Mu opioid receptor (Oprm1) knockdown in the medial preoptic area (MPOA) on patterns of gene expression in the MPOA of adolescent male rats
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ABSTRACT:
PROVIDER: PRJNA622805 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11472057_1.fastq.gz | Fastqsanger.gz | |||
| SRR11472057_2.fastq.gz | Fastqsanger.gz | |||
| SRR11472058_1.fastq.gz | Fastqsanger.gz | |||
| SRR11472058_2.fastq.gz | Fastqsanger.gz | |||
| SRR11472059_1.fastq.gz | Fastqsanger.gz |
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Project description:We investigate effects of Oprm1 downregulation in the MPOA on gene expression profiles in adolescent male rats using RNA-Seq. We conducted differential gene expression analysis of RNA-Seq data using the EdgeR Bioconductor Package. We evaluated differential gene expression between Oprm1 knockdown and control groups and found 349 genes were differentially expressed, with some genes being involved in neuronal signaling exhibited altered expression due to Oprm1 knockdown.
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Project description:Characterization of mu opioid receptor cells in a new Oprm1-cre mouse
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Project description:we derived, validated, and applied a novel MOR-specific Cre mouse line, inserting a T2A cleavable peptide sequence and the Cre coding sequence into the MOR 3’UTR. Importantly, this line shows specificity and fidelity of MOR expression throughout the brain and with respect to function, there were no differences in behavioral responses to morphine when compared to wild type mice, nor are there any alterations in Oprm1 gene expression or receptor density. To assess Cre recombinase activity, MOR-Cre mice were crossed with the floxed GFP-reporters, RosaLSLSun1-sfGFP or RosaLSL-GFP-L10a. The latter allowed for cell type specific RNA sequencing via TRAP (Translating Ribosome Affinity Purification) of striatal MOR+ neurons following opioid withdrawal.
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Project description:The neuronal cell death results in neurodegenerative diseases. The extracellular environment plays a critical role in regulating cell viability. In this study, we explore how intercellular communication contributes to the survival of retinal ganglion cells (RGCs) following the optic nerve crush (ONC). By performing single-cell RNA-seq on whole retinal cells, we observed transcriptomic responses in non-RGC retinal cells to the injury, with astrocytes and Müller glia having the most interactions with RGCs. By comparing the RGC subclasses showing distinct resilience cell death, we identified top 47 interactions that are stronger in the high-survival RGCs, likely representing neuroprotective interactions. We performed functional assays on one of the receptors, Mu-opioid receptor (Oprm1). Although Oprm1 is preferentially expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs), its neuroprotective effect could be transferred to multiple RGC subclasses by specific overexpressing Oprm1 in pan-RGCs. Our study provides an atlas of cell-cell interactions in both intact and post-ONC retina and an effective strategy to predict molecular mechanisms in neuroprotection, underlying the principal role played by extracellular environment in supporting neuron survival.
2023-10-01 | GSE241268 | GEO
Project description:The opioid receptors are important regulators of pain, reward, and addiction. Limited evidence suggests the mu and delta opioid receptors form a heterodimer (MDOR), which may act as a negative feedback brake on opioid-induced analgesia. However, evidence for the MDOR in vivo is indirect and limited, and there are few selective tools available. We recently published the first MDOR-selective antagonist, D24M, allowing us to test the role of the MDOR in mice. We thus co-treated CD-1 mice with D24M and opioids in tail flick, paw incision, and chemotherapy-induced peripheral neuropathy pain models. D24M treatment enhanced oxymorphone anti-nociception in all models by 52.3%-628%. This enhancement could not be replicated with the mu and delta selective antagonists CTAP and naltrindole, and D24M had a mild transient effect in the Rotarod test, suggesting this increase is selective to the MDOR. However, D24M had no effect on morphine or buprenorphine, suggesting that only specific opioids interact with the MDOR. To find a mechanism we performed phosphoproteomic analysis on brainstems of mice. We found that the kinases Src and CaMKII were repressed by oxymorphone, which was restored by D24M. We were able to confirm the role of Src and CaMKII in D24M-enhanced anti-nociception using small molecule inhibitors (KN93, Src-I1). Together these results provide direct in vivo evidence that the MDOR acts as an opioid negative feedback brake, which occurs via the repression of Src and CaMKII signal transduction. These results further suggest that MDOR antagonism could be a means to improve clinical opioid therapy.
