Morphine effects on striatal transcriptome in four inbred mouse strains
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE7762 | GEO | 2007/06/14
SECONDARY ACCESSION(S): PRJNA99893
REPOSITORIES: GEO
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Project description:Opioid analgesics are frequently prescribed in the United States and worldwide. However, serious side effects such as addiction, immunosuppression and gastrointestinal symptoms limit long term use. In the current study using a chronic morphine-murine model a longitudinal approach was undertaken to investigate the role of morphine modulation of gut microbiome as a mechanism contributing to the negative consequences associated with opioids use. The results revealed a significant shift in the gut microbiome and metabolome within 24 hours following morphine treatment when compared to placebo. Morphine induced gut microbial dysbiosis exhibited distinct characteristic signatures profiles including significant increase in communities associated with pathogenic function, decrease in communities associated with stress tolerance. Collectively, these results reveal opioids-induced distinct alteration of gut microbiome, may contribute to opioids-induced pathogenesis. Therapeutics directed at these targets may prolong the efficacy long term opioid use with fewer side effects.
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Project description:Using an oral self-administration paradigm, we have seen morphine increase neural activity in the Paraventricular Nucleus of the Thalamus (PVT). Morphine binds primarily to Mu Opioid Receptors (MORs), which are highly expressed in the PVT. Translating Ribosome Affinity Purification (TRAP)-Sequencing was conducted on PVT neurons that express MORs
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Project description:A great number of studies have investigated changes induced by morphine exposure in gene expression using several experimental models. In this study, we examined gene expression changes during chronic exposure to morphine during maturation and differentiation of zebrafish CNS. Our study identified different functional classes of genes and individual candidates involved in the mechanisms underlying susceptibility to morphine actions related to CNS development. These results open new lines to study the treatment of pain and the molecular mechanisms involved in addiction. We also found a set of zebrafish-specific morphine-induced genes, which may be putative targets in human models for addiction and pain processes. Zebrafish embryos were divided into two experimental groups: control embryos and embryos at 5 hpf exposed to 10 nM morphine and collected at 24 hpf (covering the complete embryogenesis). Morphine was administered to the embryos in their water environment, i.e., diluted in E3 embryonic medium. The exposition to begun at the stage of 5 hpf (end of blastula) is continuous, in order to study the chronic effects of the exposure to drug. Microarray experiments were performed using six replicates for each condition, which contained the RNA of approximately one hundred embryos to minimize the influence of potential individual differences between the animals and technical variation introduced by tissue preparation. We previously reported that a concentration of 10 nM morphine is the highest concentration that can be used without a toxic effect on the embryos, and close to 5% of the morphine diluted in the E3 medium is detected in the embryo.
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Project description:Morphine and other opioids continue to be commonly utilized as clinical analgesics, despite their numerous adverse side effects, including respiratory depression, addiction, and tolerance. The modulation of µ-opioid receptor (MOR) signaling and subsequent behavioral output is one viable approach to improve opioid therapy. Heat shock protein 90 (Hsp90) is a molecular chaperone protein that has recently been implicated in downstream MOR signaling within the brain in mice. Here we identify a context-dependent impact on MOR signaling in which the inhibition of Hsp90 within the spinal cord promotes morphine induced anti-nociception. We show that intrathecal and not systemic administration of the Hsp90 inhibitors 17-AAG or KU-32 amplifies morphine-induced anti-nociception in both thermal and mechanical pain models. Further, we demonstrate that the inhibition of Hsp90 allows for ERK phosphorylation after opioid treatment. ERK activation was localized within the dorsal horns of the spinal cord, which are heavily populated with primary afferents responsible for nociception. The behavioral effects observed with Hsp90 inhibitors were abolished upon intrathecal U0126 (ERK inhibitor) and cycloheximide (translation inhibitor) treatment, suggesting that downstream ERK phosphorylation and rapid protein translation are responsible for the observed amplification of anti-nociception. Quantitative proteomic analysis identified upregulated RSK with spinal cord Hsp90 inhibition, which we further found was necessary for the observed enhancement of anti-nociception. Taken together, we have uncovered a novel downstream MOR ERK/RSK cascade, localized to the spinal cord and repressed by Hsp90, whose modulation may allow for enhanced efficacy and decreased side effects during opioid therapy.
2020-04-24 | PXD015060 | Pride
Project description:Sickle cell disease is the most common genetic disorder in African-Americans. The opioid analgesic, morphine, has long been the treatment for the severe pain associated with this disease. Here we reveal that the opioid antagonist, naloxone, possesses potent analgesic activity in two strains of sickle cell mice (NY1DD and hBERK1) and not in their respective controls (ICR-CD1 and C57BL/6J) when administered by three parenteral routes. In the NY1DD sickle mice, naloxone (i.c.v.) possessed ~300-fold greater potency than morphine (i.c.v.). Other opioid antagonists (naltrexone, norbinaltorphimine, naltrindole) were substantially less effective in producing analgesia. Naloxone and morphine were synergistic in NY1DD mice, suggesting that analgesia was mediated via different receptor systems. Since microarray analysis suggested naloxone-induced down-regulation of the CCR5 chemokine receptor in NY1DD mice but not in control mice, the role of its endogenous ligand, CCL5 (RANTES), was investigated. Keywords: Comparison of drug induced gene expression
2007-12-20 | GSE6479 | GEO
Project description:Opioids analgesics are frequently prescribed in the United States and worldwide. However, serious side effects such as addiction, immunosuppression and gastrointestinal symptoms limit their use. It has been recently demonstrated that morphine treatment results in significant disruption in gut barrier function leading to increased translocation of gut commensal bacteria. Further study indicated distinct alterations in the gut microbiome and metabolome following morphine treatment, contributing to the negative consequences associated with opioid use. However, it is unclear how opioids modulate gut homeostasis in the context of a hospital acquired bacterial infection. In the current study, a mouse model of C. rodentium infection was used to investigate the role of morphine in the modulation of gut homeostasis in the context of a hospital acquired bacterial infection. Citrobacter rodentium is a natural mouse pathogen that models intestinal infection by enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) and causes attaching and effacing lesions and colonic hyperplasia. Morphine treatment resulted in 1) the promotion of C. rodentium systemic dissemination, 2) increase in virulence factors expression with C. rodentium colonization in intestinal contents, 3) altered gut microbiome, 4) damaged integrity of gut epithelial barrier function, 5) inhibition of C. rodentium-induced increase in goblet cells, and 6) dysregulated IL-17A immune response. This is the first study to demonstrate that morphine promotes pathogen dissemination in the context of intestinal C. rodentium infection, indicating morphine modulates virulence factor-mediated adhesion of pathogenic bacteria and induces disruption of mucosal host defense during C. rodentium intestinal infection in mice. This study demonstrates and further validates a positive correlation between opioid drug use/abuse and increased risk of infections, suggesting over-prescription of opioids may increase the risk in the emergence of pathogenic strains and should be used cautiously. Therapeutics directed at maintaining gut homeostasis during opioid use may reduce the comorbidities associated with opioid use for pain management.
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