Morphine effects on striatal transcriptome in mice

Global transcriptional analysis of mouse striata following acute and chronic exposure to morphine reveals multiple physiological factors which may affect opioid-related phenotypes and implicates a number of gene networks, including glucocorticoid receptor regulated genes, in the response to this opioid

Effects of morphine treatment on pro-opiomelanocortin systems in rat brain

In previous studies to determine whether chronic opiate administration might negatively feedback upon endogenous opioid systems in the CNS, investigators found no changes in steady-state concentrations of opioid peptides following morphine pelleting. However, since only steady-state levels were measured, it was still not clear whether morphine treatment altered the release and/or biosynthesis of opioid-containing neurons. The goal of the present study was to assess the effects of chronic morphine pelleting on the dynamics of [beta]-endorphin ([beta]E) biosynthesis in rats. Hence, at several times during a 7-day morphine treatment, concentrations of total [beta]E-immunoreactivity (-ir), as well as chromatographically sieved forms of [beta]E, were determined by RIA, and mRNA levels of pro-opiomelanocortin (POMC) were measured by a solution phase protection assay using a mouse or rat POMC 32P-labelled riboprobe. Concentrations of total [beta]E-ir or different forms of [beta]E-ir peptides (i.e. [beta]-lipotropin, [beta]E1-31, or [beta]E1-27/[beta]E1-26) in the hypothalamus or midbrain following either 1 or 7 days of treatment were similar in morphine- and placebo-pelleted animals. However, a significant increase in total hypothalamic [beta]E-ir was observed following 3 days of morphine pelleting; chromatographic analyses indicated that this was primarily due to a selective increase in the opiate inactive forms of [beta]E, i.e. [beta]E1-27/[beta]E1-26. After 7 days of pelleting, morphine-treated animals tended to have lower POMC mRNA levels than those of placebo controls (20 to 50% decrease in different studies). The accumulation of hypothalamic [beta]E-ir at 3 days, and the apparent decline in POMC mRNA levels at 7 days, lend support to the hypothesis that morphine negatively feeds back upon POMC neurons in the brain by inhibiting [beta]E release and biosynthesis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28522/1/0000319.pd

Alterations in the Activity of Spinal and Thalamic Opioid Systems in a Mice Neuropathic Pain Model

Clinical studies have reported lower effectivity of opioid drugs in therapy of neuropathic pain. Therefore, to determine the changes in endogenous opioid systems in this pain more precisely, we have studied the changes in the pain-related behavior on days 1, 14, and 28 following a chronic constriction injury (CCI) to the sciatic nerve in mice. In parallel, we have studied the changes of mu-(MOP), delta-(DOP) and kappa-(KOP) receptors, proenkephalin (PENK) and prodynorphin (PDYN) mRNA levels, as well as GTP gamma S binding of opioid receptors on the ipsi- and contralateral parts of the spinal cord and thalamus on the 14th day following CCI, as on this day the greatest manifestation of pain-related behavior was observed. On ipsilateral spinal cord, the decrease in MOP/DOP/KOP receptor and increase in PDYN/PENK mRNA expression was observed. In thalamus, MOP/DOP/KOP receptor expression decreased contralaterally. On ipsilateral side, there were no changes in PDYN/PENK or DOP/KOP receptor expression, but MOP mRNA decreased. The spinal GTP gamma S binding of MOP/DOP/KOP receptor ligands decreased on the ipsilateral side, yet the effect was less pronounced for DOP receptor ligands. In thalamus, a decrease was observed on the contralateral side for all opioid receptor ligands, especially for DOP ligand. A less pronounced decrease in GTP gamma S binding of spinal DOP ligands may indicate a weaker stimulation of ascending nociceptive pathways, which could explain the absence of decreased activity of DOP receptor ligands in neuropathy. These findings may suggest that drugs with a higher affinity for the DOP receptor will perform better in neuropathic pain. (C) 2018 Published by Elsevier Ltd on behalf of IBRO

Controlling complexity: the clinical relevance of mouse complex genetics.

