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Morphine effects on striatal transcriptome in mice.

Korostynski M, Piechota M, Kaminska D, Solecki W, Przewlocki R - Genome Biol. (2007)

Bottom Line: Using microarray-based gene expression profiling in striatum, we found 618 (false discovery rate < 1%) morphine-responsive transcripts.Using whole-genome transcriptional analysis of morphine effects in the striatum, we were able to reveal multiple physiological factors that may influence opioid-related phenotypes and to relate particular gene networks to this complex trait.The results also suggest the possible involvement of GR-regulated genes in mediating behavioral response to morphine.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Neuropharmacology, Institute of Pharmacology PAS, Smetna 12, 31-343, Krakow, Poland.

ABSTRACT

Background: Chronic opiate use produces molecular and cellular adaptations in the nervous system that lead to tolerance, physical dependence, and addiction. Genome-wide comparison of morphine-induced changes in brain transcription of mouse strains with different opioid-related phenotypes provides an opportunity to discover the relationship between gene expression and behavioral response to the drug.

Results: Here, we analyzed the effects of single and repeated morphine administrations in selected inbred mouse strains (129P3/J, DBA/2J, C57BL/6J, and SWR/J). Using microarray-based gene expression profiling in striatum, we found 618 (false discovery rate < 1%) morphine-responsive transcripts. Through ontologic classification, we linked particular sets of genes to biologic functions, including metabolism, transmission of nerve impulse, and cell-cell signaling. We identified numerous novel morphine-regulated genes (for instance, Olig2 and Camk1g), and a number of transcripts with strain-specific changes in expression (for instance, Hspa1a and Fzd2). Moreover, transcriptional activation of a pattern of co-expressed genes (for instance, Tsc22d3 and Nfkbia) was identified as being mediated via the glucocorticoid receptor (GR). Further studies revealed that blockade of the GR altered morphine-induced locomotor activity and development of physical dependence.

Conclusion: Our results indicate that there are differences between strains in the magnitude of transcriptional response to acute morphine treatment and in the degree of tolerance in gene expression observed after chronic morphine treatment. Using whole-genome transcriptional analysis of morphine effects in the striatum, we were able to reveal multiple physiological factors that may influence opioid-related phenotypes and to relate particular gene networks to this complex trait. The results also suggest the possible involvement of GR-regulated genes in mediating behavioral response to morphine.

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Morphine-induced changes in gene expression correlated with the behavioral response. Transcriptional and behavioral responses to morphine were compared across the four inbred strains of mice with specific opioid-related phenotype (C57BL/6J, DBA/2J, 129P3/J, and SWR/J). Behavioral data were gathered as described in the Materials and methods section. The results were obtained by using Pearson correlation (Additional data file 5). Correlation between each opioid-related trait and transcriptional response to acute morphine is presented on the left panel along with chronic morphine on the right panel. Positive correlations between changes in gene expression and behavioral response are highlighted by red color (+), and negative ones are highlighted by the blue color (-).
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Figure 7: Morphine-induced changes in gene expression correlated with the behavioral response. Transcriptional and behavioral responses to morphine were compared across the four inbred strains of mice with specific opioid-related phenotype (C57BL/6J, DBA/2J, 129P3/J, and SWR/J). Behavioral data were gathered as described in the Materials and methods section. The results were obtained by using Pearson correlation (Additional data file 5). Correlation between each opioid-related trait and transcriptional response to acute morphine is presented on the left panel along with chronic morphine on the right panel. Positive correlations between changes in gene expression and behavioral response are highlighted by red color (+), and negative ones are highlighted by the blue color (-).

Mentions: To identify transcriptional response associated with specific opioid-related traits, changes in mRNA level were correlated with morphine-induced behavioral traits (Additional data file 5). Severe symptoms of opioid withdrawal observed in SWR/J mice were associated with strong transcriptional activation of cytotoxic T lymphocyte-associated protein 2 (Ctla2a) and methionine adenosyltransferase II (Mat2a) genes after acute administration of morphine, whereas changes in gene expression of adenosine A2a receptor (Adora2a) were negatively related to the level of morphine physical dependence across the four inbred mouse strains (Figure 7). A role of functional activation of the adenosine A2a receptor in opioid withdrawal was previously reported [29].


Morphine effects on striatal transcriptome in mice.

