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Raise-Abdullahi P, Rahmani M, Tabaei NS, Rezamohammadi F, Vafaei AA, Ghanbari A, Rashidipour H, Meamar M, Rashidy-Pour A. Corticosteroid receptor antagonism in the medial prefrontal cortex reduces morphine-induced place preference and dopamine transporter expression decline in rats. Neuroscience 2025; 567:209-218. [PMID: 39793849 DOI: 10.1016/j.neuroscience.2025.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 12/12/2024] [Accepted: 01/07/2025] [Indexed: 01/13/2025]
Abstract
Corticosteroid signaling plays a critical role in modulating the neural systems underlying reward and addiction, but the specific contributions of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in the medial prefrontal cortex (mPFC) to opioid reward and dopaminergic plasticity remain unclear. Here, we investigated the effects of intra-mPFC injection of corticosteroid receptor ligand (corticosterone; CORT), glucocorticoid receptor antagonist (RU38486; RU), and mineralocorticoid receptor antagonist (spironolactone; SP) on morphine-induced conditioned place preference (CPP) and dopamine transporter (DAT) expression in the mPFC. Adult male Wistar rats received intra-mPFC injections of CORT, RU, SP, or their respective vehicles prior to morphine CPP conditioning. Blockade of GRs with RU (10 or 100 ng) or MRs with a low dose of SP (10 ng) attenuated the expression of morphine CPP. Morphine reduced DAT expression in the mPFC, but RU and SP prevented this effect. These findings demonstrate that corticosteroid receptor signaling within the mPFC modulates the rewarding properties of morphine and morphine-induced dopaminergic plasticity. This preclinical study suggests that targeting GRs and MRs in the mPFC could be a possible therapeutic approach for treating opioid addiction. By targeting these receptors, it may be possible to reduce opioid reward and counteract the neuroadaptations in dopamine systems associated with addiction.
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Affiliation(s)
| | - Mehrnoush Rahmani
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Narges Sadat Tabaei
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Abbas Ali Vafaei
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran; Department of Physiology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Ghanbari
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Hamed Rashidipour
- College of International Education, Dalian Medical University, Dalian, China
| | - Morvarid Meamar
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran; Clinical Research Development Unit, Kowsar Educational Research and Therapeutic Hospital, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Rashidy-Pour
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran; Department of Physiology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran.
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Dabrowski KR, Daws SE. Morphine-Driven m6A Epitranscriptomic Neuroadaptations in Primary Cortical Cultures. Mol Neurobiol 2024; 61:10684-10704. [PMID: 38780720 PMCID: PMC11584444 DOI: 10.1007/s12035-024-04219-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 05/02/2024] [Indexed: 05/25/2024]
Abstract
Opioid overdose is the leading cause of accidental death in the United States and remains a major public health concern, despite significant resources aimed at combating opioid misuse. Neurobiological research to elucidate molecular and cellular consequences of opioid exposure is required to define avenues to explore for reversal of opioid-induced neuroadaptations. Opioids impart well-documented regulation of the transcriptome and epigenetic modifications in the brain, but opioid-induced epitranscriptomic posttranscriptional regulation of RNA is vastly understudied. N6-methyladenosine (m6A) RNA methylation is significantly enriched in the brain and involved in learning, memory, and reward. m6A modifications have not been studied in opioid use disorder, despite being the most common RNA modification. We detected significant regulation of m6A-modifying enzymes in rat primary cortical cultures following morphine treatment, including AlkB Homolog 5 (Alkbh5). The m6a demethylase ALKBH5 functions as an m6A eraser, removing m6A modifications from mRNA. We hypothesized that chronic opioid treatment regulates m6A modifications through modulation of Alkbh5 and profiled m6A modifications in primary cortical cultures following chronic morphine treatment and Alkbh5 knock-down. We observed differential regulation of m6A modifications for a common set of transcripts following morphine or Alkbh5 knock-down, and the two treatments elicited concordant m6A epitranscriptomic profiles, suggesting that a subset of morphine-driven m6A modifications may be mediated through downregulation of Alkbh5 in cortical cultures. Gene Ontology terms of commonly regulated transcripts included serotonin secretion, synapse disassembly, neuron remodeling, and immune response. Thus, we conclude that morphine can drive epitranscriptomic changes, a subset of which may occur in an Alkbh5-dependent manner.
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Affiliation(s)
- Konrad R Dabrowski
- Center for Substance Abuse Research, Temple University, Philadelphia, PA, USA
- Department of Biology, Temple University, Philadelphia, PA, USA
| | - Stephanie E Daws
- Center for Substance Abuse Research, Temple University, Philadelphia, PA, USA.
- Department of Neural Sciences, Temple University, Philadelphia, PA, USA.
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Sun XY, Hou ZJ, Zhang WG, Chen Y, Yao HB. HTFSMMA: Higher-Order Topological Guided Small Molecule-MicroRNA Associations Prediction. J Comput Biol 2024; 31:886-906. [PMID: 39109562 DOI: 10.1089/cmb.2024.0587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/10/2024] Open
Abstract
Small molecules (SMs) play a pivotal role in regulating microRNAs (miRNAs). Existing prediction methods for associations between SM-miRNA have overlooked crucial aspects: the incorporation of local topological features between nodes, which represent either SMs or miRNAs, and the effective fusion of node features with topological features. This study introduces a novel approach, termed high-order topological features for SM-miRNA association prediction (HTFSMMA), which specifically addresses these limitations. Initially, an association graph is formed by integrating SM-miRNA association data, SM similarity, and miRNA similarity. Subsequently, we focus on the local information of links and propose target neighborhood graph convolutional network for extracting local topological features. Then, HTFSMMA employs graph attention networks to amalgamate these local features, thereby establishing a platform for the acquisition of high-order features through random walks. Finally, the extracted features are integrated into the multilayer perceptron to derive the association prediction scores. To demonstrate the performance of HTFSMMA, we conducted comprehensive evaluations including five-fold cross-validation, leave-one-out cross-validation (LOOCV), SM-fixed local LOOCV, and miRNA-fixed local LOOCV. The area under receiver operating characteristic curve values were 0.9958 ± 0.0024 (0.8722 ± 0.0021), 0.9986 (0.9504), 0.9974 (0.9111), and 0.9977 (0.9074), respectively. Our findings demonstrate the superior performance of HTFSMMA over existing approaches. In addition, three case studies and the DeLong test have confirmed the effectiveness of the proposed method. These results collectively underscore the significance of HTFSMMA in facilitating the inference of associations between SMs and miRNAs.
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Affiliation(s)
- Xiao-Yan Sun
- School of Computer Science and Artificial Intelligence & Aliyun Big Data, Changzhou University, Changzhou, China
| | - Zhen-Jie Hou
- School of Computer Science and Artificial Intelligence & Aliyun Big Data, Changzhou University, Changzhou, China
| | - Wen-Guang Zhang
- School of Life Sciences, Inner Mongolia Agricultural University, Hohhot, China
| | - Yan Chen
- School of Computer Science and Artificial Intelligence & Aliyun Big Data, Changzhou University, Changzhou, China
| | - Hai-Bin Yao
- School of Computer Science and Artificial Intelligence & Aliyun Big Data, Changzhou University, Changzhou, China
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Onkar A, Khan F, Goenka A, Rajendran RL, Dmello C, Hong CM, Mubin N, Gangadaran P, Ahn BC. Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications. ACS APPLIED MATERIALS & INTERFACES 2024; 16:6709-6742. [PMID: 38315446 DOI: 10.1021/acsami.3c16839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2024]
Abstract
Information exchange is essential for the brain, where it communicates the physiological and pathological signals to the periphery and vice versa. Extracellular vesicles (EVs) are a heterogeneous group of membrane-bound cellular informants actively transferring informative calls to and from the brain via lipids, proteins, and nucleic acid cargos. In recent years, EVs have also been widely used to understand brain function, given their "cell-like" properties. On the one hand, the presence of neuron and astrocyte-derived EVs in biological fluids have been exploited as biomarkers to understand the mechanisms and progression of multiple neurological disorders; on the other, EVs have been used in designing targeted therapies due to their potential to cross the blood-brain-barrier (BBB). Despite the expanding literature on EVs in the context of central nervous system (CNS) physiology and related disorders, a comprehensive compilation of the existing knowledge still needs to be made available. In the current review, we provide a detailed insight into the multifaceted role of brain-derived extracellular vesicles (BDEVs) in the intricate regulation of brain physiology. Our focus extends to the significance of these EVs in a spectrum of disorders, including brain tumors, neurodegenerative conditions, neuropsychiatric diseases, autoimmune disorders, and others. Throughout the review, parallels are drawn for using EVs as biomarkers for various disorders, evaluating their utility in early detection and monitoring. Additionally, we discuss the promising prospects of utilizing EVs in targeted therapy while acknowledging the existing limitations and challenges associated with their applications in clinical scenarios. A foundational comprehension of the current state-of-the-art in EV research is essential for informing the design of future studies.
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Affiliation(s)
- Akanksha Onkar
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, California 94143, United States
| | - Fatima Khan
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States
| | - Anshika Goenka
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, United States
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Crismita Dmello
- Department of Neurological Surgery and Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States
| | - Chae Moon Hong
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Nida Mubin
- Department of Medicine, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
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Koijam AS, Singh KD, Nameirakpam BS, Haobam R, Rajashekar Y. Drug addiction and treatment: An epigenetic perspective. Biomed Pharmacother 2024; 170:115951. [PMID: 38043446 DOI: 10.1016/j.biopha.2023.115951] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 11/23/2023] [Accepted: 11/27/2023] [Indexed: 12/05/2023] Open
Abstract
Drug addiction is a complex disease affected by numerous genetic and environmental factors. Brain regions in reward pathway, neuronal adaptations, genetic and epigenetic interactions causing transcriptional enhancement or repression of multiple genes induce different addiction phenotypes for varying duration. Addictive drug use causes epigenetic alterations and similarly epigenetic changes induced by environment can promote addiction. Epigenetic mechanisms include DNA methylation and post-translational modifications like methylation, acetylation, phosphorylation, ubiquitylation, sumoylation, dopaminylation and crotonylation of histones, and ADP-ribosylation. Non-coding RNAs also induce epigenetic changes. This review discusses these above areas and stresses the need for exploring epidrugs as a treatment alternative and adjunct, considering the limited success of current addiction treatment strategies. Epigenome editing complexes have lately been effective in eukaryotic systems. Targeted DNA cleavage techniques such as CRISPR-Cas9 system, CRISPR-dCas9 complexes, transcription activator-like effector nucleases (TALENs) and zinc-finger nucleases (ZFNs) have been exploited as targeted DNA recognition or anchoring platforms, fused with epigenetic writer or eraser proteins and delivered by transfection or transduction methods. Efficacy of epidrugs is seen in various neuropsychiatric conditions and initial results in addiction treatment involving model organisms are remarkable. Epidrugs present a promising alternative treatment for addiction.
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Affiliation(s)
- Arunkumar Singh Koijam
- Insect Bioresources Laboratory, Animal Bioresources Programme, Institute of Bioresources & Sustainable Development, Department of Biotechnology, Govt. of India, Takyelpat, Imphal 795001, Manipur, India
| | - Kabrambam Dasanta Singh
- Insect Bioresources Laboratory, Animal Bioresources Programme, Institute of Bioresources & Sustainable Development, Department of Biotechnology, Govt. of India, Takyelpat, Imphal 795001, Manipur, India
| | - Bunindro Singh Nameirakpam
- Insect Bioresources Laboratory, Animal Bioresources Programme, Institute of Bioresources & Sustainable Development, Department of Biotechnology, Govt. of India, Takyelpat, Imphal 795001, Manipur, India
| | - Reena Haobam
- Department of Biotechnology, Manipur University, Canchipur, Imphal 795003, Manipur, India
| | - Yallappa Rajashekar
- Insect Bioresources Laboratory, Animal Bioresources Programme, Institute of Bioresources & Sustainable Development, Department of Biotechnology, Govt. of India, Takyelpat, Imphal 795001, Manipur, India.
