Single Cell RNAseq Uncovers a Robust Transcriptional Response to Morphine by Glia
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE118918 | GEO | 2018/08/23
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.
2018-04-16 | E-MTAB-5550 | biostudies-arrayexpress
Project description:Opioids are widely used, effective analgesics to manage severe acute and chronic pain, although they have recently come under scrutiny because of epidemic levels of abuse. While these compounds act on numerous central and peripheral pain pathways, the neuroanatomical substrate for opioid analgesia is not fully understood. By means of single-cell transcriptomics and manipulation of morphine-responsive neurons, have identified an ensemble of neurons in the rostral ventromedial medulla (RVM) that regulates mechanical nociception in mice. Among these, forced activation or silencing of excitatory RVMBDNF projection neurons mimicked or completely reversed morphine-induced mechanical antinociception, respectively, via a brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)-dependent mechanism and activation of inhibitory spinal galanin-positive neurons. Our results reveal a specific RVM-spinal circuit that scales mechanical nociception whose function confers the antinociceptive properties of morphine.
2024-08-30 | GSE253816 | 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.
2020-02-18 | E-MTAB-7503 | biostudies-arrayexpress
Project description:Opioid use is associated with worse outcome in HIV-infected patients. The exacerbated disease progression by opioids is mainly driven by increased epithelial damage and less regenerative response. The present study investigates how opioids potentiate HIV disease progression by impairing intestinal epithelial self-repair. Abnormal intestinal morphology and reduced epithelial proliferation were observed in HIV-infected humanized mice, which were exposed to opioids. For this study, we had 4 groups of BLT humanized mice- (A) Untreated, (B) Morphine treated, (C) HIV infected and (D) HIV infected + Morphine treated. HIV infection was done for 4 weeks and Morphine treatment was done for 7 days. Morphine treatment was done via subcutaneous implantation of slow-release morphine pellet in individual mouse in the appropriate groups. In other groups, a matching Placebo pellet was implanted.
2020-01-11 | E-MTAB-7883 | biostudies-arrayexpress
Project description:The United States is currently facing a severe opioid epidemic, therefore addressing how opioids induce rewarding behaviors could be key to a solution for this medical and societal crisis. Recently, the endogenous cannabinoid system has emerged as a hot topic in the study of opioid reward but relatively little is known about how chronic opioid exposure may affect this system. In the present study, we investigated how chronic morphine may modulate the endogenous cannabinoid system in the ventral tegmental area (VTA), a critical region in the mesolimbic reward circuitry. Our studies found that the VTA expresses 32 different proteins or genes related to the endogenous cannabinoid system; 3 of these proteins or genes were significantly affected after chronic morphine exposure. We also investigated the effects of acute and chronic morphine treatment on the production of the primary endocannabinoids, 2-Arachidonoylglycerol (2-AG) and anandamide (AEA), and identified that acute, but not chronic, morphine treatment significantly reduced AEA production in the VTA; 2-AG levels were unchanged in either condition. Lastly, our studies exhibited a systemic enhancement of 2-AG tone via inhibition of monoacylglycerol lipase (MAGL)-mediated degradation and the pharmacological activation of cannabinoid receptor 2 (CB2R) significantly suppressed chronic morphine-induced conditioned place preference. Taken together, our studies offer a broad picture of chronic morphine-induced alterations of the VTA endogenous cannabinoid system, provide several uncharacterized targets that could be used to develop novel therapies, and identify how manipulation of the endocannabinoid system can mitigate opioid reward to directly address the ongoing opioid epidemic.