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Project description:Neural systems underlying important behaviors are usually highly conserved across species. The medial preoptic area (MPOA) has been demonstrated to play a crucial role in reward associated with affiliative, nonsexual, social communication in songbirds. However, the role of MPOA in affiliative, rewarding social behaviors (eg, social play behavior) in mammals remains largely unknown. Here we applied our insights from songbirds to rats to determine whether opioids in the MPOA govern social play behavior in rats. Using an immediate early gene (ie, Egr1, early growth response 1) expression approach, we identified increased numbers of Egr1-labeled cells in the MPOA after social play in adolescent male rats. We also demonstrated that cells expressing mu opioid receptors (MORs, gene name Oprm1) in the MPOA displayed increased Egr1 expression when adolescent rats were engaged in social play using double immunofluorescence labeling of MOR and Egr1. Furthermore, using short hairpin RNA-mediated gene silencing we revealed that knockdown of Oprm1 in the MPOA reduced the number of total play bouts and the frequency of pouncing. Last, RNA sequencing differential gene expression analysis identified genes involved in neuronal signaling with altered expression after Oprm1 knockdown, and identified Egr1 as potentially a key modulator for Oprm1 in the regulation of social play behavior. Altogether, these results show that the MPOA is involved in social play behavior in adolescent male rats and support the hypothesis that the MPOA is part of a conserved neural circuit across vertebrates in which opioids act to govern affiliative, intrinsically rewarded social behaviors.
| S-EPMC7643862 | biostudies-literature
Project description:Tramadol, a widely used analgesic, has recently been explored for its potential anti-cancer effects. However, the antitumor dosage of tramadol is over its current clinical application. Its primary metabolite, O-desmethyltramadol, has a higher affinity for the μ-opioid receptor and exhibits stronger pharmacological activity. Hence, we sought to examine whether the cytotoxic effect of O-desmethyltramadol was better than tramadol on breast cancer cells. Our results showed that O-desmethyltramadol significantly reduced cell viability in MDA-MB-231 and MCF-7 breast cancer cells, at least, ten-fold efficacy than tramadol. The presence of a μ-opioid receptor antagonist alvimopan did not alter these cytotoxic effects of tramadol and O-desmethyltramadol, indicating a non-opioid receptor-mediated mechanism. Compared with antitumor activity of tramadol mediated through ER stress, we confirmed that O-desmethyltramadol induced endoplasmic reticulum stress proteins, p-eIF2α/ eIF2α ratio, ATF4, and CHOP in western blot analysis and ATF4, DDIT3, and CHAC1 mRNAs in real-time polymerase chain reaction. Beyond the opioid receptor-mediated pathway, we further analyzed the differential functions of O-desmethyltramadol than tramadol using the RNA-seq analysis. The pathway enrichment analyses revealed that O-desmethyltramadol influenced immune and inflammatory pathways, such as TNF and IL-6/JAK/STAT3 signaling in MDA-MB-231 cells, while in MCF-7 cells, it affected metabolic and transcriptional pathways, including mTOR and MAPK signaling. Gene Set Enrichment Analysis further highlighted O-desmethyltramadol’s role in interferon response and tumor microenvironment modulation. Four upregulated genes and five downregulated genes were modulated by O-desmethyltramadol in MDA-MB-231 and MCF-7 cells. Overall, our findings indicated that O-desmethyltramadol exerted potent anti-cancer effects through multiple non-opioid mechanisms, with distinct response from tramadol depending on breast cancer subtype.
2025-05-28 | GSE292968 | GEO
Project description:Through a comparative analysis of RGC subclasses exhibiting varying levels of resilience to cell death, based on cell-cell interaction analysis, we identified the Mu-opioid receptor, encoded by the Oprm1 gene, as a novel neuroprotective factor for pan-RGCs. Functionally and with the sequencing dataset deposited here, we validated Oprm1 as a neuroprotective factor for RGCs, by demonstrating that overexpression of Oprm1 in RGCs not only led to a markedly increased survival rate of RGCs following several different types of retinal injuries, but also significantly improved visually-guided perception behaviors.
2023-12-26 | GSE248537 | GEO
Project description:Acute myeloid leukemia (AML) is a type of heterogeneous and fatal hematopoietic malignancy. The ten-eleven translocation (TET) mediated DNA demethylation is known to be critically associated with AML pathogenesis. Through chemical compound screening, we found that the opioid receptor agonist, loperamide hydrochloride (OPA1), significantly suppresses AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, were then verified in AML cells in vitro, and t(11q23) and t(8;21) AML mouse models in vivo. OPA1-induced activation of OPRM1 enhanced the transcription of TET2, increased DNA 5-hydroxymethylcytosine (5hmC) modification, and in turn, activated NFκB signaling. Notably, AML with TET2 mutations or chemotherapy resistance were highly sensitive to OPA1. Our results reveal a previously unknown OPRM1-TET2-5hmC-TRAF2 regulatory axis in AML, and suggest that opioid agonists, particularly OPA1, an FDA-approved antidiarrheal drug, have therapeutic potential in AML, especially in TET2 mutated and chemotherapy-resistant AML, which have a poor prognosis.
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Project description:Single nuclear RNA-sequencing from tissue dissected from the ventral medial preoptic area (VMPO) of the hypothalamus in saline and LPS injected mice
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