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Occhipinti C, La Russa R, Iacoponi N, Lazzari J, Costantino A, Di Fazio N, Del Duca F, Maiese A, Fineschi V. miRNAs and Substances Abuse: Clinical and Forensic Pathological Implications: A Systematic Review. Int J Mol Sci 2023; 24:17122. [PMID: 38069445 PMCID: PMC10707252 DOI: 10.3390/ijms242317122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 11/17/2023] [Accepted: 11/28/2023] [Indexed: 12/18/2023] Open
Abstract
Substance addiction is a chronic and relapsing brain disorder characterized by compulsive seeking and continued substance use, despite adverse consequences. The high prevalence and social burden of addiction are indisputable; however, the available intervention is insufficient. The modulation of gene expression and aberrant adaptation of neural networks are attributed to the changes in brain functions under repeated exposure to addictive substances. Considerable studies have demonstrated that miRNAs are strong modulators of post-transcriptional gene expression in substance addiction. The emerging role of microRNA (miRNA) provides new insights into many biological and pathological processes in the central nervous system: their variable expression in different regions of the brain and tissues may play a key role in regulating the pathophysiological events of addiction. This work provides an overview of the current literature on miRNAs involved in addiction, evaluating their impaired expression and regulatory role in neuroadaptation and synaptic plasticity. Clinical implications of such modulatory capacities will be estimated. Specifically, it will evaluate the potential diagnostic role of miRNAs in the various stages of drug and substance addiction. Future perspectives about miRNAs as potential novel therapeutic targets for substance addiction and abuse will also be provided.
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Affiliation(s)
- Carla Occhipinti
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa, Italy; (C.O.); (N.I.); (J.L.); (A.C.)
| | - Raffaele La Russa
- Department of Clinical Medicine, Public Health, Life Sciences, and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy;
| | - Naomi Iacoponi
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa, Italy; (C.O.); (N.I.); (J.L.); (A.C.)
| | - Julia Lazzari
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa, Italy; (C.O.); (N.I.); (J.L.); (A.C.)
| | - Andrea Costantino
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa, Italy; (C.O.); (N.I.); (J.L.); (A.C.)
| | - Nicola Di Fazio
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome, Italy; (N.D.F.); (F.D.D.); (V.F.)
| | - Fabio Del Duca
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome, Italy; (N.D.F.); (F.D.D.); (V.F.)
| | - Aniello Maiese
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa, Italy; (C.O.); (N.I.); (J.L.); (A.C.)
| | - Vittorio Fineschi
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome, Italy; (N.D.F.); (F.D.D.); (V.F.)
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Przybylowicz PK, Sokolowska KE, Rola H, Wojdacz TK. DNA Methylation Changes in Blood Cells of Fibromyalgia and Chronic Fatigue Syndrome Patients. J Pain Res 2023; 16:4025-4036. [PMID: 38054109 PMCID: PMC10695140 DOI: 10.2147/jpr.s439412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 11/13/2023] [Indexed: 12/07/2023] Open
Abstract
Purpose Fibromyalgia (FM) and Chronic Fatigue Syndrome (CFS) affect 0.4% and 1% of society, respectively, and the prevalence of these pain syndromes is increasing. To date, no strong association between these syndromes and the genetic background of affected individuals has been shown. Therefore, it is plausible that epigenetic changes might play a role in the development of these syndromes. Patients and Methods Three previous studies have attempted to elaborate the involvement of genome-wide methylation changes in blood cells in the development of fibromyalgia and chronic fatigue syndrome. These studies included 22 patients with fibromyalgia and 127 patients with CFS, and the results of the studies were largely discrepant. Contradicting results of those studies may be attributed to differences in the omics data analysis approaches used in each study. We reanalyzed the data collected in these studies using an updated and coherent data-analysis framework. Results Overall, the methylation changes that we observed overlapped with previous results only to some extent. However, the gene set enrichment analyses based on genes annotated to methylation changes identified in each of the analyzed datasets were surprisingly coherent and uniformly associated with the physiological processes that, when affected, may result in symptoms characteristic of fibromyalgia and chronic fatigue syndrome. Conclusion Methylomes of the blood cells of patients with FM and CFS in three independent studies have shown methylation changes that appear to be implicated in the pathogenesis of these syndromes.
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Affiliation(s)
| | | | - Hubert Rola
- Independent Clinical Epigenetics Laboratory, Pomeranian Medical University, Szczecin, Poland
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Rezayof A, Ghasemzadeh Z, Sahafi OH. Addictive drugs modify neurogenesis, synaptogenesis and synaptic plasticity to impair memory formation through neurotransmitter imbalances and signaling dysfunction. Neurochem Int 2023; 169:105572. [PMID: 37423274 DOI: 10.1016/j.neuint.2023.105572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 07/01/2023] [Accepted: 07/05/2023] [Indexed: 07/11/2023]
Abstract
Drug abuse changes neurophysiological functions at multiple cellular and molecular levels in the addicted brain. Well-supported scientific evidence suggests that drugs negatively affect memory formation, decision-making and inhibition, and emotional and cognitive behaviors. The mesocorticolimbic brain regions are involved in reward-related learning and habitual drug-seeking/taking behaviors to develop physiological and psychological dependence on the drugs. This review highlights the importance of specific drug-induced chemical imbalances resulting in memory impairment through various neurotransmitter receptor-mediated signaling pathways. The mesocorticolimbic modifications in the expression levels of brain-derived neurotrophic factor (BDNF) and the cAMP-response element binding protein (CREB) impair reward-related memory formation following drug abuse. The contributions of protein kinases and microRNAs (miRNAs), along with the transcriptional and epigenetic regulation have also been considered in memory impairment underlying drug addiction. Overall, we integrate the research on various types of drug-induced memory impairment in distinguished brain regions and provide a comprehensive review with clinical implications addressing the upcoming studies.
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Affiliation(s)
- Ameneh Rezayof
- Department of Animal Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
| | - Zahra Ghasemzadeh
- Department of Animal Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Oveis Hosseinzadeh Sahafi
- Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
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Reddy D, Wickman JR, Ajit SK. Epigenetic regulation in opioid induced hyperalgesia. NEUROBIOLOGY OF PAIN (CAMBRIDGE, MASS.) 2023; 14:100146. [PMID: 38099284 PMCID: PMC10719581 DOI: 10.1016/j.ynpai.2023.100146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/14/2023] [Accepted: 11/21/2023] [Indexed: 12/17/2023]
Abstract
About 25 million American adults experience pain daily and one of the most commonly prescribed drugs to treat pain are opioids. Prolonged opioid usage and dose escalations can cause a paradoxical response where patients experience enhanced pain sensitivity. This opioid induced hyperalgesia (OIH) is a major hurdle when treating pain in the clinic because its underlying mechanisms are still not fully understood. OIH is also commonly overlooked and lacks guidelines to prevent its onset. Research on pain disorders and opioid usage have recognized potential epigenetic drivers of disease including DNA methylation, histone modifications, miRNA regulation, but their involvement in OIH has not been well studied. This article discusses epigenetic changes that may contribute to pathogenesis, with an emphasis on miRNA alterations in OIH. There is a crucial gap in knowledge including how multiple epigenetic modulators contribute to OIH. Elucidating the epigenetic changes underlying OIH and the crosstalk among these mechanisms could lead to the development of novel targets for the prevention and treatment of this painful phenomena.
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Affiliation(s)
- Deepa Reddy
- Department of Pharmacology & Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA
| | - Jason R. Wickman
- Department of Pharmacology & Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA
| | - Seena K. Ajit
- Department of Pharmacology & Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA
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Zanda MT, Floris G, Daws SE. Orbitofrontal cortex microRNAs support long-lasting heroin seeking behavior in male rats. Transl Psychiatry 2023; 13:117. [PMID: 37031193 PMCID: PMC10082780 DOI: 10.1038/s41398-023-02423-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 03/23/2023] [Accepted: 03/29/2023] [Indexed: 04/10/2023] Open
Abstract
Recovery from opioid use disorder (OUD) and maintenance of abstinence from opioid use is hampered by perseverant drug cravings that may persist for months after cessation of drug use. Drug cravings can intensify during the abstinence period, a phenomenon referred to as the 'incubation of craving' that has been well-described in preclinical studies. We previously reported that animals that self-administered heroin at a dosage of 0.075 mg/kg/infusion (HH) paired with discrete drug cues displayed robust incubation of heroin craving behavior after 21 days (D) of forced abstinence, an effect that was not observed with a lower dosage (0.03 mg/kg/infusion; HL). Here, we sought to elucidate molecular mechanisms underlying long-term heroin seeking behavior by profiling microRNA (miRNA) pathways in the orbitofrontal cortex (OFC), a brain region that modulates incubation of heroin seeking. miRNAs are small noncoding RNAs with long half-lives that have emerged as critical regulators of drug seeking behavior but their expression in the OFC has not been examined in any drug exposure paradigm. We employed next generation sequencing to detect OFC miRNAs differentially expressed after 21D of forced abstinence between HH and HL animals, and proteomics analysis to elucidate miRNA-dependent translational neuroadaptations. We identified 55 OFC miRNAs associated with incubation of heroin craving, including miR-485-5p, which was significantly downregulated following 21D forced abstinence in HH but not HL animals. We bidirectionally manipulated miR-485-5p in the OFC to demonstrate that miR-485-5p can regulate long-lasting heroin seeking behavior after extended forced abstinence. Proteomics analysis identified 45 proteins selectively regulated in the OFC of HH but not HL animals that underwent 21D forced abstinence, of which 7 were putative miR-485-5p target genes. Thus, the miR-485-5p pathway is dysregulated in animals with a phenotype of persistent heroin craving behavior and OFC miR-485-5p pathways may function to support long-lasting heroin seeking.
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Affiliation(s)
- Mary Tresa Zanda
- Center for Substance Abuse Research, Temple University, Philadelphia, PA, USA
- Department of Neural Sciences, Temple University, Philadelphia, PA, USA
| | - Gabriele Floris
- Center for Substance Abuse Research, Temple University, Philadelphia, PA, USA
- Department of Neural Sciences, Temple University, Philadelphia, PA, USA
| | - Stephanie E Daws
- Center for Substance Abuse Research, Temple University, Philadelphia, PA, USA.
- Department of Neural Sciences, Temple University, Philadelphia, PA, USA.
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Fu X, Zhang Y. Research progress of p38 as a new therapeutic target against morphine tolerance and the current status of therapy of morphine tolerance. J Drug Target 2023; 31:152-165. [PMID: 36264036 DOI: 10.1080/1061186x.2022.2138895] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
With the development of the medical industry, new painkillers continue to appear in people's field of vision, but so far no painkiller can replace morphine. While morphine has a strong analgesic effect, it is also easy to produce pain sensitivity and tolerance. Due to the great inter-individual differences in patient responses, there are few clear instructions on how to optimise morphine administration regimens, which complicates clinicians' treatment strategies and limits the effectiveness of morphine in long-term pain therapy. P38MAPK is a key member of the MAPK family. Across recent years, it has been discovered that p38MAPK rises dramatically in a wide range of morphine tolerance animal models. Morphine tolerance can be reduced or reversed by inhibiting p38MAPK. However, the role and specific mechanism of p38MAPK are not clear. In this review, we synthesise the relevant findings, highlight the function and potential mechanism of p38MAPK in morphine tolerance, as well as the present status and efficacy of morphine tolerance therapy, and underline the future promise of p38MAPK targeted morphine tolerance treatment.
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Affiliation(s)
- Xiao Fu
- Inner Mongolia Medical University, Hohhot, China
| | - Yanhong Zhang
- Department of Anesthesiology, People's Hospital Affiliated to Inner Mongolia Medical University, Hohhot, China
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Chen J, Wang J, Zou L, Zhu S, Li K, Liao L, Ruan J, Chu H. Effects of moxibustion on miRNA-133b, Pitx3/TH, and neurotransmitters in the midbrain of rats with diarrhea-predominant irritable bowel syndrome. JOURNAL OF ACUPUNCTURE AND TUINA SCIENCE 2022. [DOI: 10.1007/s11726-022-1343-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Abstract
Objective
To investigate the mechanism of moxibustion in the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D), by observing the effects of moxibustion at Tianshu (ST25) and Shangjuxu (ST37) on microRNA-133b (miRNA-133b), pituitary homeobox family factor 3 (Pitx3)/tyrosine hydroxylase (TH), and neurotransmitters in the brain tissue of IBS-D rats.
