Effects of opiates on the growth of neuron‐enriched cultures from chick embryonic brain

Sakellaridis, Nikolaos; Mangoura, Dimitra; Vernadakis, Antonia

doi:10.1016/0736-5748(86)90066-3

Cited by 41 publications

(8 citation statements)

References 31 publications

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“…During development, endogenous opioid neuropeptides typically act by inhibiting the growth of the nervous system (21,77,78). Opiate drugs such as morphine also affect neural development (9,12,14,16,17,42,52,54,58,62,66,70,74). Presumably opiate drugs disrupt the normal interactions between endogenous opioid peptides and their receptors.…”

Section: Introductionmentioning

confidence: 99%

Morphine Inhibits Purkinje Cell Survival and Dendritic Differentiation in Organotypic Cultures of the Mouse Cerebellum

Hauser

Gurwell

Turbek

1994

Experimental Neurology

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The effects of morphine on the morphogenesis and survival of calbindin-D 28k immunoreactive Purkinje cells was studied in organotypic explant cultures isolated from 1-or 7-day-old mouse cerebella. To reduce experimental variability, bilaterally matched pairs of organotypic cultures were used to compare the effects of opiate drug treatment. One explant within each pair was untreated, while the remaining explant was continuously treated for 7 to 10 days with morphine, morphine plus naloxone, or naloxone alone. In explants derived from 1-day-old mice, morphine treatment significantly reduced Purkinje cell dendritic length compared to symmetrically-matched untreated control explants. The concentration of morphine estimated to cause a half-maximal reduction (EC 50 ) in dendritic length was 4.9 × 10 −8 M. At higher concentrations (EC 50 = 3.6 × 10 −6 M), morphine also significantly decreased the number of Purkinje cells in explants from 1-day-old mice compared to untreated explants. Electron microscopy identified increased numbers of degenerating Purkinje cells in explants derived from 1-day-old mice. This showed that high concentrations (10 −5 M) of morphine reduced Purkinje cell numbers by decreasing their rate of survival. In explants derived from 7-day-old mice, morphine (10 −5 M) neither affected Purkinje cell dendritic length nor cell numbers compared to symmetrically-matched untreated (control) explants. Collectively, these findings suggest that morphine per se, through a direct action on the cerebellum, can affect Purkinje cell differentiation and survival. The results additionally suggest there is a critical period during development when Purkinje cells are especially vulnerable to the effects of morphine.

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Section: Introductionmentioning

confidence: 99%

Morphine Inhibits Purkinje Cell Survival and Dendritic Differentiation in Organotypic Cultures of the Mouse Cerebellum

Hauser

Gurwell

Turbek

1994

Experimental Neurology

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“…Numerous studies have indicated that endogenous opioid peptides, products of proenkephalin or pro-opiomelanocortin, inhibit DNA synthesis in in vitro neuronal or glial cultures or in neuroblastoma cells (1)(2)(3)(4). These studies were supported by the observation that opioid antagonists could stimulate DNA synthesis and proliferation in some neuroblastoma cell lines.…”

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confidence: 96%

Agonist Activation of δ-Opioid Receptor but not μ-Opioid Receptor Potentiates Fetal Calf Serum or Tyrosine Kinase Receptor-Mediated Cell Proliferation in a CellLine-Specific Manner

et al. 1997

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SUMMARY-enkephalin. This ␦-opioid agonist effect was not observed at FCS concentrations Ͼ0.1% and could be blocked by pretreating cells with pertussis toxin, indicating that G i /G o were involved in this action. In addition, ␦-opioid agonists could potentiate CHO cell proliferation stimulated by those growth factors that are mediated by tyrosine kinase receptors (i.e., insulin, insulin-like growth factor 1, and fibroblast-derived growth factor b). This ␦-opioid agonist potentiation of growth apparently was dependent on the level of ␦-opioid receptors that were expressed and had cell-line selectivity. Activation of ␦-opioid receptors expressed in Rat-1 or NIH3T3 fibroblast did not result in a modulation of the cell growth induced by FCS or by growth factors. Interestingly, in CHO cells transfected with -opioid receptor cDNA, activation with agonists did not produce a potentiation of FCS-stimulated proliferation. This lack of -opioid receptor effect was not due to the differences among CHO clones. In a CHO cell line transfected with both ␦-opioid receptor cDNA and -opioid receptor cDNA, activation of ␦-but not -opioid receptors resulted in a potentiation of growth. These data suggest that ␦-and -opioid receptors in CHO cells activate similar but divergent second messenger pathways, resulting in the differential regulation of cell growth.Numerous studies have indicated that endogenous opioid peptides, products of proenkephalin or pro-opiomelanocortin, inhibit DNA synthesis in in vitro neuronal or glial cultures or in neuroblastoma cells (1-4). These studies were supported by the observation that opioid antagonists could stimulate DNA synthesis and proliferation in some neuroblastoma cell lines. The opioid antagonist, naltrexone, stereoselectively stimulates cell proliferation in murine neuroblastoma NS20Y and N1E-115 cells, human neuroblastoma SK-N-MC cells, and human fibrosarcoma cells (5). This antagonistic effect on NS20Y cells was demonstrated further by the ability of in vivo administration of naltrexone to stimulate the growth of these cells when they were implanted in rodents (6).The suppression effects exhibited by opioid peptide agonists and the stimulatory effects exhibited by naltrexone on neuroblastoma proliferation were rather surprising. By contrast, a substantial volume of evidence suggests that activation of GPCRs could lead to the enhancement of cell proliferation, mitogenesis, and tumorigenicity. Activation of bombesin receptors in Swiss 3T3 fibroblasts and small-cell lung carcinomas resulted in a stimulation of the mitogenic response (7,8). Activation of transfected serotonin receptors (5-HT 1B , 5-HT 1C , 5-HT 2 ), muscarinic receptors, or ␣ 2 -adrenergic receptors in Chinese hamster lung fibroblasts, Rat-1 fibroblasts, or NIH3T3 fibroblasts resulted in increases in DNA synthesis, which are incidents of foci formation and growth rates (9 -13). These positive effects on growth exhibited by GPCRs were demonstrated further by the ability of constitutively active receptor mutants (14)

