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Neonatal Opioid Exposure and Withdrawal: Molecular and Behavioral Consequences

新生儿阿片类药物暴露和戒断：分子和行为后果

基本信息

批准号：
9911467
负责人：
Julie A Blendy
金额：
$ 71.08万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9911467
关键词：
Address Adenine Adult Affect Affinity Chromatography Alleles Animal Model Anti-Inflammatory Agents Area Behavior Behavioral Biological Assay Biological Response Modifiers Brain region Canis familiaris Cells Clinical Complex Crying Data Development Diarrhea Distress Early Diagnosis Early treatment Enterobacteria phage P1 Cre recombinase Environment Exhibits Exposure to Genes Genetic Genetic Predisposition to Disease Genomics Genotype Guanine Heroin Hospitals Hour Human Immune Immune response Immunosuppression Infant Innate Immune Response Innate Immune System Lead Length of Stay Life Link Lymphokines Measures Mediating Messenger RNA Methadone Microglia Modeling Molecular Morphine Mus Natural Immunity Neonatal Neonatal Abstinence Syndrome Neuroimmune system Newborn Infant Nucleus Accumbens Opiate Addiction Opioid Opioid Receptor Pain Pathway interactions Perinatal Exposure Peripheral Pharmaceutical Preparations Pharmacological Treatment Phenotype Polypharmacy Pregnant Women Presynaptic Terminals Public Health Receptor Cell Receptor Gene Regulation Ribosomes Risk Role Seizures Severities Single Nucleotide Polymorphism Sleeplessness Syndrome Testing Therapeutic Time Tooth structure Translating Tremor United States Weight Gain Wild Type Mouse Withdrawal Withdrawal Symptom base complement system cytokine experience experimental study gastrointestinal gene discovery genetic risk factor genomic variation high risk in utero insight interest midbrain central gray substance molecular marker mouse model mu opioid receptors neonate neuroinflammation neuronal cell body new technology novel novel therapeutics opioid epidemic opioid exposure opioid use opioid withdrawal pup response transcriptome

项目摘要

Project Summary Opioid use among pregnant women is a growing public health concern in the United States. Infants exposed to opioids in utero are at high risk of exhibiting Neonatal Opioid Withdrawal Syndrome (NOWS), a combination of physical withdrawal symptoms including high pitched crying, sleeplessness, irritability, gastrointestinal distress, and in the worst cases, seizures. The complexity of this syndrome is amplified by a variety of clinical factors such as duration of maternal opioid exposure, maternal polypharmacy, environment, and genetics. The complexity of in utero opioid exposure and NOWS make it very difficult to investigate underlying molecular mechanisms that could ultimately inform early diagnosis and treatment. Therefore, we have developed a much needed mouse model of 3- trimester opioid exposure and withdrawal. Based on preliminary evidence, we hypothesize that microglia activation and immune mediators contribute to the severity of NOWS and a common SNP in the -opioid receptor modulates these effects. Using morphine as a prototypical opioid, we will exploit our model to test these hypotheses. First we will fully characterize the role of the innate immune system in NOWS and determine if regulation of neuroinflammation has therapeutic potential by pharmacological treatment with the anti- inflammatory drug, ibudilast. Second, as recent clinical findings suggest that genomic variation in the gene that encodes the -opioid receptor (Oprm1 A118G) may influence NOWS severity, we will use our mouse line that contains the equivalent Oprm1 A118G SNP to determine the impact of Oprm1 genetics on microglia activation and immune mediators. Using our model of 3-trimester opioid exposure and withdrawal we will use TRAP-Seq, a new technology for retrieving mRNAs within the ribosomal complex that are actively being translated, in our case in cells expressing m-opioid receptors, to interrogate the changing transcriptome following opioid exposure and withdrawal. This project is likely to have a sustained and powerful impact on the field because we will address mechanisms through which perinatal exposure to opiates results in NOWS, and how genetics and immune response contribute.

项目总结