Methods
Healthy Sprague-Dawley rats were randomly divided into a normal group, a model group, a moxibustion group, and a Western medicine group, with 12 rats in each group. Except for the normal group, the IBS-D rat model was established by mother-offspring separation and acetic acid enema combined with restraint stress stimulation in all the other groups. No intervention was performed in the normal and model groups. Mild moxibustion was applied to both Tianshu (ST25) and Shangjuxu (ST37) in the moxibustion group. Rifaximin was given by gavage in the Western medicine group. The physical status of rats in each group was observed at different periods. After the intervention, hematoxylineosin staining was performed to observe the histopathological morphology of rat colon; enzyme-linked immunosorbent assay was used to measure the levels of dopamine (DA), noradrenaline (NE), and 5-hydroxytryptamine (5-HT) in plasma, colon, and midbrain tissue of rats; the relative expression levels of miRNA-133b, Pitx3 mRNA, and TH mRNA in the midbrain tissue were measured by real-time fluorescence quantitative polymerase chain reaction, and the relative expression levels of Pitx3 and TH proteins in the midbrain tissue were measured by Western blotting and immunofluorescence.
Results
The body weights of rats among groups and at different time points were statistically different (P<0.01). The body weight of the normal group was higher than that of the other groups over time (P<0.01). After modeling, the minimum volume threshold of abdominal withdrawal reflex (AWR) was significantly lower (P<0.01) and the loose stool rate was significantly higher (P<0.01) in the model, moxibustion, and Western medicine groups compared with the normal group; the miRNA-133b expression in the midbrain tissue was significantly lower (P<0.01), the expression levels of Pitx3 and TH in the midbrain tissue were significantly higher (P<0.01), and the levels of DA, NE, and 5-HT in plasma, colon and midbrain tissue were significantly higher (P<0.01). After the intervention, the minimum volume threshold of AWR was significantly higher (P<0.01), the loose stool rate was significantly lower (P<0.01), the miRNA-133b expression was significantly increased (P<0.01 or P<0.05) and the expression levels of Pitx3 and TH were significantly decreased (P<0.01) in the midbrain tissue, the levels of DA, NE, and 5-HT in plasma, colon, and midbrain tissue were significantly reduced (P<0.01) in the moxibustion and Western medicine groups compared with the model group; the levels of 5-HT in the colon and midbrain tissue of the moxibustion group were significantly lower than those in the Western medicine group (P<0.05), and there was no statistical difference compared with the remaining groups (P>0.05). Linear correlation analysis showed that miRNA-133b was negatively correlated with Pitx3 (r<0, P<0.01); Pitx3 with TH, TH with DA, and NE with 5-HT were positively correlated (r>0, P<0.01).
Conclusion
Moxibustion at Tianshu (ST25) and Shangjuxu (ST37) improves diarrhea symptoms and visceral hypersensitivity in IBS-D rats. The mechanism may be related to up-regulating miRNA-133b, inhibiting Pitx3/TH, and reducing neurotransmitter expression levels in the midbrain tissue.
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Zhao Y, Qin F, Han S, Li S, Zhao Y, Wang H, Tian J, Cen X. MicroRNAs in drug addiction: Current status and future perspectives. Pharmacol Ther 2022; 236:108215. [DOI: 10.1016/j.pharmthera.2022.108215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/11/2022] [Accepted: 05/16/2022] [Indexed: 12/21/2022]
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Gillespie A, Mayberry HL, Wimmer ME, Sillivan SE. microRNA expression levels in the nucleus accumbens correlate with morphine-taking but not morphine-seeking behaviour in male rats. Eur J Neurosci 2022; 55:1742-1755. [PMID: 35320877 PMCID: PMC9314918 DOI: 10.1111/ejn.15650] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/04/2022] [Accepted: 03/15/2022] [Indexed: 12/01/2022]
Abstract
A powerful motivation to seek opioids remains after drug cessation and intensifies during extended periods of abstinence. Unfortunately, biomarkers associated with continued drug seeking have not been described. Moreover, previous studies have focused on the effects of early abstinence with little exploration into the long-term drug-induced mechanisms that occur after extended abstinence. Here we demonstrated that 30 days (D) of forced abstinence results in a time-dependent increase in morphine seeking in a rat model of morphine self-administration (SA). We measured expression of known drug-responsive microRNAs (miRNAs) in the nucleus accumbens, an area critical for reward-related plasticity, during early or late abstinence in animals that underwent either a cue-induced relapse test or no relapse test. miRNAs are small noncoding RNAs that represent suitable biomarker candidates due to their long-lasting nature. mir-32-5p levels during early abstinence negatively correlated with active lever pressing in both cue-exposed and cue-naïve animals. mir-1298-5p positively correlated with drug SA history after a relapse test during late abstinence. When animals underwent acute abstinence with no relapse test, mir-1298-5p correlated with drug infusions and active lever pressing during SA. In late abstinence with no relapse test, mir-137-3p negatively correlated with drug infusions. Regulation of mir-32-5p target genes and significant correlation of target gene mRNA with mir-32-5p was observed after abstinence. These results indicate that lasting regulation of miRNA expression is associated with drug intake following morphine SA. In addition, we conclude that the miRNA profile undergoes regulation from early to late abstinence and miRNA expression may indicate past drug history.
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Affiliation(s)
- Aria Gillespie
- Center for Substance Abuse ResearchTemple UniversityPhiladelphiaPennsylvaniaUSA,Department of Neural SciencesTemple UniversityPhiladelphiaPAUSA
| | - Hannah L. Mayberry
- Department of Psychology and Neuroscience Program, College of Liberal ArtsTemple UniversityPhiladelphiaPennsylvaniaUSA
| | - Mathieu E. Wimmer
- Department of Psychology and Neuroscience Program, College of Liberal ArtsTemple UniversityPhiladelphiaPennsylvaniaUSA
| | - Stephanie E. Sillivan
- Center for Substance Abuse ResearchTemple UniversityPhiladelphiaPennsylvaniaUSA,Department of Neural SciencesTemple UniversityPhiladelphiaPAUSA
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Farrokhfar S, Tiraihi T, Movahedin M, Azizi H. Morphine Induces Differential Gene Expression in Transdifferentiated Neuron-Like Cells from Adipose-Derived Stem Cells. BIOL BULL+ 2022. [DOI: 10.1134/s1062359022130052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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16
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Exosomal microRNAs have great potential in the neurorestorative therapy for traumatic brain injury. Exp Neurol 2022; 352:114026. [DOI: 10.1016/j.expneurol.2022.114026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 02/09/2022] [Accepted: 02/22/2022] [Indexed: 11/19/2022]
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Zhang Y, Liu J, Xie C, Wu P. Overexpression of miR-133b protects against isoflurane-induced learning and memory impairment. Exp Ther Med 2021; 22:1207. [PMID: 34584552 DOI: 10.3892/etm.2021.10641] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 11/17/2020] [Indexed: 12/21/2022] Open
Abstract
A number of microRNAs (miRs) have been identified as being involved in the regulation of anesthesia-induced cognitive impairment. The aim of the present study was to investigated the role and potential mechanism of miR-133b in isoflurane-induced learning and memory impairment. An animal model of isoflurane exposure was established using neonatal Sprague-Dawley rats. The rats were trained for Morris water maze (MWM) testing to assess their spatial learning and memory ability. Reverse transcription-quantitative polymerase chain reaction was used for the measurement of miR-133b expression in hippocampal tissues and primary hippocampal neuron cultures. Cell viability was assessed using a Cell Counting Kit-8 assay, and flow cytometric analysis was used to determine the rate of apoptosis. The MWM test results indicated that during the training period, the time required to locate the platform was significantly increased for rats exposed to isoflurane, and this increased time was reduced by the overexpression of miR-133b. The results of a probe trial indicated that isoflurane exposure increased escape latency and decreased the time spent in the platform area for isoflurane-treated rats; however, these effects were reversed by the injection of miR-133b agomir. The in vitro experiments demonstrated that the overexpression of miR-133b attenuated the reduction of neuronal cell viability induced by isoflurane, and inhibited the isoflurane-induced apoptosis of hippocampal neurons. In conclusion, the present study revealed that the overexpression of miR-133b attenuated isoflurane-induced learning and memory impairment in rats. Furthermore, miR-133b overexpression promoted the viability of hippocampal neurons and their resistance to apoptosis when exposed to isoflurane.
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Affiliation(s)
- Yu Zhang
- Department of Anesthesiology, Jining No. 1 People's Hospital, Jining, Shandong 272000, P.R. China
| | - Jinyong Liu
- Department of Anesthesiology, Jining No. 1 People's Hospital, Jining, Shandong 272000, P.R. China
| | - Cuili Xie
- Department of Anesthesiology, Jining No. 1 People's Hospital, Jining, Shandong 272000, P.R. China
| | - Pingping Wu
- Clinical Laboratory, Jining No. 1 People's Hospital, Jining, Shandong 272000, P.R. China
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Saad L, Zwiller J, Kalsbeek A, Anglard P. Epigenetic Regulation of Circadian Clocks and Its Involvement in Drug Addiction. Genes (Basel) 2021; 12:1263. [PMID: 34440437 PMCID: PMC8394526 DOI: 10.3390/genes12081263] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/04/2021] [Accepted: 08/11/2021] [Indexed: 12/19/2022] Open
Abstract
Based on studies describing an increased prevalence of addictive behaviours in several rare sleep disorders and shift workers, a relationship between circadian rhythms and addiction has been hinted for more than a decade. Although circadian rhythm alterations and molecular mechanisms associated with neuropsychiatric conditions are an area of active investigation, success is limited so far, and further investigations are required. Thus, even though compelling evidence connects the circadian clock to addictive behaviour and vice-versa, yet the functional mechanism behind this interaction remains largely unknown. At the molecular level, multiple mechanisms have been proposed to link the circadian timing system to addiction. The molecular mechanism of the circadian clock consists of a transcriptional/translational feedback system, with several regulatory loops, that are also intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape shows profound changes in the addictive brain, with significant alterations in histone modification, DNA methylation, and small regulatory RNAs. The combination of these two observations raises the possibility that epigenetic regulation is a common plot linking the circadian clocks with addiction, though very little evidence has been reported to date. This review provides an elaborate overview of the circadian system and its involvement in addiction, and we hypothesise a possible connection at the epigenetic level that could further link them. Therefore, we think this review may further improve our understanding of the etiology or/and pathology of psychiatric disorders related to drug addiction.
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Affiliation(s)
- Lamis Saad
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; (L.S.); (J.Z.)
- The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), 1105 BA Amsterdam, The Netherlands;
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Jean Zwiller
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; (L.S.); (J.Z.)
- Centre National de la Recherche Scientifique (CNRS), 75016 Paris, France
| | - Andries Kalsbeek
- The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), 1105 BA Amsterdam, The Netherlands;
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Patrick Anglard
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; (L.S.); (J.Z.)
- Institut National de la Santé et de la Recherche Médicale (INSERM), 75013 Paris, France
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Nasirishargh A, Kumar P, Ramasubramanian L, Clark K, Hao D, Lazar SV, Wang A. Exosomal microRNAs from mesenchymal stem/stromal cells: Biology and applications in neuroprotection. World J Stem Cells 2021; 13:776-794. [PMID: 34367477 PMCID: PMC8316862 DOI: 10.4252/wjsc.v13.i7.776] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/29/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are extensively studied as cell-therapy agents for neurological diseases. Recent studies consider exosomes secreted by MSCs as important mediators for MSCs' neuroprotective functions. Exosomes transfer functional molecules including proteins, lipids, metabolites, DNAs, and coding and non-coding RNAs from MSCs to their target cells. Emerging evidence shows that exosomal microRNAs (miRNAs) play a key role in the neuroprotective properties of these exosomes by targeting several genes and regulating various biological processes. Multiple exosomal miRNAs have been identified to have neuroprotective effects by promoting neurogenesis, neurite remodeling and survival, and neuroplasticity. Thus, exosomal miRNAs have significant therapeutic potential for neurological disorders such as stroke, traumatic brain injury, and neuroinflammatory or neurodegenerative diseases and disorders. This review discusses the neuroprotective effects of selected miRNAs (miR-21, miR-17-92, miR-133, miR-138, miR-124, miR-30, miR146a, and miR-29b) and explores their mechanisms of action and applications for the treatment of various neurological disease and disorders. It also provides an overview of state-of-the-art bioengineering approaches for isolating exosomes, optimizing their yield and manipulating the miRNA content of their cargo to improve their therapeutic potential.
