) or etorphine minipumps (250 g/kg/day) for 1-7 days and -opioid receptor density or mRNA levels in whole brain were assessed or mice were tested for etorphine analgesia following 7 days of treatment. In control CXBK mice, -receptor density was Ϸ40% less than that for the Swiss Webster, although mRNA abundance was similar in both strains. Etorphine's potency was 4-fold greater in control Swiss Webster compared to CXBK mice. Etorphine treatment decreased (Ϸ25-40%) -receptor density similarly in both strains throughout treatment. The magnitude of analgesic tolerance to etorphine was 8-fold in both mouse strains. Etorphine produced a biphasic effect on receptor mRNA in both strains with levels decreased (25%) by 3 days and increased (30 -40%) at 7 days. mRNA levels remained elevated (55%) 16 h following the end of the 7 day etorphine treatment. Taken together, these data suggest that in vivo etorphine treatment that produces -opioid receptor downregulation and tolerance, can regulate -opioid receptor mRNA abundance. Receptor downregulation may initially induce decreases in mRNA levels since downregulation preceded a decrease in gene expression. Prolonged (Ͼ3 days) receptor downregulation may be responsible for increasing message levels and may be important in recovery of receptors following treatment. In addition, the magnitude of changes in receptor density, mRNA, and tolerance were similar in both CXBK and Swiss Webster mice, indicating that the mechanisms required for receptor regulation and its functional consequences are independent of basal -opioid receptor density. Synapse 37:118 -124, 2000.

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Section: Discussionsupporting

confidence: 93%

In vivo regulation of ?-opioid receptor density and gene expression in CXBK and outbred Swiss Webster mice

Duttaroy

Yoburn

2000

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“…This finding of a reduction in OGFr with OGF treatment is consonant with a previous report [27], wherein OGFr binding was reduced in pancreatic tumors removed from xenografted mice that were treated chronically with OGF. Furthermore, treatment with other opioids has been documented to reduce the expression of classic opioid receptors [45,46]. Therefore, in the present study it can be postulated that OGFr expression adjusts to the excess of OGF by administration of exogenous peptide, resulting in a downregulation of OGFr.…”

Section: Discussionmentioning

confidence: 66%

The Opioid Growth Factor Inhibits Established Ovarian Cancer in Nude Mice and Can Be Combined with Taxol or Cisplatin to Enhance Growth Inhibition

Donahue¹,

Zagon²,

McLaughlin³

2011

JCT

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Ovarian cancer is the 5th leading cause of cancer-related mortality in women. Seventy-five percent of ovarian cancer patients present in advanced stages, and receive cytoreductive surgery and adjuvant chemotherapy. However, within 2 years 65% of these patients relapse and thereafter only receive palliative care. Novel therapies based on the biology of these cancers are urgently needed. The opioid growth factor (OGF)-OGF receptor (OGFr) axis is an endogenous opioid system known to inhibit proliferation of human ovarian cancer cells in tissue culture, but does not affect cell survival. The present study determined whether OGF in combination with standard of care chemotherapy, provides an inhibitory effect on the growth of human ovarian cancer cells in vitro. In addition, this investigation assessed whether OGF biotherapy, alone or in combination with taxol or cisplatin, inhibits tumor growth in mice with xenografts of ovarian cancer. The combination of OGF (10–6 M) with taxol (10–9 M or 10–10 M) or cisplatin (0.01 ug/ml or 0.001 ug/ml) markedly reduced cell number and DNA synthesis in vitro to a greater extent than individual compounds. OGF, but not taxol or cisplatin, altered growth in an opioid receptor mediated and reversible manner. Female nu/nu mice inoculated subcutaneously with SKOV-3 cells, and treated with OGF (10 mg/kg) for 5 weeks commencing at the time tumors became measurable, had tumor volumes and weight that were reduced by up to 50% from animals receiving saline. The combination of OGF with taxol (3 mg/kg, weekly) or cisplatin (4 mg/kg, weekly for 2 weeks) for 37 days reduced tumor volumes and weight in contrast to mice receiving individual agents alone. Moreover, OGF treatment in mice receiving cisplatin provided protection against the weight loss associated with cisplatin alone. All treatments suppressed DNA synthesis and angiogenesis, whereas exposure to taxol or cisplatin, but not OGF, induced apoptosis. Additive inhibitory effects on DNA synthesis and angiogenesis were recorded in animals treated with both OGF and taxol, or OGF and cisplatin, in comparison to individual compounds alone. OGF and OGFr were detected in tumor tissue; however OGFr expression was reduced 51% - 81% by OGF treatment. This preclinical evidence demonstrates that OGF biotherapy markedly inhibits ovarian tumorigenesis in a non-toxic manner, and can be combined with taxol or cisplatin to provide an enhanced therapeutic benefit