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“…Now that opioid receptors have been cloned, they can be stably overexpressed in differentiated cell lines with properties characteristic of neurons (Yasuda et al, 1993;Banerjee et al, 1996: Toth et al, 1995, and the molecular basis of receptor desensitization can be directly addressed. Opioid peptides are abundant during embryonic development (Sakellaridis et al, 1986), Opiates and opioid peptides, acting through the K-, p-, and ô-opioid receptors, have been shown to dissociate initially Gã,dy trimeric complexes, thereby inhibiting adenylate cyclase and blocking calcium entry either by hyperpolarizing K~channels (Grunt and Williams, 1993) or directly blocking activation of N-type calcium channels (Herlitze et al, 1996;Ikeda, 1996). Desensitization and tolerance following prolonged exposure to agonists are commonly observed with morphine and other opioids used in the treatment of pain.…”

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confidence: 99%

Chronic Exposure to κ‐Opioids Enhances the Susceptibility of Immortalized Neurons (F‐11κ7) to Apoptosis‐Inducing Drugs by a Mechanism that May Involve Ceramide

Dawson

Goswami

1997

Journal of Neurochemistry

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Chronic exposure of embryonic brain to opioids leads to microcephaly and developmental abnormalities. An immortalized mouse neuroblastoma X dorsal root ganglion hybrid cell line stably transfected to overexpress K-opioid receptors (F-1 lK 7) showed complete loss of K-receptor binding to [3H]U69,593after exposure to the K-agonist U69,593 for 24 h. U69,593 had no measurable effect on cell viability as determined by either cell viability or DNA fragmentation assays. However, when cell death (apoptosis) was induced by either staurosporine or the phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002, cells pretreated with U69,593 for 24 h showed increased apoptosis compared with untreated cells. Thus, staurosporine (50 nM), wortmannin (4 1sM), and LY294002 (30 ‚uM) treatment for 24 h induced a 50% loss of cell viability and DNA fragmentation in 24 h. U69,593 pretreatment produced the same killing at lower concentrations, namely, 20 nM staurosporine, 2 p.M wortmannin, and 14 ‚uM LY294002, respectively. The effects of U69,593 were time-, dose-, and naloxone-reversible, suggesting that they are receptor-mediated. However, coaddition of U69,593 at the same time as staurosporine, wortmannin, or LY294002 did not enhance apoptosis. All three drugs that induced apoptosis were found to increase the level of ceramide, and pretreatment with U69,593 further increased the rate of formation of ceramide, a lipid that induces apoptosis in cells. We propose that chronic exposure to K-receptor agonists promotes increased vulnerability of neurons to apoptosis.

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Effects of opiates on the growth of neuron‐enriched cultures from chick embryonic brain

Cited by 41 publications

References 31 publications

Morphine Inhibits Purkinje Cell Survival and Dendritic Differentiation in Organotypic Cultures of the Mouse Cerebellum

Morphine Inhibits Purkinje Cell Survival and Dendritic Differentiation in Organotypic Cultures of the Mouse Cerebellum

Agonist Activation of δ-Opioid Receptor but not μ-Opioid Receptor Potentiates Fetal Calf Serum or Tyrosine Kinase Receptor-Mediated Cell Proliferation in a CellLine-Specific Manner

Chronic Exposure to κ‐Opioids Enhances the Susceptibility of Immortalized Neurons (F‐11κ7) to Apoptosis‐Inducing Drugs by a Mechanism that May Involve Ceramide

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