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Mentions: Morphine treatment altered the expression of 618 transcripts covered by 661 probe sets (FDR < 1%, rank > 3; Additional data file 1). A group of transcripts (56 probe sets) with a high level of significance (rank > 7) was used in hierarchical clustering analysis to present example patterns of genes with altered expression (Figure 2). To validate the results obtained by microarrays, quantitative real-time reverse transcription polymerase chain reaction (qPCR) experiments were performed using aliquots of the nonpooled total RNA. From the list of the most significant 56 probe sets, novel morphine-responsive genes with putative neuronal function were selected. The treatment factor in MANOVA was significant for all of the transcripts examined by qPCR. Equal upregulation (about 1.5-fold to 2-fold) of mRNAs for serum/glucocorticoid regulated kinase 3 (Sgk3) and calcium/calmodulin-dependent protein kinase I gamma (Camk1g) was observed after acute and chronic morphine exposure in all four strains of mice. Greater than twofold induction of zinc finger and BTB domain containing 16 (Zbtb16/Zfp145) mRNA after acute treatment was confirmed, and this induction was lower after prolonged administration. Furthermore, an increase in the abundance of the frizzled homolog 2 (Fzd2) transcript after chronic morphine exposure was detected in all four strains, with the greatest fold change in C57BL/6J mice (Figure 2).
Morphine effects on striatal transcriptome in mice
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.
Affiliation: Department of Molecular Neuropharmacology, Institute of Pharmacology PAS, Smetna 12, 31-343, Krakow, Poland.
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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