Experimental animal models are essential to obtain basic knowledge of the underlying biological mechanisms in human diseases. Here, we review major contributions to biomedical research and discoveries that were obtained in the mouse model by using forward genetics approaches and that provided key insights into the biology of human diseases and paved the way for the development of novel therapeutic approaches

Identification of cis-Regulatory Elements in the Mammalian Genome: The cREMaG Database

Background: A growing number of gene expression-profiling datasets provides a reliable source of information about gene co-expression. In silico analyses of the properties shared among the promoters of co-expressed genes facilitates the identification of transcription factors (TFs) involved in the co-regulation of those genes. Our previous experience with microarray data led to the development of a database suitable for the examination of regulatory motifs in the promoters of co-expressed genes. Methodology: We introduce the cREMaG (cis-Regulatory Elements in the Mammalian Genome) system designed for in silico studies of the promoter properties of co-regulated mammalian genes. The cREMaG system offers an analysis of data obtained from human, mouse, rat, bovine and canine gene expression-profiling studies. More than eight analysis parameters can be utilized in user-defined combinations. The selection of alternative transcription start sites and information about CpG islands are also available. Conclusions: Using the cREMaG system, we successfully identified TFs mediating transcriptional responses in reference gene sets. The cREMaG system facilitates in silico studies of mammalian transcriptional gene regulation. The resource is freely available a

Comparison of an addictive potential of μ-opioid receptor agonists with G protein bias : behavioral and molecular modeling studies

Among different approaches to the search for novel—safer and less addictive—opioid analgesics, biased agonism has received the most attention in recent years. Some μ-opioid receptor agonists with G protein bias, including SR compounds, were proposed to induce diminished side effects. However, in many aspects, behavioral effects of those compounds, as well as the mechanisms underlying differences in their action, remain unexplored. Here, we aimed to evaluate the effects of SR-14968 and SR-17018, highly G protein-biased opioid agonists, on antinociception, motor activity and addiction-like behaviors in C57BL/6J mice. The obtained results showed that the compounds induce strong and dose-dependent antinociception. SR-14968 causes high, and SR-17018 much lower, locomotor activity. Both agonists develop reward-associated behavior and physical dependence. The compounds also cause antinociceptive tolerance, however, developing more slowly when compared to morphine. Interestingly, SR compounds, in particular SR-17018, slow down the development of antinociceptive tolerance to morphine and inhibit some symptoms of morphine withdrawal. Therefore, our results indicate that SR agonists possess rewarding and addictive properties, but can positively modulate some symptoms of morphine dependence. Next, we have compared behavioral effects of SR-compounds and PZM21 and searched for a relationship to the substantial differences in molecular interactions that these compounds form with the µ-opioid receptor

Regulation of the immediate-early genes arc and zif268 in a mouse operant model of cocaine seeking reinstatement

Reinstatement of extinguished operant responding for drug is an appropriate model of relapse to drug abuse. Due to the difficulty of implementing in mice the procedure of instrumental intravenous self-administration, mechanisms of reinstatement have so far been studied almost exclusively in rats. A mouse model of reinstatement of cocaine seeking has recently been characterized (Soria et al. 2008). The aim of the present study was to assess regional brain activation, as measured by induction of the immediate early genes (IEG) arc and zif268, during priming-or cue-elicited reinstatement of cocaine seeking using this new mouse model and the in situ hybridization technique. We have demonstrated that cue-elicited reinstatement of cocaine seeking was associated with induction of the IEG in the medial prefrontal cortex (prelimbic and infralimbic) and basolateral amygdala. Priming-induced reinstatement produced a more widespread up-regulation of those genes in forebrain regions including medial prefrontal, orbitofrontal and motor cortex, dorsal striatum and basolateral amygdala. These patterns of IEG expression are in agreement with previous results obtained in rats and thus indicate that the new mouse model of reinstatement is functionally equivalent to rat models. That comparability adds to the usefulness of the mouse model as a tool for addressing neurobiological mechanisms of addiction. © Springer-Verlag 2011.This work was supported by the EU grant LSHM-CT-2007-037669 (PHECOMP), the Polish Ministry of Science and Higher Education subsidiary grant No. 478/6. PR UE/2007/7, statutory funds from the Institute of Pharmacology, Polish Academy of Sciences, the Spanish Ministerio de Ciencia e Innovacion (SAF 2007-64062), the Catalan Government (S6R 2009-00131) and the ICREA Foundation (ICREA-Academia 2008).Peer Reviewe

Geography of knowledge sources in knowledge intensive business services and creative industries: the case of design industry

Geography of knowledge sources in knowledge intensive business services and creative industries: the case study of design industry This thesis examines the creation and transfer of knowledge within knowledge-intensive business services and creative industries, with special attention being paid to the design industry. To obtain the required information it was implemented a series of in-depth interviews with representatives of selected design studios. Acquired knowledge provides in- depth probe into the issue of creation and transmission of knowledge and the nature of innovation in the design industry. The main finding is that for the creation and transfer of knowledge within the design industry existence of networks between the design studios and specific subjects is essential. Key words: knowledge sources, innovation, network