Endogenous opioid systems regulate cell proliferation in the developing rat brain

Zagon, Ian S.; MacLaughlin, Patricia J.

doi:10.1016/0006-8993(87)91440-5

Cited by 219 publications

(86 citation statements)

References 23 publications

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“…In the cerebellum, [ 3 H]-thymidine incorporation by neuroblasts of the external granular layer (EGL) in 6-day-old rats is inhibited by systemic administration of Met-enkephalin, while treatment with the opioid antagonist naltrexone, at dosages sufficient to completely block opioid receptors, is reported to increase [ 3 H]-thymidine incorporation compared to untreated controls 56 . These and other experiments suggest that endogenous opioids are normally available to cells in the developing CNS in sufficient quantities to tonically inhibit growth 17,18,41,[54][55][56] . In support of this hypothesis, opioid peptide levels and opioid binding are greatly increased in the rat cerebellum 48,49 28,32,43,52 .…”

Section: Introductionmentioning

confidence: 71%

“…Although the above findings suggest that endogenous opioids are present during development and tonically inhibit growth 17,18,[54][55][56][57] , few studies have attempted to identify the potential cellular sites of opioid synthesis in the developing central nervous system (CNS). Recent reports have demonstrated the presence of proenkephalin mRNA by Northern analysis of confluent glial cultures that are enriched in astrocytes (i.e., 95-97% astrocytes) 28,32,43,52 .…”

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confidence: 99%

“…Although endogenous opioid peptides are involved in numerous functions, these neuropeptides have recently been proposed as negative trophic regulators of neuronal proliferation 56 and differentiation 17,18 . Therefore, opioid production by astrocyte cells might be one mechanism by which glia might influence the growth of opioid-receptor containing neurons during development.…”

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confidence: 99%

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Cellular localization of proenkephalin mRNA and enkephalin peptide products in cultured astrocytes

et al. 1990

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To identify the possible cellular sites of opioid gene expression during ontogeny, proenkephalin mRNA and enkephalin peptide expression were examined, respectively, by in situ hybridization and immunocytochemistry in organotypic explants of rat cerebellum and in astrocyte-enriched cultures of murine cerebral hemispheres. High levels of proenkephalin mRNA and enkephalin immunoreactivity were detected in immature cells identified as astrocytes. Double-labeling studies combining in situ hybridization and immunocytochemical localization of the astrocytic marker, glial fibrillary acidic protein, provided direct evidence that proenkephalin mRNA is expressed by astrocytes in culture. Based on previous studies that Met-enkephalin can inhibit astrocyte growth in vitro, the present results suggest that proenkephalin gene expression by astrocytes is important during central nervous system maturation. KeywordsNeural development; In situ hybridization; Endogenous opioids; Proenkephalin A; Glial fibrillary acidic protein; Astrocyte; In vitroThe growth of neuronal and non-neuronal cells of the postnatal rat cerebral cortex, hippocampus, and cerebellum is modified by experimental manipulation of endogenous opioid systems (i.e, endogenous opioids and opioid receptors). Cellular differentiation 17,18 , cell number and packing density 54,55 , and cortical thickness 54,55 are modifiable by treatment with opioid antagonist drugs in vivo. In the cerebellum, [ 3 H]-thymidine incorporation by neuroblasts of the external granular layer (EGL) in 6-day-old rats is inhibited by systemic administration of Met-enkephalin, while treatment with the opioid antagonist naltrexone, at dosages sufficient to completely block opioid receptors, is reported to increase [ 3 H]-thymidine incorporation compared to untreated controls 56 . These and other experiments suggest that endogenous opioids are normally available to cells in the developing CNS in sufficient quantities to tonically inhibit growth 17,18,41,[54][55][56] . In support of this hypothesis, opioid peptide levels and opioid binding are greatly increased in the rat cerebellum 48,49 28,32,43,52 . In the present study, proenkephalin (proenkephalin A) mRNA and enkephalin peptide expression were examined by in situ hybridization and immunocytochemistry, respectively, in primary cultures of the developing CNS (i) to identify the specific cellular sites of proenkephalin gene and peptide expression, and (ii) to determine whether opioids are expressed by replicating astrocytes prior to their reaching confluence. We were particularly interested in determining whether rapidly dividing cells in astrocyte-enriched cultures express the proenkephalin gene prior to reaching confluence, because we have recently found that the proenkephalin peptide product, Met-enkephalin, selectively inhibits type 1 astrocyte proliferation at this time (i.e., at 4 or 6 days in vitro) 46,47 . Initial studies localized high levels of proenkephalin mRNA in cells with astrocytic morphology irrespective of culture conditi...

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Section: Introductionmentioning

confidence: 71%

mentioning

confidence: 99%

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confidence: 99%

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Cellular localization of proenkephalin mRNA and enkephalin peptide products in cultured astrocytes

et al. 1990

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“…Endogenous opioid systems are present during development and can modify nervous system maturation (16,21,77,78). During development, endogenous opioid neuropeptides typically act by inhibiting the growth of the nervous system (21,77,78).…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

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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Modulation of the estrogen-regulated proteins cathepsin D and pS2 by opioid agonists in hormone-sensitive breast cancer cell lines (MCF7 and T47D): Evidence for an interaction between the two systems

et al. 1998

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In many cancer cell lines, including breast, prostate, lung, brain, head and neck, retina, and the gastrointestinal tract, opioids decrease cell proliferation in a dose-dependent and reversible manner. Opioid and/or other neuropeptide receptors mediate this decrease. We report that only the steroid-hormone-sensitive cell lines MCF7 and T47D respond to opioid growth inhibition in a dose-dependent manner. Therefore, an interaction of the opioid and steroid receptor system might exist, as is the case with insulin. To investigate this interaction, we have assayed two estrogen-inducible proteins (pS2 and the lysosomal enzyme cathepsin D) in MCF7 and T47D cells. When cells were grown in the presence of FBS (in which case a minimal quantity of estrogens and/or opioids is provided by the serum), we observed either no effect of etorphine or ethylketocyclazocine (EKC) or an increase of secretion and/or production of pS2 and cathepsin D. However, when cells were cultured in charcoal-stripped serum and in the absence of phenol red, the effect of the two opioids is different: EKC decreased the production and/or secretion of pS2 and cathepsin D, whereas etorphine increased their synthesis and/or secretion. The differential effect of the two general opioids was attributed to their different receptor selectivity. Furthermore, the variations of the ratio of secreted/produced protein and the use of cycloheximide indicate that opioids selectively modify the regulatory pathway of each protein discretely. In conclusion, through the interaction with opioid and perhaps other membrane-receptor sites, opioid agonists modify in a dose-dependent manner the production and the secretion of two estrogen-regulated proteins. Opioids may therefore disturb hormonal signals mediated by the estrogen receptors. Hence, these chemicals may have potential endocrine disrupting activities.

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Endogenous opioid systems regulate cell proliferation in the developing rat brain

Cited by 219 publications

References 23 publications

Cellular localization of proenkephalin mRNA and enkephalin peptide products in cultured astrocytes

Cellular localization of proenkephalin mRNA and enkephalin peptide products in cultured astrocytes

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

Modulation of the estrogen-regulated proteins cathepsin D and pS2 by opioid agonists in hormone-sensitive breast cancer cell lines (MCF7 and T47D): Evidence for an interaction between the two systems

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