Gene expression profiling following short-term and long-term morphine exposure in mice uncovers genes involved in food intake

Abstract

Addictive drugs including opioids activate signal transduction pathways that regulate gene expression in the brain. However, changes in CNS gene expression following morphine exposure are poorly understood. We determined changes in gene expression following short-and long-term morphine treatment in the hypothalamus and pituitary using genome-wide DNA microarray analysis and confirmed those alterations in gene expression by real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. In the hypothalamus, short-term morphine administration up-regulated (at least 2-fold) 39 genes and down-regulated six genes. Long-term morphine treatment up-regulated 35 genes and down-regulated 51 genes. In the pituitary, shortterm morphine administration up-regulated 110 genes and down-regulated 29 genes. Long-term morphine treatment up-regulated 85 genes and down-regulated 37 pituitary genes. Microarray analysis uncovered several genes involved in food intake (neuropeptide Y, agouti-related protein, and cocaine and amphetamine-regulated transcript) whose expression was strongly altered by morphine exposure in either the hypothalamus or pituitary. Subsequent RT-PCR analysis confirmed similar regulation in expression of these genes in the hypothalamus and pituitary. Finally, we found functional correlation between morphine-induced alterations in food intake and Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported NIH Public Access regulation of genes involved in this process. Changes in genes related to food intake may uncover new pathways related to some of the physiological effects of opioids.

Effects of Neonatal Stress and Morphine on Murine Hippocampal Gene Expression

“…Our results in regards to Neuropeptide Y (NPY) are also similar to a recent study showing 4 day morphine administration to mice caused an up-regulation of hypothalamic NPY gene expression (32). In addition, we found an up-regulation of galanin gene expression after morphine administration that is consistent with previous work demonstrating an increase in galanin gene expression in mouse locus ceruleus and ventral tegmental region tissues after chronic morphine treatment (33).…”

Differential Changes in Expression of Stress- and Metabolic-Related Neuropeptides in the Rat Hypothalamus during Morphine Dependence and Withdrawal

“…We have previously reported an elevation of NPY expression in hypothalamic samples of chronic morphine treated rats [16]. Furthermore, increased hypothalamic levels of NPY and co-expressed Agouti-related peptide (AgRP) mRNA were detected in mice chronically exposed to morphine [24]. By contrast, in the present study, we did not reveal significantly increased NPY mRNA levels on the final day (day 7 th ) that might be explained either by species difference or by different morphine treatment paradigm used in the present experiment.…”

“…Recent microarray studies on various brain sites have revealed several genes that are differentially expressed in morphine-treated mice compared to controls [24], [28]. Within the mouse hypothalamus NPY and AgRP mRNA levels were upregulated while POMC mRNA down-regulated by 4 days morphine treatment [24].…”

Alterations in Phosphorylated CREB Expression in Different Brain Regions following Short- and Long-Term Morphine Exposure: Relationship to Food Intake

“…Using microarray techniques, our laboratory showed that long-term morphine treatment increased hypothalamic and pituitary NPY and AgRP expression as well as the pituitary CART expression, whereas the same treatment decreased pituitary NPY receptor and hypothalamic peptide YY expression [41]. In contrast, short-term morphine exposure decreased the pituitary leptin receptor and hypothalamic and pituitary adiponutrin expression.…”