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Affiliation(s)
- Aida Nasirishargh
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
| | - Priyadarsini Kumar
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
| | - Lalithasri Ramasubramanian
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, United States
| | - Kaitlin Clark
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
| | - Dake Hao
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
| | - Sabrina V Lazar
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
| | - Aijun Wang
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
- Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, United States.
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20
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Kai Yue, Chen K, Ma B, Pi M. Global Effects of Heroin Self-Administration on microRNA Expression Profiles in Rat Brain. NEUROCHEM J+ 2021. [DOI: 10.1134/s1819712421020161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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21
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Delivery of Therapeutic Agents to the Central Nervous System and the Promise of Extracellular Vesicles. Pharmaceutics 2021; 13:pharmaceutics13040492. [PMID: 33916841 PMCID: PMC8067091 DOI: 10.3390/pharmaceutics13040492] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 03/26/2021] [Accepted: 03/30/2021] [Indexed: 12/17/2022] Open
Abstract
The central nervous system (CNS) is surrounded by the blood–brain barrier (BBB), a semipermeable border of endothelial cells that prevents pathogens, solutes and most molecules from non-selectively crossing into the CNS. Thus, the BBB acts to protect the CNS from potentially deleterious insults. Unfortunately, the BBB also frequently presents a significant barrier to therapies, impeding passage of drugs and biologicals to target cells within the CNS. This review provides an overview of different approaches to deliver therapeutics across the BBB, with an emphasis in extracellular vesicles as delivery vehicles to the CNS.
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Singh T, Yadav S. Role of microRNAs in neurodegeneration induced by environmental neurotoxicants and aging. Ageing Res Rev 2020; 60:101068. [PMID: 32283224 DOI: 10.1016/j.arr.2020.101068] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 03/02/2020] [Accepted: 04/04/2020] [Indexed: 02/06/2023]
Abstract
The progressive loss of neuronal structure and functions resulting in the death of neurons is considered as neurodegeneration. Environmental toxicants induced degeneration of neurons is accelerated with aging. In adult brains, most of the neurons are post-mitotic, and their loss results in the development of diseases like amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). Neurodegenerative diseases have several similarities at the sub-cellular and molecular levels, such as synaptic degeneration, oxidative stress, inflammation, and cognitive decline, which are also known in brain aging. Identification of these similarities at the molecular level offers hope for the development of new therapeutics to ameliorate all neurodegenerative diseases simultaneously. Aging is known as the most strongly associated additive factor in the pathogenesis of neurodegenerative diseases. Studies carried out so far identified several genes, which are responsible for selective degeneration of neurons in different neurodegenerative diseases. Countless efforts have been made in identifying therapeutics for neurodegenerative diseases; however, the discovery of effective therapy remains elusive. Findings made in the last two decades identified microRNAs (miRNAs) as the most potent post-transcription regulatory RNA molecule, which can condition protein levels in the cell and tissue-specific manner. Identification of miRNAs, which regulate both neurotoxicant and aging-associated degeneration of brain cells, raises the possibility that roads leading to aging and neurotoxicant induced neurodegeneration cross at some point. Identification of miRNAs, which are common to aging and neurotoxicant induced neurodegeneration, will help in understanding the complex mechanism of neurodegenerative disease development. In the future, the use of natural miRNAs in vivo in therapy will be able to tackle several issues of aging and neurodegeneration. In the present review, we have provided a summary of findings made on the role of miRNAs in neurodegeneration and explored the common link made by miRNAs between aging and neurotoxicants induced neurodegeneration.
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Affiliation(s)
- Tanisha Singh
- Developmental Toxicology Division, Systems Toxicology and Health Risk Assessment Group, CSIR- Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan,31 Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India; Department of Neurological Surgery, School of Medicine, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, Pennsylvania-15213, USA.
| | - Sanjay Yadav
- Developmental Toxicology Division, Systems Toxicology and Health Risk Assessment Group, CSIR- Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan,31 Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India; Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Raebareli, Munsiganj, Raebareli 229405, UP, India.
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23
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Zhang H, Wang Q, Wang Q, Liu A, Qin F, Sun Q, Li Q, Gu Y, Tang Z, Lu S, Lu Z. Circular RNA expression profiling in the nucleus accumbens: Effects of electroacupuncture treatment on morphine-induced conditioned place preference. Addict Biol 2020; 25:e12794. [PMID: 31240833 DOI: 10.1111/adb.12794] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 04/16/2019] [Accepted: 05/23/2019] [Indexed: 11/30/2022]
Abstract
Electroacupuncture (EA) has been developed on the basis of traditional Chinese acupuncture. EA can suppress craving in opioid addicts and opioid-seeking responses in rodents. However, the molecular mechanism of EA on the rewarding properties of morphine and craving responses is not known. Here, we have applied a conditioned place preference paradigm in mice to measure morphine-induced rewarding effects along with EA treatment. Circular RNAs (circRNAs) can function as micro RNA (miRNA) sponges to effectively regulate gene expression levels. CircRNA profiling within the nucleus accumbens (NAc) was performed in EA-treated and sham-treated mice. Following RNAseq, data were analyzed by gene ontology (GO) and Kyoto Encyclopedia Genes and Genomes (KEGG) tools. We identified 112 significantly differentially expressed circRNAs, including 51 that were up-regulated and 61 that were down-regulated. Our bioinformatics analyses show that these differentially expressed circRNAs map into pathways that are mainly involved with renin secretion and the cGMP-PKG signaling. We further constructed a circRNA-miRNA network that predicts the potential roles of the differentially expressed circRNAs and the interaction of circRNAs with miRNAs. Our secondary sequencing and bioinformatics analysis in the NAc after EA treatment on morphine-induced CPP provides putative novel targets on molecular mechanisms involved in morphine reinforcement and possibly craving.
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Affiliation(s)
- Han Zhang
- First Clinical Medical College Nanjing University of Chinese Medicine China
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education Nanjing University of Chinese Medicine China
| | - Qian Wang
- International Education college Nanjing University of Chinese Medicine China
| | - Qisheng Wang
- First Clinical Medical College Nanjing University of Chinese Medicine China
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education Nanjing University of Chinese Medicine China
| | - Anlong Liu
- First Clinical Medical College Nanjing University of Chinese Medicine China
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education Nanjing University of Chinese Medicine China
| | - Fenfen Qin
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education Nanjing University of Chinese Medicine China
- College of Pharmacy Nanjing University of Chinese Medicine China
| | - Qinmei Sun
- First Clinical Medical College Nanjing University of Chinese Medicine China
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education Nanjing University of Chinese Medicine China
| | - Qian Li
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education Nanjing University of Chinese Medicine China
| | - Yun Gu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education Nanjing University of Chinese Medicine China
| | - Zongxiang Tang
- School of Medicine and Life Science Nanjing University of Chinese Medicine China
| | - Shengfeng Lu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education Nanjing University of Chinese Medicine China
| | - Zhigang Lu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education Nanjing University of Chinese Medicine China
- College of Pharmacy Nanjing University of Chinese Medicine China
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Pei G, Xu L, Huang W, Yin J. RETRACTED: The protective role of microRNA-133b in restricting hippocampal neurons apoptosis and inflammatory injury in rats with depression by suppressing CTGF. Int Immunopharmacol 2020; 78:106076. [PMID: 31830619 DOI: 10.1016/j.intimp.2019.106076] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 11/14/2019] [Accepted: 11/21/2019] [Indexed: 02/03/2023]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Concern was raised about the integrity of the images in Figures 5, 6A and 8A, which appear to contain suspected duplications, as detailed here: https://pubpeer.com/publications/773D824533241B2186D16AA3FFCB3F and here: https://docs.google.com/spreadsheets/d/1r0MyIYpagBc58BRF9c3luWNlCX8VUvUuPyYYXzxWvgY/edit#gid=262337249. Additional suspected image duplications were detected within Figure 7A. Our analysis suggested these image anomalies represent either direct duplications of the entire image, or contain several repeated features between or within an image. The journal requested the corresponding author comment on these concerns and provide the raw data. The authors did not respond to this request and therefore the Editor-in-Chief decided to retract the article.
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Affiliation(s)
- Gaoyou Pei
- Intervention Department, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, China
| | - Liguo Xu
- Intervention Department, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, China
| | - Wenhao Huang
- Intervention Department, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, China
| | - Jianjun Yin
- Health Examination Department, Qingdao Hiser Medica, Qingdao 266000, Shandong, China.
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Decreased Level of Blood MicroRNA-133b in Men with Opioid Use Disorder on Methadone Maintenance Therapy. J Clin Med 2019; 8:jcm8081105. [PMID: 31349687 PMCID: PMC6722972 DOI: 10.3390/jcm8081105] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/14/2019] [Accepted: 07/24/2019] [Indexed: 12/20/2022] Open
Abstract
Although previous animal studies have indicated that certain micro ribonucleic acids (microRNAs) play a part in the pathway of opioid addiction, whether such findings extend to human models is yet unknown. This study aims to investigate the important microRNA expressions in patients with opioid use disorder (OUD) on methadone maintenance treatment (MMT) compared to healthy controls and analyze the correlation between microRNAs and opioid characteristics among the patients. We recruited 50 patients and 25 controls, and both groups were matched regarding gender, age, and body mass index. Serum microRNAs (miR-133b, miR-23b, miR-190, miR-206, miR-210, and miR-21) were measured. The age of OUD onset, duration of MMT participation, and recent daily methadone dosage were considered the opioid characteristics. We adopted the t-test to compare the difference between patients and controls and Pearson's correlation to evaluate the association between microRNAs and opioid profiles. Only the level of miR-133b in OUD patients on MMT was significantly lower than that in healthy controls. We did not detect differences of any other microRNA expressions between the two groups. Furthermore, we found no evidence to support the association between microRNAs and opioid characteristics. This study indicates that miR-133b values may be decreased in OUD patients on MMT.
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Félix L, Coimbra AM, Valentim AM, Antunes L. Review on the use of zebrafish embryos to study the effects of anesthetics during early development. Crit Rev Toxicol 2019; 49:357-370. [PMID: 31314655 DOI: 10.1080/10408444.2019.1617236] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Over the years, the potential toxicity of anesthetics has raised serious concerns about its safe use during pregnancy. As evidence emerged from research in animal models, showing that some anesthetic drugs are potential teratogenic, the determination of the risk of exposures to anesthetic drugs at early life stages became mandatory. However, due to inaccessibility and ethical constrains related to experimental conditions, the use of early life stages in mammalian models is limited. In this regard, some animal and nonanimal models have been suggested to surpass mammalian use in experimentation. Among them, the zebrafish embryo test has been recognized as a promising alternative in toxicology research, as well as an inexpensive and practical test. Substantial information collected from developmental research following compounds exposure, has contributed to the application of zebrafish assays in research, although only a few studies have focused on the use of early life stages of zebrafish to evaluate the developmental effects of anesthetics. Based on the recent advances of science and technology, there is a clear potential for zebrafish early life stages to provide new insights into anesthetics teratogenicity. This review provides an overview of recent anesthesia research using zebrafish embryos, demonstrating its usefulness to the anesthesia field, discussing the recent findings on various aspects related to the effects of anesthetics during early life development and the strengths and limitations of this model system.