2021-04-08 | PXD023096 | Pride
Project description:Opioids are powerful analgesics but carry many contingencies that can lead to opioid-use disorder. Significant energy has been invested in understanding the molecular actions of the opioid alkaloids, particularly their relationship with the opioid receptors at the cell surface. However, there is growing awareness of the opioid-receptor-independent and intracellular actions of opioids that may contribute to their overall pharmacology. The investigation of these interactions is stymied by a lack of relevant opioid chemical tools to probe intracellular actions of the opioids. To investigate the intracellular interactions of the opioids, we designed and developed two opioid probes: photo-click morphine (PCM-2) as a photo-affinity probe for morphine and dialkynyl-acetyl morphine (DAAM) as a metabolic acetate reporter for heroin. Application of these probes to SH-SY5Y, HEK293T, and U2OS cells revealed that PCM-2 and DAAM primarily localize to the lysosome by confocal microscopy and chemical proteomics studies. Interaction site identification by mass spectrometry revealed the mitochondria phosphate carrier protein, solute carrier family 25 member 3, SLC25A3, and histone H2B as acetylation targets of DAAM. This study provides the first chemical probes for the study of the intracellular targets of opioid alkaloids.
2024-05-07 | PXD045676 | Pride
Project description:Opioid use disorder is a public health crisis that leads to tremendous suffering for patients as well as substantial social and economic cost for society. There are currently available treatments for patients with opioid use disorder, but they remain intolerable or ineffective for many. The need to develop new avenues for therapeutics development in this space is great. There is a tremendous amount of work that has been done in models of substance use disorders, including opioid use disorder, demonstrating that prolonged exposure to drugs of abuse leads to marked dysregulation of the transcriptional and epigenetic landscape of important limbic substructures. It is widely believed that these changes in the regulation of gene expression in response to drugs may be a key driving factor in the perpetuation of drug taking and seeking behaviors. Thus, development of interventions that could shape transcriptional regulation in response to drugs of abuse would be of high value. Over the past decade there has been a surge in research demonstrating that the resident bacteria of the gastrointestinal tract, collectively the gut microbiome, can have tremendous influence on neurobiological and behavioral plasticity. Previous work from our group and others has demonstrated that alterations in the gut microbiome can alter behavioral responses to opioids in multiple different paradigms. Additionally, we have previously reported that depletion of the gut microbiome with antibiotics markedly shifts the transcriptome of the nucleus accumbens following prolonged morphine exposure. In this manuscript we present a comprehensive analysis of the effects of the gut microbiome on transcriptional regulation of the nucleus accumbens following morphine by utilizing germ-free, antibiotic treated, and control mice. This allows for detailed understanding of the role of the microbiome in regulating baseline transcriptomic control, as well as response to morphine. We find that germ-free status leads to a marked gene dysregulation in a manner distinct to adult mice treated with antibiotics, and that altered gene pathways are highly related to cellular metabolic processes. These data provide additional insight into the role of the gut microbiome in modulating brain function and lay a foundation for further study in this area.
2023-07-01 | GSE229978 | GEO
Project description:Opioids such as morphine have many beneficial properties as analgesics, however, opioids may induce multiple adverse gastrointestinal symptoms. We have recently demonstrated that morphine treatment results in significant disruption in gut barrier function leading to increased translocation of gut commensal bacteria. However, it is unclear how opioids modulate the gut homeostasis. By using a mouse model of morphine treatment, we studied effects of morphine treatment on gut microbiome. We characterized phylogenetic profiles of gut microbes, and found a significant shift in the gut microbiome and increase of pathogenic bacteria following morphine treatment when compared to placebo. In the present study, wild type mice (C57BL/6J) were implanted with placebo, morphine pellets subcutaneously. Fecal matter were taken for bacterial 16s rDNA sequencing analysis at day 3 post treatment. A scatter plot based on an unweighted UniFrac distance matrics obtained from the sequences at OTU level with 97% similarity showed a distinct clustering of the community composition between the morphine and placebo treated groups. By using the chao1 index to evaluate alpha diversity (that is diversity within a group) and using unweighted UniFrac distance to evaluate beta diversity (that is diversity between groups, comparing microbial community based on compositional structures), we found that morphine treatment results in a significant decrease in alpha diversity and shift in fecal microbiome at day 3 post treatment compared to placebo treatment. Taxonomical analysis showed that morphine treatment results in a significant increase of potential pathogenic bacteria. Our study shed light on effects of morphine on the gut microbiome, and its role in the gut homeostasis.
2018-04-16 | E-MTAB-5546 | biostudies-arrayexpress
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
2022-10-04 | GSE214560 | GEO
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