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“…However, the mechanisms involved in opioid receptor regulation after opioid agonist and antagonist treatment are different. For example, opioid agonist treatment is associated with changes in gene expression of opioid receptors (Kim et al, 1995;Sehba et al, 1997;Duttaroy and Yoburn, 2000) but antagonist treatment is not (Jenab et al, 1995;Unterwald et al, 1995;however, see Brodsky et al, 1995;Castelli et al, 1997;Duttaroy et al, 1999). Thus, it was not certain that GRK-2 and DYN-2 would be involved in opioid agonist-induced OR regulation in vivo.…”

Section: Discussionmentioning

confidence: 99%

Opioid Agonists Differentially Regulate μ-Opioid Receptors and Trafficking Proteins in Vivo

Patel

Rajashekara

et al. 2002

Mol Pharmacol

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Chronic opioid agonist treatment produces tolerance and in some cases opioid receptor internalization and down-regulation. Both morphine and etorphine induce tolerance; however, only etorphine produces -opioid receptor (OR) down-regulation. In vitro studies implicate dynamin-2 (DYN-2) and Gprotein receptor kinase-2 (GRK-2) in these processes. Therefore, we examined etorphine and morphine effects on regulation of GRK-2 and DYN-2 in mouse spinal cord. Mice were treated for 7 days with etorphine (200 g/kg/day infusion) or morphine (40 mg/kg/day infusion ϩ one 25-mg implant pellet). Controls were implanted with a placebo pellet. On the 7th day after implantation mice were tested for i. determined. Both etorphine and morphine produced significant tolerance (ED 50 shift ϭ 7.6-and 7.3-fold for morphine and etorphine, respectively). Etorphine decreased spinal OR density by Ϸ30%, whereas morphine did not change OR density. Etorphine increased (Ϸ70%) DYN-2 protein abundance and decreased its mRNA (31%), whereas it had no effect on GRK-2 protein and mRNA abundance. Morphine had no effect on either DYN-2 or GRK-2 protein or mRNA abundance. These data raise the possibility that unequal receptor regulation by etorphine and morphine might be due to differential regulation of trafficking proteins. Overall, receptor down-regulation associated with chronic etorphine treatment may accelerate dynamin-related activity. Finally, the decrease in DYN-2 mRNA may be related to stabilization of DYN-2 protein abundance, which might inhibit transcription.Opioid agonists have been shown to produce tolerance and in some cases internalization and down-regulation of opioid

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Agonist regulation of the expression of the delta opioid receptor in NG108‐15 cells

Cited by 18 publications

References 20 publications

In vivo regulation of ?-opioid receptor density and gene expression in CXBK and outbred Swiss Webster mice

In vivo regulation of ?-opioid receptor density and gene expression in CXBK and outbred Swiss Webster mice

The Opioid Growth Factor Inhibits Established Ovarian Cancer in Nude Mice and Can Be Combined with Taxol or Cisplatin to Enhance Growth Inhibition

Opioid Agonists Differentially Regulate μ-Opioid Receptors and Trafficking Proteins in Vivo

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