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Affiliation(s)
- Luís Félix
- Institute for Research and Innovation in Health, Laboratory Animal Science, Institute of Molecular and Cell Biology, University of Porto , Porto , Portugal.,Centre for the Research and Technology of Agro-Environmental and Biological Sciences, University of Trás-os-Montes and Alto Douro , Vila Real , Portugal
| | - Ana Maria Coimbra
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences, University of Trás-os-Montes and Alto Douro , Vila Real , Portugal
| | - Ana Maria Valentim
- Institute for Research and Innovation in Health, Laboratory Animal Science, Institute of Molecular and Cell Biology, University of Porto , Porto , Portugal.,Centre for the Research and Technology of Agro-Environmental and Biological Sciences, University of Trás-os-Montes and Alto Douro , Vila Real , Portugal
| | - Luís Antunes
- Institute for Research and Innovation in Health, Laboratory Animal Science, Institute of Molecular and Cell Biology, University of Porto , Porto , Portugal.,Centre for the Research and Technology of Agro-Environmental and Biological Sciences, University of Trás-os-Montes and Alto Douro , Vila Real , Portugal
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The Emerging Perspective of Morphine Tolerance: MicroRNAs. Pain Res Manag 2019; 2019:9432965. [PMID: 31182985 PMCID: PMC6515020 DOI: 10.1155/2019/9432965] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 04/03/2019] [Indexed: 12/26/2022]
Abstract
Morphine has unfavorable side effects including analgesic tolerance. Morphine tolerance counteracts analgesic efficacy and drives dose escalation. The mechanisms underlying morphine tolerance remain disputed, which has prevented the development of therapies to maximize and sustain analgesic efficacy. Morphine tolerance is an adaptive process induced by chronic morphine that has been shown to result from complex alterations at the molecular level with μ opioid receptors (MORs), as well as at the synaptic, cellular, and circuit levels. MicroRNAs are noncoding RNAs that have been proposed to regulate gene expression and degradation at the posttranscriptional level, including the MOR, as well as synaptic plasticity and neuroplasticity, in both the peripheral and central nervous systems. This review covers some of the most striking microRNA functions involved in morphine tolerance and presents limitations on our knowledge of their physiological roles.
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Liu H, Xiong W, Liu F, Lin F, He J, Liu C, Lin Y, Dong S. MicroRNA-133b regulates the growth and migration of vascular smooth muscle cells by targeting matrix metallopeptidase 9. Pathol Res Pract 2019; 215:1083-1088. [PMID: 30926224 DOI: 10.1016/j.prp.2019.02.022] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 01/22/2019] [Accepted: 02/01/2019] [Indexed: 12/25/2022]
Abstract
Atherosclerosis is a systemic disease affecting the whole arterial tree of the human body, and it is the leading cause of cardiovascular diseases.Vascular smooth muscle cells (VSMCs) have been identified to play a key role in the development of atherosclerosis. MicroRNAs (miRNAs) are a group of endogenous small non-coding RNAs, and they play a critical role in many biological processes including regulating cell proliferation, migration and apoptosis. However, till now, the expression and role of miR-133b in atherosclerosis remain largely unknown. Therefore, our purpose was to investigate the expression and role of miR-133b in atherosclerosis and to explore the underlying mechanism. The results showed that miR-133b was down-regulated in the blood and vascular plaque tissues of rabbits with atherosclerosis. Matrix metallopeptidase 9 (MMP-9) was a direct target of miR-133b. In addition, our data indicated that miR-133b mimic could significantly inhibit rVSMC cell proliferation activity, migration ability and induce cell apoptosis compared with the control group, and all these effects were reversed by MMP-9-plasmid. Taken together, these findings highlight an important role for miR-133b/MMP-9 axis in atherosclerosis. And miR-133b might be a valuable clinical marker and therapeutic target for atherosclerosis.
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Affiliation(s)
- Huadong Liu
- Cardiovascular Department, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center, Shenzhen 518000, China
| | - Wei Xiong
- Cardiovascular Department, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center, Shenzhen 518000, China
| | - Feng Liu
- Cardiovascular Department, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center, Shenzhen 518000, China
| | - Feng Lin
- Cardiovascular Department, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center, Shenzhen 518000, China
| | - Junbo He
- Cardiovascular Department, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center, Shenzhen 518000, China
| | - Cheng Liu
- Cardiovascular Department, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center, Shenzhen 518000, China
| | - Yaowang Lin
- Cardiovascular Department, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center, Shenzhen 518000, China
| | - Shaohong Dong
- Cardiovascular Department, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center, Shenzhen 518000, China.
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Bao W, Volgin AD, Alpyshov ET, Friend AJ, Strekalova TV, de Abreu MS, Collins C, Amstislavskaya TG, Demin KA, Kalueff AV. Opioid Neurobiology, Neurogenetics and Neuropharmacology in Zebrafish. Neuroscience 2019; 404:218-232. [PMID: 30710667 DOI: 10.1016/j.neuroscience.2019.01.045] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 01/22/2019] [Accepted: 01/23/2019] [Indexed: 01/28/2023]
Abstract
Despite the high prevalence of medicinal use and abuse of opioids, their neurobiology and mechanisms of action are not fully understood. Experimental (animal) models are critical for improving our understanding of opioid effects in vivo. As zebrafish (Danio rerio) are increasingly utilized as a powerful model organism in neuroscience research, mounting evidence suggests these fish as a useful tool to study opioid neurobiology. Here, we discuss the zebrafish opioid system with specific focus on opioid gene expression, existing genetic models, as well as its pharmacological and developmental regulation. As many human brain diseases involve pain and aberrant reward, we also summarize zebrafish models relevant to opioid regulation of pain and addiction, including evidence of functional interplay between the opioid system and central dopaminergic and other neurotransmitter mechanisms. Additionally, we critically evaluate the limitations of zebrafish models for translational opioid research and emphasize their developing utility for improving our understanding of evolutionarily conserved mechanisms of pain-related, addictive, affective and other behaviors, as well as for fostering opioid-related drug discovery.
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Affiliation(s)
- Wandong Bao
- School of Pharmacy and School of Life Sciences, Southwest University, Chongqing, China
| | - Andrey D Volgin
- Military Medical Academy, St. Petersburg, Russia; Institute of Experimental Medicine, Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia; Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia; Scientific Research Institute of Physiology and Basic Medicine, Novosibirsk, Russia
| | - Erik T Alpyshov
- School of Pharmacy and School of Life Sciences, Southwest University, Chongqing, China
| | - Ashton J Friend
- Tulane University School of Science and Engineering, New Orleans, LA, USA; The International Zebrafish Neuroscience Research Consortium, New Orleans, LA, USA
| | - Tatyana V Strekalova
- Sechenov First Moscow State Medical University, Institute of Molecular Medicine, Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, Moscow, Russia; Department of Neuroscience, Maastricht University, Maastricht, Netherlands; Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Murilo S de Abreu
- The International Zebrafish Neuroscience Research Consortium, New Orleans, LA, USA; Bioscience Institute, University of Passo Fundo (UPF), Passo Fundo, RS, Brazil
| | - Christopher Collins
- ZENEREI Research Center, Slidell, LA, USA; The International Zebrafish Neuroscience Research Consortium, New Orleans, LA, USA
| | - Tamara G Amstislavskaya
- Scientific Research Institute of Physiology and Basic Medicine, Novosibirsk, Russia; The International Zebrafish Neuroscience Research Consortium, New Orleans, LA, USA
| | - Konstantin A Demin
- Institute of Experimental Medicine, Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia; Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
| | - Allan V Kalueff
- School of Pharmacy and School of Life Sciences, Southwest University, Chongqing, China; Institute of Experimental Medicine, Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia; Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia; Ural Federal University, Ekaterinburg, Russia; Granov Russian Research Center of Radiology and Surgical Technologies, Ministry of Healthcare of Russian Federation, Pesochny, Russia; Scientific Research Institute of Physiology and Basic Medicine, Novosibirsk, Russia; ZENEREI Research Center, Slidell, LA, USA; The International Zebrafish Neuroscience Research Consortium, New Orleans, LA, USA.
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Cao DN, Shi JJ, Wu N, Li J. Modulation of miR-139-5p on chronic morphine-induced, naloxone-precipitated cAMP overshoot in vitro. Metab Brain Dis 2018; 33:1501-1508. [PMID: 29916183 DOI: 10.1007/s11011-018-0257-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 05/28/2018] [Indexed: 10/14/2022]
Abstract
Chronic exposure to morphine can produce tolerance, dependence and addiction, but the underlying neurobiological basis is still incompletely understood. c-Jun, as an important component of the activator protein-1 transcription factor, is supposed to take part in regulating gene expression in AC/cAMP/PKA signaling. MicroRNA (miRNA) has emerged as a critical regulator of neuronal functions. Although a number of miRNAs have been reported to regulate the μ-opioid receptor expression, there has been no report about miRNAs to regulate chronic morphine-induced, naloxone-precipitated cAMP overshoot. Our results showed that chronic morphine pretreatment induced naloxone-precipitated cAMP overshoot in concentration- and time-dependent manners in HEK 293/μ cells. Chronic morphine pretreatment alone elevated both c-Jun protein and miR-139-5p expression levels, while dramatically artificial elevation of miR-139-5p inhibited c-Jun at the translational level. Furthermore, dramatically artificial upregulation of intracellular miR-139-5p limited chronic morphine-induced, naloxone-precipitated cAMP overshoot. These findings suggested that miR-139-5p was involved in regulating chronic morphine-induced, naloxone-precipitated cAMP overshoot in a negative feedback manner through its target c-Jun, which extends our understanding of neurobiological mechanisms underlying morphine dependence and addiction.
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Affiliation(s)
- Dan-Ni Cao
- Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing, 100850, China
| | - Jing-Jing Shi
- Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing, 100850, China
| | - Ning Wu
- Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing, 100850, China.
| | - Jin Li
- Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing, 100850, China.
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Melo Z, Ishida C, Goldaraz MDLP, Rojo R, Echavarria R. Novel Roles of Non-Coding RNAs in Opioid Signaling and Cardioprotection. Noncoding RNA 2018; 4:ncrna4030022. [PMID: 30227648 PMCID: PMC6162605 DOI: 10.3390/ncrna4030022] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 09/10/2018] [Accepted: 09/12/2018] [Indexed: 12/16/2022] Open
Abstract
Cardiovascular disease (CVD) is a significant cause of morbidity and mortality across the world. A large proportion of CVD deaths are secondary to coronary artery disease (CAD) and myocardial infarction (MI). Even though prevention is the best strategy to reduce risk factors associated with MI, the use of cardioprotective interventions aimed at improving patient outcomes is of great interest. Opioid conditioning has been shown to be effective in reducing myocardial ischemia-reperfusion injury (IRI) and cardiomyocyte death. However, the molecular mechanisms behind these effects are under investigation and could provide the basis for the development of novel therapeutic approaches in the treatment of CVD. Non-coding RNAs (ncRNAs), which are functional RNA molecules that do not translate into proteins, are critical modulators of cardiac gene expression during heart development and disease. Moreover, ncRNAs such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are known to be induced by opioid receptor activation and regulate opioid signaling pathways. Recent advances in experimental and computational tools have accelerated the discovery and functional characterization of ncRNAs. In this study, we review the current understanding of the role of ncRNAs in opioid signaling and opioid-induced cardioprotection.
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Affiliation(s)
- Zesergio Melo
- CONACyT-Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Sierra Mojada #800 Col. Independencia, Guadalajara 44340, Jalisco, Mexico.
| | - Cecilia Ishida
- Programa de Genomica Computacional, Centro de Ciencias Genomicas, Universidad Nacional Autonoma de Mexico, Cuernavaca 62210, Morelos, Mexico.
| | - Maria de la Paz Goldaraz
- Departamento de Anestesiologia, Hospital de Especialidades UMAE CMNO, Instituto Mexicano del Seguro Social, Guadalajara 44340, Jalisco, Mexico.
| | - Rocio Rojo
- Departamento de Anestesiologia, Hospital de Especialidades UMAE CMNO, Instituto Mexicano del Seguro Social, Guadalajara 44340, Jalisco, Mexico.
| | - Raquel Echavarria
- CONACyT-Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Sierra Mojada #800 Col. Independencia, Guadalajara 44340, Jalisco, Mexico.