Korostynski M, Piechota M, Kaminska D, Solecki W, Przewlocki R - Genome Biol. (2007)

Morphine-induced changes in gene expression correlated with the behavioral response. Transcriptional and behavioral responses to morphine were compared across the four inbred strains of mice with specific opioid-related phenotype (C57BL/6J, DBA/2J, 129P3/J, and SWR/J). Behavioral data were gathered as described in the Materials and methods section. The results were obtained by using Pearson correlation (Additional data file 5). Correlation between each opioid-related trait and transcriptional response to acute morphine is presented on the left panel along with chronic morphine on the right panel. Positive correlations between changes in gene expression and behavioral response are highlighted by red color (+), and negative ones are highlighted by the blue color (-).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2394777&req=5

Figure 7: Morphine-induced changes in gene expression correlated with the behavioral response. Transcriptional and behavioral responses to morphine were compared across the four inbred strains of mice with specific opioid-related phenotype (C57BL/6J, DBA/2J, 129P3/J, and SWR/J). Behavioral data were gathered as described in the Materials and methods section. The results were obtained by using Pearson correlation (Additional data file 5). Correlation between each opioid-related trait and transcriptional response to acute morphine is presented on the left panel along with chronic morphine on the right panel. Positive correlations between changes in gene expression and behavioral response are highlighted by red color (+), and negative ones are highlighted by the blue color (-).
Mentions: To identify transcriptional response associated with specific opioid-related traits, changes in mRNA level were correlated with morphine-induced behavioral traits (Additional data file 5). Severe symptoms of opioid withdrawal observed in SWR/J mice were associated with strong transcriptional activation of cytotoxic T lymphocyte-associated protein 2 (Ctla2a) and methionine adenosyltransferase II (Mat2a) genes after acute administration of morphine, whereas changes in gene expression of adenosine A2a receptor (Adora2a) were negatively related to the level of morphine physical dependence across the four inbred mouse strains (Figure 7). A role of functional activation of the adenosine A2a receptor in opioid withdrawal was previously reported [29].

Bottom Line: Using microarray-based gene expression profiling in striatum, we found 618 (false discovery rate < 1%) morphine-responsive transcripts.Using whole-genome transcriptional analysis of morphine effects in the striatum, we were able to reveal multiple physiological factors that may influence opioid-related phenotypes and to relate particular gene networks to this complex trait.The results also suggest the possible involvement of GR-regulated genes in mediating behavioral response to morphine.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Neuropharmacology, Institute of Pharmacology PAS, Smetna 12, 31-343, Krakow, Poland.

ABSTRACT

Background: Chronic opiate use produces molecular and cellular adaptations in the nervous system that lead to tolerance, physical dependence, and addiction. Genome-wide comparison of morphine-induced changes in brain transcription of mouse strains with different opioid-related phenotypes provides an opportunity to discover the relationship between gene expression and behavioral response to the drug.

Results: Here, we analyzed the effects of single and repeated morphine administrations in selected inbred mouse strains (129P3/J, DBA/2J, C57BL/6J, and SWR/J). Using microarray-based gene expression profiling in striatum, we found 618 (false discovery rate < 1%) morphine-responsive transcripts. Through ontologic classification, we linked particular sets of genes to biologic functions, including metabolism, transmission of nerve impulse, and cell-cell signaling. We identified numerous novel morphine-regulated genes (for instance, Olig2 and Camk1g), and a number of transcripts with strain-specific changes in expression (for instance, Hspa1a and Fzd2). Moreover, transcriptional activation of a pattern of co-expressed genes (for instance, Tsc22d3 and Nfkbia) was identified as being mediated via the glucocorticoid receptor (GR). Further studies revealed that blockade of the GR altered morphine-induced locomotor activity and development of physical dependence.

Conclusion: Our results indicate that there are differences between strains in the magnitude of transcriptional response to acute morphine treatment and in the degree of tolerance in gene expression observed after chronic morphine treatment. Using whole-genome transcriptional analysis of morphine effects in the striatum, we were able to reveal multiple physiological factors that may influence opioid-related phenotypes and to relate particular gene networks to this complex trait. The results also suggest the possible involvement of GR-regulated genes in mediating behavioral response to morphine.

Show MeSH
Related in: MedlinePlus