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Zygmunt M, Piechota M, Rodriguez Parkitna J, Korostyński M. Decoding the transcriptional programs activated by psychotropic drugs in the brain. GENES BRAIN AND BEHAVIOR 2018; 18:e12511. [PMID: 30084543 DOI: 10.1111/gbb.12511] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 07/25/2018] [Accepted: 08/03/2018] [Indexed: 01/01/2023]
Abstract
Analysis of drug-induced gene expression in the brain has long held the promise of revealing the molecular mechanisms of drug actions as well as predicting their long-term clinical efficacy. However, despite some successes, this promise has yet to be fulfilled. Here, we present an overview of the current state of understanding of drug-induced gene expression in the brain and consider the obstacles to achieving a robust prediction of the properties of psychoactive compounds based on gene expression profiles. We begin with a comprehensive overview of the mechanisms controlling drug-inducible transcription and the complexity resulting from expression of noncoding RNAs and alternative gene isoforms. Particular interest is placed on studies that examine the associations within drug classes with regard to the effects on gene transcription, alterations in cell signaling and neuropharmacological drug properties. While the ability of gene expression signatures to distinguish specific clinical classes of psychotropic and addictive drugs remains unclear, some reports show that under specific constraints, drug properties can be predicted based on gene expression. Such signatures offer a simple and effective way to classify psychotropic drugs and screen novel psychoactive compounds. Finally, we note that the amount of data regarding molecular programs activated in the brain by drug treatment has grown exponentially in recent years and that future advances may therefore come in large part from integrating the currently available high-throughput data sets.
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Affiliation(s)
- Magdalena Zygmunt
- Department of Molecular Neuropharmacology, Institute of Pharmacology of the Polish Academy of Sciences, Krakow, Poland
| | - Marcin Piechota
- Department of Molecular Neuropharmacology, Institute of Pharmacology of the Polish Academy of Sciences, Krakow, Poland
| | - Jan Rodriguez Parkitna
- Department of Molecular Neuropharmacology, Institute of Pharmacology of the Polish Academy of Sciences, Krakow, Poland
| | - Michał Korostyński
- Department of Molecular Neuropharmacology, Institute of Pharmacology of the Polish Academy of Sciences, Krakow, Poland
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MicroRNA-mediated downregulation of potassium-chloride-cotransporter and vesicular γ-aminobutyric acid transporter expression in spinal cord contributes to neonatal cystitis-induced visceral pain in rats. Pain 2018; 158:2461-2474. [PMID: 28885452 DOI: 10.1097/j.pain.0000000000001057] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Loss of GABAergic inhibition in pain pathways has been considered to be a key component in the development of chronic pain. In the present study, we intended to examine whether miR-92b-mediated posttranscriptional dysregulation of spinal potassium chloride cotransporter (KCC2) and vesicular γ-aminobutyric acid transporter (VGAT) plays a major role in the development and maintenance of long-term visceral hyperalgesia in neonatal zymosan-treated rats. Neonatal cystitis was induced by transurethral zymosan administration from postnatal (P) days 14 to 16 (protocol 1). Two other zymosan protocols were also used: adult rechallenge on P57 to 59 following neonatal P14 to 16 exposures (protocol 2), and adult zymosan exposures on P57 to 59 (protocol 3). Both neonatal and adult bladder inflammation protocols demonstrated an increase in spinal miR-92b-3p expression and subsequent decrease in KCC2 and VGAT expression in spinal dorsal horn neurons. In situ hybridization demonstrated a significant upregulation of miR-92b-3p in the spinal dorsal horn neurons of neonatal cystitis rats compared with saline-treated controls. In dual in situ hybridization and immunohistochemistry studies, we further demonstrated coexpression of miR-92b-3p with targets KCC2 and VGAT in spinal dorsal horn neurons, emphasizing a possible regulatory role both at pre- and post-synaptic levels. Intrathecal administration of lentiviral pLSyn-miR-92b-3p sponge (miR-92b-3p inhibitor) upregulated KCC2 and VGAT expression in spinal dorsal horn neurons. In behavioral studies, intrathecal administration of lentiviral miR-92b-3p sponge attenuated an increase in visceromotor responses and referred viscerosomatic hypersensitivity following the induction of cystitis. These findings indicate that miR-92b-3p-mediated posttranscriptional regulation of spinal GABAergic system plays an important role in sensory pathophysiology of zymosan-induced cystitis.
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MiR-133b targets Sox9 to control pathogenesis and metastasis of breast cancer. Cell Death Dis 2018; 9:752. [PMID: 29970901 PMCID: PMC6030174 DOI: 10.1038/s41419-018-0715-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 04/28/2018] [Accepted: 05/09/2018] [Indexed: 02/07/2023]
Abstract
The miR-133b, a commonly recognized muscle-specific miRNA, was reported to be deregulated in many kinds of cancers. However, its potential roles in tumorigenesis remain greatly elusive. Herein, we demonstrate that miR-133b is significantly suppressed in human breast cancer specimens, which is reversely correlated to histological grade of the cancer. Ectopic expression of miR-133b suppresses clonogenic ability and metastasis-relevant traits in vitro, as well as carcinogenesis and pulmonary metastasis in vivo. Further studies have identified Sox9, c-MET, and WAVE2 as direct targets of miR-133b, in which Sox9 contributes to all miR-133b-endowed effects including cell proliferation, colony formation, as well as cell migration and invasion in vitro. Moreover, re-expression of Sox9 reverses miR-133b-mediated metastasis suppression in vivo. Taken together, these findings highlight an important role for miR-133b in the regulation of tumorigenesis and metastatic potential of breast cancer and suggest a potential application of miR-133b in cancer treatment.
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Shen H, Yao X, Li H, Li X, Zhang T, Sun Q, Ji C, Chen G. Role of Exosomes Derived from miR-133b Modified MSCs in an Experimental Rat Model of Intracerebral Hemorrhage. J Mol Neurosci 2018; 64:421-430. [PMID: 29455449 DOI: 10.1007/s12031-018-1041-2] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Accepted: 02/06/2018] [Indexed: 12/11/2022]
Abstract
Intracerebral hemorrhage (ICH) has poor outcomes due to high mortality and morbidity, but until now, the effective treatments remain limited. MicroRNAs (miRNAs) are vital regulators of gene expression and demonstrated to be linked to the pathogenesis of various central nervous system (CNS) diseases. Exosomes are considered as cell-to-cell communication vectors and secreted largely by mesenchymal stromal cells (MSCs). The present study investigated the role of miR-133b delivered by exosomes secreted from MSCs to brain tissues in rats after ICH. An autologous arterial blood ICH model in adult male Sprague-Dawley (SD) rats was used in this study. At 72 h after transfection with miR-133b mimics in MSCs, miR-133b-modified MSC-derived exosomes were collected from medium of MSCs and then injected to rats via tail vein. The levels of miR-133b in secreted exosomes and brain tissues of rats in various groups and the levels of RhoA, phosphorylations of extracellular signal regulating kinase (ERK1/2), and cAMP response element-binding protein (CREB) were detected by real-time PCR and western blot analysis, respectively. The effects of miR-133b on neuronal apoptosis and degeneration were respectively evaluated by TUNEL and fluoro-jade B staining. The miR-133b levels were reduced in brain tissues of rats at 24 h and peaked at 72 h after ICH. At 24 h after miR-133b-modified exosome administration, the level of miR-133b was significantly increased, while the apoptotic and neurodegenerative neurons were obviously reduced in brain tissues after ICH. The results of western blot analysis showed that miR-133b modified exosomes treatment remarkably suppressed RhoA expression and activated ERK1/2/CREB in brain tissues after ICH. Collectively, our investigation suggested that exosomes derived from miR-133b modified MSCs exhibited neuroprotective role for anti-apoptotic effect of miR-133b mediating RhoA and ERK1/2/CREB in rats after ICH.
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Affiliation(s)
- Haitao Shen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province, 215006, China
| | - Xiyang Yao
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province, 215006, China
| | - Haiying Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province, 215006, China
| | - Xiang Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province, 215006, China
| | - Tiejun Zhang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province, 215006, China
| | - Qing Sun
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province, 215006, China.
| | - Chengyuan Ji
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province, 215006, China.
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province, 215006, China
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Generation and Characterization of Antibodies against Opioid Receptors from Zebrafish. Int J Mol Sci 2018; 19:ijms19010014. [PMID: 29301275 PMCID: PMC5795966 DOI: 10.3390/ijms19010014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 12/04/2017] [Accepted: 12/08/2017] [Indexed: 02/07/2023] Open
Abstract
The opioid system is well conserved among species and plays a critical role in pain and addiction systems. The use of zebrafish as an experimental model to study development and genetics is extraordinary and has been proven to be relevant for the study of different diseases. The main drawback to its use for the analysis of different pathologies is the lack of protein tools. Antibodies that work in other models are not suitable for zebrafish due to the low degree of homology that exists among the opioid receptor protein sequences in different species. Here we report the successful generation and characterization of antibodies against the mu, delta 1 and delta 2 opioid receptors in zebrafish. The antibodies obtained, which are specific for each receptor due to the use of the C-terminus as antigens, work for Western blotting and immunohistochemistry. In addition, the antibodies against mu and delta 1 opioid receptors, but not those against delta 2, are able to immunoprecipitate the corresponding receptor from zebrafish lysates. The development of opioid receptor antibodies is an asset to the further study of the endogenous opioid system in zebrafish.
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Huang R, Chen M, Yang L, Wagle M, Guo S, Hu B. MicroRNA-133b Negatively Regulates Zebrafish Single Mauthner-Cell Axon Regeneration through Targeting tppp3 in Vivo. Front Mol Neurosci 2017; 10:375. [PMID: 29209165 PMCID: PMC5702462 DOI: 10.3389/fnmol.2017.00375] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 10/27/2017] [Indexed: 12/30/2022] Open
Abstract
Axon regeneration, fundamental to nerve repair, and functional recovery, relies on rapid changes in gene expression attributable to microRNA (miRNA) regulation. MiR-133b has been proved to play an important role in different organ regeneration in zebrafish, but its role in regulating axon regeneration in vivo is still controversial. Here, combining single-cell electroporation with a vector-based miRNA-expression system, we have modulated the expression of miR-133b in Mauthner-cells (M-cells) at the single-cell level in zebrafish. Through in vivo imaging, we show that overexpression of miR-133b inhibits axon regeneration, whereas down-regulation of miR-133b, promotes axon outgrowth. We further show that miR-133b regulates axon regeneration by directly targeting a novel regeneration-associated gene, tppp3, which belongs to Tubulin polymerization-promoting protein family. Gain or loss-of-function of tppp3 experiments indicated that tppp3 was a novel gene that could promote axon regeneration. In addition, we observed a reduction of mitochondrial motility, which have been identified to have a positive correlation with axon regeneration, in miR-133b overexpressed M-cells. Taken together, our work provides a novel way to study the role of miRNAs in individual cell and establishes a critical cell autonomous role of miR-133b in zebrafish M-cell axon regeneration. We propose that up-regulation of the newly founded regeneration-associated gene tppp3 may enhance axonal regeneration.
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Affiliation(s)
- Rongchen Huang
- Chinese Academy of Sciences Key Laboratory of Brain Function and Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Min Chen
- Chinese Academy of Sciences Key Laboratory of Brain Function and Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Leiqing Yang
- Chinese Academy of Sciences Key Laboratory of Brain Function and Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Mahendra Wagle
- Programs in Human Genetics and Biological Sciences, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, United States
| | - Su Guo
- Programs in Human Genetics and Biological Sciences, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, United States
| | - Bing Hu
- Chinese Academy of Sciences Key Laboratory of Brain Function and Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China
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Huang B, Jiang XC, Zhang TY, Hu YL, Tabata Y, Chen Z, Pluchino S, Gao JQ. Peptide modified mesenchymal stem cells as targeting delivery system transfected with miR-133b for the treatment of cerebral ischemia. Int J Pharm 2017; 531:90-100. [PMID: 28827201 DOI: 10.1016/j.ijpharm.2017.08.073] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 07/12/2017] [Accepted: 08/12/2017] [Indexed: 12/13/2022]
Abstract
Mesenchymal stem cells (MSCs) have been regarded as potential targeting vehicles and demonstrated to exert therapeutic benefits for brain diseases. Direct homing to diseased tissue is crucial for stem cell-based therapy. In this study, a peptide-based targeting approach was established to enhance cell homing to cerebral ischemic lesion. Palmitic acid-peptide painted onto the cell membrane was able to direct MSCs to ischemic tissues without any observed cell cytotoxicity and influence on differentiation, thus reducing accumulation of cells in peripheral organs and increasing engraftment of cells in the targeted tissues. With enhanced cell homing, MSCs were used to deliver miR-133b to increase the expression level of miR-133b in an ischemic lesion and further improve therapeutic effects. This study is the first to develop MSCs co-modified with targeting peptide and microRNAs as potential targeting therapeutic agents. This targeting delivery system is expected to be applicable to other cell types and other diseases aside from stroke.
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Affiliation(s)
- Bing Huang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Xin-Chi Jiang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Tian-Yuan Zhang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Yu-Lan Hu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Yasuhiko Tabata
- Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
| | - Zhong Chen
- Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Stefano Pluchino
- Department of Clinical Neurosciences, Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridgeshire, UK
| | - Jian-Qing Gao
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.
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Li H, Tao R, Wang J, Xia L. Upregulation of miR-375 level ameliorates morphine analgesic tolerance in mouse dorsal root ganglia by inhibiting the JAK2/STAT3 pathway. J Pain Res 2017; 10:1279-1287. [PMID: 28603428 PMCID: PMC5457281 DOI: 10.2147/jpr.s125264] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Several lines of evidence indicate that microRNAs (miRNAs) modulate tolerance to the analgesic effects of morphine via regulation of pain-related genes, making dysregulation of miRNA levels a clinical target for controlling opioid tolerance. However, the precise mechanisms by which miRNAs regulate opioid tolerance are unclear. In the present study, we noted that the miR-375 level was downregulated but the expression of Janus kinase 2 (JAK2) was upregulated in mouse dorsal root ganglia (DRG) following chronic morphine treatment. The miR-375 levels and JAK2 expression were correlated with the progression of morphine tolerance, and upregulation of miR-375 level could significantly hinder morphine tolerance. This was ameliorated by JAK2 knockdown. Prolonged morphine exposure induced the expression of brain-derived neurotrophic factor (BDNF) in a time-dependent manner in the DRG. This was regulated by the miR-375 and JAK2–signal transducer and activator of transcription 3 (STAT3) pathway, and inhibition of this pathway decreased BDNF production, and thus, attenuated morphine tolerance. More importantly, we found that miR-375 could target JAK2 and increase BDNF expression in a JAK2/STAT3 pathway-dependent manner.
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Affiliation(s)
- Haiqin Li
- Department of Clinical Pain, The People's Hospital of Henan Province, Zhengzhou, People's Republic of China
| | - Rong Tao
- Department of Clinical Pain, The People's Hospital of Henan Province, Zhengzhou, People's Republic of China
| | - Jing Wang
- Department of Clinical Pain, The People's Hospital of Henan Province, Zhengzhou, People's Republic of China
| | - Lingjie Xia
- Department of Clinical Pain, The People's Hospital of Henan Province, Zhengzhou, People's Republic of China
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Li H, Xiang Z, Liu Y, Xu B, Tang J. MicroRNA-133b Inhibits Proliferation, Cellular Migration, and Invasion via Targeting LASP1 in Hepatocarcinoma Cells. Oncol Res 2017; 25:1269-1282. [PMID: 28117027 PMCID: PMC7841022 DOI: 10.3727/096504017x14850151453092] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
MicroRNAs (miRs), a class of small noncoding RNAs, are key gene regulators through inducing translational repression or degradation of their target genes. However, the regulatory mechanism of miR-133b underlying hepatocellular carcinoma (HCC) growth and metastasis remains largely unclear. Here we found that miR-133b was significantly downregulated in HCC tissues and cell lines. Moreover, low miR-133b levels were significantly associated with the malignant progression of HCC. LASP1, upregulated in HCC tissues and cell lines, was then identified as a novel target of miR-133b in HCC HepG2 and Hep3B cells. Moreover, the increased expression of LASP1 was associated with HCC progression. An in vitro study showed that overexpression of miR-133b inhibited the proliferation, migration, and invasion of HepG2 and Hep3B cells. Similarly, knockdown of LASP1 reduced HepG2 and Hep3B cell proliferation, migration, and invasion. Furthermore, overexpression of LASP1 attenuated the suppressive effect of miR-133b on the malignant phenotypes of HepG2 and Hep3B cells, suggesting that miR-133b may inhibit HCC growth and metastasis via targeting LASP1. In addition, overexpression of miR-133b inhibits tumor growth of HepG2 and Hep3B cells in vivo. Therefore, the miR-133b/LASP1 axis may become a potential target for the treatment of HCC.
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Wang J, Xu W, Zhong T, Song Z, Zou Y, Ding Z, Guo Q, Dong X, Zou W. miR-365 targets β-arrestin 2 to reverse morphine tolerance in rats. Sci Rep 2016; 6:38285. [PMID: 27922111 PMCID: PMC5138852 DOI: 10.1038/srep38285] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 11/07/2016] [Indexed: 01/08/2023] Open
Abstract
Morphine tolerance is a challenging clinical problem that limits its clinical application in pain treatment. Non-coding microRNAs (miRNAs) modulate gene expression in a post transcriptional manner, and their dysregulation causes various diseases. However, the significance of miRNAs in morphine tolerance is still poorly understood. In the present study, we hypothesized that microRNA-365 (miR-365) is a key functional small RNA that reverses morphine tolerance through regulation of β-arrestin 2 in rats. Here, microarray analysis and quantitative real-time PCR showed that miR-365 was robustly decreased in the spinal cord after chronic morphine administration. In situ hybridization and immunochemistry double staining showed that miR-365 was expressed in neurons of the spinal cord. We identified β-arrestin 2 as the target gene of miR-365 by bioinformatics analysis and luciferase reporter assay. The data showed that overexpression of miR-365 prevented and reversed established morphine tolerance, and increased expression of miR-365 caused a decrease in expression of β-arrestin 2 protein. miR-365 downregulation is involved in the development and maintenance of morphine tolerance through regulation of β-arrestin 2, and miR-365 upregulation provides a promising and novel approach for treatment of morphine tolerance.
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Affiliation(s)
- Jian Wang
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Wei Xu
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Tao Zhong
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zongbin Song
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yu Zou
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zhuofeng Ding
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Qulian Guo
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xinzhong Dong
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Wangyuan Zou
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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Zhu HJ, Han ZY, He SF, Jin SY, Xu SJ, Fang XD, Zhang Y. Specific MicroRNAs comparisons in hypoxia and morphine preconditioning against hypoxia-reoxgenation injury with and without heart failure. Life Sci 2016; 170:82-92. [PMID: 27919821 DOI: 10.1016/j.lfs.2016.11.028] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 11/10/2016] [Accepted: 11/30/2016] [Indexed: 01/01/2023]
Abstract
AIMS Ischemia reperfusion (I/R) injury is an inevitable event arising during the cardiovascular diseases development and the process of potent surgical treatments. microRNAs (miRNAs) are critical regulators of multiple cell processes including I/R injury. The present study aims to quantify miRNA alterations and regulated genes upon hypoxia-reoxygenation (H/R) injury in a rat heart failure model comparing with normal cardiomyocytes. MAIN METHODS Chronic heart failure was established by injecting doxorubicin (2mg/kg/week) for 6weeks, then H/R was performed on primary cultured cardiomyocytes isolated from normal and failed heart. Cellular injury was evaluated by detecting LDH release levels, cell variability and apoptotic rate. Dysregulated miRNAs in control, hypoxia preconditioning (HPC) and morphine preconditioning (MPC) groups under two conditions were quantified by microarray analysis. Fas protein expression was analyzed using Western Blotting analysis. KEY FINDINGS Chronic heart failure was confirmed with lower ejection fraction (EF), and significant cellular injury. HPC could reverse the injury induced by H/R in normal heart rather than failed heart, otherwise, MPC significantly attenuated cellular injury dose dependently in both conditions. There was 12 miRNAs significantly altered after doxorubicin injection, 7 downregulated and 5 upregulated. miR-133b-5p, miR-6216, miR-664-1-5p and let7e-5p were differentially expressed after HPC and MPC treatments. The direct interaction between miR-133b-5p and target gene Fas were established. The Fas protein expression was manipulated by MPC not HPC affording protective effect against H/R injury. SIGNIFICANCE We investigated that miR-133b-5p might play a particularly important role in the cardioprotective effect of MPC by regulating the target gene Fas.
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Affiliation(s)
- Hai-Juan Zhu
- Department of Anaesthesiology, Anhui Women and Child Health Care Hospital, Hefei 230601, China
| | - Zheng-Yi Han
- Department of Anaesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Shu-Fang He
- Department of Anaesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Shi-Yun Jin
- Department of Anaesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Shi-Jin Xu
- Department of Anaesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Xiang-Dong Fang
- Department of Anaesthesiology, Anhui Women and Child Health Care Hospital, Hefei 230601, China
| | - Ye Zhang
- Department of Anaesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
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43
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Carrick WT, Burks B, Cairns MJ, Kocerha J. Noncoding RNA Regulation of Dopamine Signaling in Diseases of the Central Nervous System. Front Mol Biosci 2016; 3:69. [PMID: 27826551 PMCID: PMC5078498 DOI: 10.3389/fmolb.2016.00069] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2016] [Accepted: 10/07/2016] [Indexed: 01/11/2023] Open
Abstract
Dopaminergic neurotransmission mediates a majority of the vital central nervous system functions. Disruption of these synaptic events provokes a multitude of neurological pathologies, including Parkinson's, schizophrenia, depression, and addiction. Growing evidence supports a key role for noncoding RNA (ncRNA) regulation in the synapse. This review will discuss the role of both short and long ncRNAs in dopamine signaling, including bioinformatic examination of the pathways they target. Specifically, we focus on the contribution of ncRNAs to dopaminergic dysfunction in neurodegenerative as well as psychiatric disease.
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Affiliation(s)
- William T Carrick
- Department of Chemistry, Georgia Southern University Statesboro, GA, USA
| | - Brandi Burks
- Department of Chemistry, Georgia Southern University Statesboro, GA, USA
| | - Murray J Cairns
- School of Biomedical Sciences and Pharmacy and the Hunter Medical Research Institute, University of Newcastle Callaghan, NSW, Australia
| | - Jannet Kocerha
- Department of Chemistry, Georgia Southern University Statesboro, GA, USA
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He SF, Zhu HJ, Han ZY, Wu H, Jin SY, Irwin MG, Zhang Y. MicroRNA-133b-5p Is Involved in Cardioprotection of Morphine Preconditioning in Rat Cardiomyocytes by Targeting Fas. Can J Cardiol 2016; 32:996-1007. [DOI: 10.1016/j.cjca.2015.10.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 10/20/2015] [Accepted: 10/22/2015] [Indexed: 12/11/2022] Open
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45
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Ding HL, Hooper JE, Batzel P, Eames BF, Postlethwait JH, Artinger KB, Clouthier DE. MicroRNA Profiling during Craniofacial Development: Potential Roles for Mir23b and Mir133b. Front Physiol 2016; 7:281. [PMID: 27471470 PMCID: PMC4943961 DOI: 10.3389/fphys.2016.00281] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 06/21/2016] [Indexed: 01/01/2023] Open
Abstract
Defects in mid-facial development, including cleft lip/palate, account for a large number of human birth defects annually. In many cases, aberrant gene expression results in either a reduction in the number of neural crest cells (NCCs) that reach the frontonasal region and form much of the facial skeleton or subsequent failure of NCC patterning and differentiation into bone and cartilage. While loss of gene expression is often associated with developmental defects, aberrant upregulation of expression can also be detrimental. microRNAs (miRNAs) are a class of non-coding RNAs that normally repress gene expression by binding to recognition sequences located in the 3′ UTR of target mRNAs. miRNAs play important roles in many developmental systems, including midfacial development. Here, we take advantage of high throughput RNA sequencing (RNA-seq) from different tissues of the developing mouse midface to interrogate the miRs that are expressed in the midface and select a subset for further expression analysis. Among those examined, we focused on four that showed the highest expression level in in situ hybridization analysis. Mir23b and Mir24.1 are specifically expressed in the developing mouse frontonasal region, in addition to areas in the perichondrium, tongue musculature and cranial ganglia. Mir23b is also expressed in the palatal shelves and in anterior epithelium of the palate. In contrast, Mir133b and Mir128.2 are mainly expressed in head and trunk musculature. Expression analysis of mir23b and mir133b in zebrafish suggests that mir23b is expressed in the pharyngeal arch, otic vesicle, and trunk muscle while mir133b is similarly expressed in head and trunk muscle. Functional analysis by overexpression of mir23b in zebrafish leads to broadening of the ethmoid plate and aberrant cartilage structures in the viscerocranium, while overexpression of mir133b causes a reduction in ethmoid plate size and a significant midfacial cleft. These data illustrate that miRs are expressed in the developing midface and that Mir23b and Mir133b may have roles in this developmental process.
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Affiliation(s)
- Hai-Lei Ding
- Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Anschutz Medical Campus Aurora, CO, USA
| | - Joan E Hooper
- Department of Cell and Developmental Biology, School of Medicine, University of Colorado Anschutz Medical Campus Aurora, CO, USA
| | - Peter Batzel
- Department of Neuroscience, University of Oregon Eugene, OR, USA
| | - B Frank Eames
- Department of Neuroscience, University of OregonEugene, OR, USA; Department of Anatomy and Cell Biology, University of SaskatchewanSaskatoon, SK, Canada
| | | | - Kristin B Artinger
- Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Anschutz Medical Campus Aurora, CO, USA
| | - David E Clouthier
- Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Anschutz Medical Campus Aurora, CO, USA
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Weng HL, Wang MJ. Effects of microRNA‑338‑3p on morphine‑induced apoptosis and its underlying mechanisms. Mol Med Rep 2016; 14:2085-92. [PMID: 27432229 DOI: 10.3892/mmr.2016.5506] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 05/25/2016] [Indexed: 11/05/2022] Open
Abstract
The aim of the present study was to investigate the effects of microRNA-338-3p (miR-338-3p) on morphine (MP)-induced apoptosis, and its underlying mechanisms. Freshly‑isolated mouse peritoneal macrophages were cultured in vitro and treated with MP following transfection with miR‑338‑3p mimic, inhibitor or controls. miR‑338‑3p expression levels increased significantly following MP treatment (P<0.01). This increase was enhanced following transfection with miR‑338‑3p mimic (P<0.05) and abrogated following transfection with miR‑338‑3p inhibitor (P<0.05). The apoptotic rate increased significantly in groups treated with MP (P<0.05); however, this increase was abrogated by transfection with miR‑338‑3p inhibitor (P<0.05). Bioinformatics software predicted that sex determining region Y‑box 4 (SOX4) was the target gene of miR‑338‑3p and this was verified using a dual‑luciferase reporter gene system. SOX4 mRNA and protein expression levels decreased significantly following MP treatment (P<0.05); however, this decrease was abrogated following transfection with miR‑338‑3p inhibitor (P<0.05). Caspase‑3 protein expression levels increased markedly following MP treatment (P<0.05); however, this increase was inhibited by transfection with miR‑338‑3p inhibitor (P<0.05). Therefore, decreased expression of miR‑338‑3p may suppress MP‑induced apoptosis, potentially via the upregulation of SOX4 expression and the caspase‑3‑dependent apoptotic signaling pathway.
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Affiliation(s)
- Hong-Liang Weng
- Department of Anesthesia, Linyi Yishui Central Hospital, Linyi, Shandong 276400, P.R. China
| | - Ming-Jing Wang
- Department of Clinical Laboratory, Linyi Yishui Central Hospital, Linyi, Shandong 276400, P.R. China
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μ Opioid Receptor Expression after Morphine Administration Is Regulated by miR-212/132 Cluster. PLoS One 2016; 11:e0157806. [PMID: 27380026 PMCID: PMC4933400 DOI: 10.1371/journal.pone.0157806] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 06/06/2016] [Indexed: 12/14/2022] Open
Abstract
Since their discovery, miRNAs have emerged as a promising therapeutical approach in the treatment of several diseases, as demonstrated by miR-212 and its relation to addiction. Here we prove that the miR-212/132 cluster can be regulated by morphine, through the activation of mu opioid receptor (Oprm1). The molecular pathways triggered after morphine administration also induce changes in the levels of expression of oprm1. In addition, miR-212/132 cluster is actively repressing the expression of mu opioid receptor by targeting a sequence in the 3’ UTR of its mRNA. These findings suggest that this cluster is closely related to opioid signaling, and function as a post-transcriptional regulator, modulating morphine response in a dose dependent manner. The regulation of miR-212/132 cluster expression is mediated by MAP kinase pathway, CaMKII-CaMKIV and PKA, through the phosphorylation of CREB. Moreover, the regulation of both oprm1 and of the cluster promoter is mediated by MeCP2, acting as a transcriptional repressor on methylated DNA after prolonged morphine administration. This mechanism explains the molecular signaling triggered by morphine as well as the regulation of the expression of the mu opioid receptor mediated by morphine and the implication of miR-212/132 in these processes.
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Role of morphine, miR-212/132 and mu opioid receptor in the regulation of Bdnf in zebrafish embryos. Biochim Biophys Acta Gen Subj 2016; 1860:1308-16. [DOI: 10.1016/j.bbagen.2016.03.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 01/29/2016] [Accepted: 03/01/2016] [Indexed: 11/18/2022]
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Tapocik JD, Ceniccola K, Mayo CL, Schwandt ML, Solomon M, Wang BD, Luu TV, Olender J, Harrigan T, Maynard TM, Elmer GI, Lee NH. MicroRNAs Are Involved in the Development of Morphine-Induced Analgesic Tolerance and Regulate Functionally Relevant Changes in Serpini1. Front Mol Neurosci 2016; 9:20. [PMID: 27047334 PMCID: PMC4805586 DOI: 10.3389/fnmol.2016.00020] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 02/29/2016] [Indexed: 12/23/2022] Open
Abstract
Long-term opioid treatment results in reduced therapeutic efficacy and in turn leads to an increase in the dose required to produce equivalent pain relief and alleviate break-through or insurmountable pain. Altered gene expression is a likely means for inducing long-term neuroadaptations responsible for tolerance. Studies conducted by our laboratory (Tapocik et al., 2009) revealed a network of gene expression changes occurring in canonical pathways involved in neuroplasticity, and uncovered miRNA processing as a potential mechanism. In particular, the mRNA coding the protein responsible for processing miRNAs, Dicer1, was positively correlated with the development of analgesic tolerance. The purpose of the present study was to test the hypothesis that miRNAs play a significant role in the development of analgesic tolerance as measured by thermal nociception. Dicer1 knockdown, miRNA profiling, bioinformatics, and confirmation of high value targets were used to test the proposition. Regionally targeted Dicer1 knockdown (via shRNA) had the anticipated consequence of eliminating the development of tolerance in C57BL/6J (B6) mice, thus supporting the involvement of miRNAs in the development of tolerance. MiRNA expression profiling identified a core set of chronic morphine-regulated miRNAs (miR's 27a, 9, 483, 505, 146b, 202). Bioinformatics approaches were implemented to identify and prioritize their predicted target mRNAs. We focused our attention on miR27a and its predicted target serpin peptidase inhibitor clade I (Serpini1) mRNA, a transcript known to be intricately involved in dendritic spine density regulation in a manner consistent with chronic morphine's consequences and previously found to be correlated with the development of analgesic tolerance. In vitro reporter assay confirmed the targeting of the Serpini1 3'-untranslated region by miR27a. Interestingly miR27a was found to positively regulate Serpini1 mRNA and protein levels in multiple neuronal cell lines. Lastly, Serpini1 knockout mice developed analgesic tolerance at a slower rate than wild-type mice thus confirming a role for the protein in analgesic tolerance. Overall, these results provide evidence to support a specific role for miR27a and Serpini1 in the behavioral response to chronic opioid administration (COA) and suggest that miRNA expression and mRNA targeting may underlie the neuroadaptations that mediate tolerance to the analgesic effects of morphine.
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Affiliation(s)
- Jenica D. Tapocik
- National Institute of Alcohol Abuse and Alcoholism, National Institutes of HealthBethesda, MD, USA
| | - Kristin Ceniccola
- Department of Pharmacology and Physiology, The George Washington UniversityWashington, DC, USA
| | - Cheryl L. Mayo
- Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of MedicineBaltimore, MD, USA
| | - Melanie L. Schwandt
- National Institute of Alcohol Abuse and Alcoholism, National Institutes of HealthBethesda, MD, USA
| | - Matthew Solomon
- National Institute of Alcohol Abuse and Alcoholism, National Institutes of HealthBethesda, MD, USA
| | - Bi-Dar Wang
- Department of Pharmacology and Physiology, The George Washington UniversityWashington, DC, USA
| | - Truong V. Luu
- Department of Pharmacology and Physiology, The George Washington UniversityWashington, DC, USA
| | - Jacqueline Olender
- Department of Pharmacology and Physiology, The George Washington UniversityWashington, DC, USA
| | - Thomas Harrigan
- Department of Pharmacology and Physiology, The George Washington UniversityWashington, DC, USA
| | - Thomas M. Maynard
- Department of Pharmacology and Physiology, The George Washington UniversityWashington, DC, USA
| | - Greg I. Elmer
- Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of MedicineBaltimore, MD, USA
| | - Norman H. Lee
- Department of Pharmacology and Physiology, The George Washington UniversityWashington, DC, USA
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50
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García-Pérez D, Núñez C, Laorden ML, Milanés MV. Regulation of dopaminergic markers expression in response to acute and chronic morphine and to morphine withdrawal. Addict Biol 2016; 21:374-86. [PMID: 25522207 DOI: 10.1111/adb.12209] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Dopamine (DA) is thought to represent a teaching signal and has been implicated in the induction of addictive behaviours. Dysfunction of DA homeostasis leading to high or low DA levels is causally linked to addiction. Previously, it has been proposed that the transcription factors Nurr1 and Pitx3, which are critical for transcription of a set of genes involved in DA metabolism in the mesolimbic pathway, are associated with addiction pathology. Using quantitative real-time polymerase chain reaction, immunofluorescence and Western blotting, we studied the effects of single morphine administration, morphine dependence and withdrawal on the DA markers DA transporters (DAT), vesicular monoamine transporters (VMAT2) and DA 2 receptor subtype (DRD2), DA 1 receptor subtype as well as tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and/or nucleus accumbens (NAc). In addition, Nurr1 and Pitx3 expression was also measured. Present data showed a high degree of colocalization of Nurr1 and Pitx3 with TH(+) neurons in the VTA. We found that the increased Nurr1 and/or Pitx3 levels during morphine dependence and in morphine-withdrawn rats were associated to an increase of DAT, VMAT2 and DRD2. Altogether, present data indicate that morphine dependence and withdrawal induced consistent alterations of most of the DA markers, which was correlated with transcription factors involved in the maintenance of DA neurons in drug-reward pathways, suggesting that Nurr1 and Pitx3 regulation might be associated with controlling adaptation to chronic morphine and to morphine withdrawal-induced alterations of DA neurons activity in the mesolimbic pathway.
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Affiliation(s)
- Daniel García-Pérez
- Group of Cellular and Molecular Pharmacology; Campus de Espinardo; University of Murcia; Spain
- IMIB, Instituto Murciano de Investigación Biosanitaria; Spain
| | - Cristina Núñez
- Group of Cellular and Molecular Pharmacology; Campus de Espinardo; University of Murcia; Spain
- IMIB, Instituto Murciano de Investigación Biosanitaria; Spain
| | - M. Luisa Laorden
- Group of Cellular and Molecular Pharmacology; Campus de Espinardo; University of Murcia; Spain
- IMIB, Instituto Murciano de Investigación Biosanitaria; Spain
| | - M. Victoria Milanés
- Group of Cellular and Molecular Pharmacology; Campus de Espinardo; University of Murcia; Spain
- IMIB, Instituto Murciano de Investigación Biosanitaria; Spain
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