Genetics and Gene X Environment Interactions during Opioid Administration

阿片类药物给药期间遗传学和基因 X 环境的相互作用

基本信息

批准号：
8391618
负责人：
DAVID J. CLARK
金额：
--
依托单位：
VETERANS ADMIN PALO ALTO HEALTH CARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-10-01 至 2014-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8391618
关键词：
ADRB2 gene Absence of pain sensation Acute Adrenergic Agents Adverse reactions Affect Amygdaloid structure Animals Anxiety Behavioral Chronic Chronic inflammatory pain Clinic Clinical Collection Complement Complex Control Animal Data Data Set Dependence Development Dimensions Disease Drug usage Environment Environmental Risk Factor Freund&apos s Adjuvant Gene Expression Genes Genetic Genetic Polymorphism HTR3A gene Haplotypes High Prevalence Human Hyperalgesia Inbred Strains Mice Individual Inflammation Injection of therapeutic agent Laboratories Link Maps Measurement Measures Medical Medicine Mental Depression Modeling Morphine Mouse Strains Mus Neurobiology Neurotransmitters Nociception Non-Steroidal Anti-Inflammatory Agents Opiate Addiction Opioid Overdose Pain Pain management Patients Pharmaceutical Preparations Phenotype Physical Dependence Population Property Psychological reinforcement Receptor Gene Regulation Relative (related person)Reporting Research Risk Sales Serotonin Receptors 5-HT-3 Signal Pathway Source Spinal Cord Spinal Ganglia Stratification Substance abuse problem Symptoms System Techniques Tissue-Specific Gene Expression Tissues Treatment Protocols Veterans Work addiction adrenergic adverse outcome animal tissue base behavior measurement chronic pain clinically relevant drug of abuse experience genetic manipulation inflammatory pain interest knockout animal knowledge base locus ceruleus structure mouse model mu opioid receptors neurobiological mechanism novel operation opioid abuse opioid misuse physical abuse physical conditioning preference prescription opioid prescription opioid abuse public health relevance rapid growth receptor function research study response therapy design therapy outcome

项目摘要

DESCRIPTION (provided by applicant): The long term use of opioids for the control of chronic pain is complicated by several factors limiting the efficacy of this approach, e.g. tolerance, opioid-induced hyperalgesia (OIH), physical dependence and abuse. It has become clear over recent years that genetic differences between individuals influence the likelihood each of these problems will develop. Moreover, the interaction of genetic factors with environmental conditions has been recognized to influence the experience of pain, the likelihood of developing opioid addiction and the likelihood of response to pain and addiction therapies. The high prevalence of pain, opioid prescribing and substance abuse in the veteran population make this topic of high relevance to the VA. Genetic approaches applied to mice chronically treated with opioids have demonstrated that the 5-opioid, 22-adrenergic and 5-HT3 receptors control several chronic opioid response "adaptations" (tolerance, OIH, physical dependence and use reinforcement). The principal objectives of the proposed work are, 1) to define the mechanisms by which the 5-opioid, 22-adrenergic and 5-HT3 receptors control each the adaptations, 2) to identify gene X environment interactions using pain as the critical and clinically relevant environmental factor, and 3) to define the mechanisms by which genetic factors and pain interact to control clinically relevant chronic opioid response adaptations. The proposed work will use a vertically integrated set of experiments focusing on the careful measurement of behaviors in mice chronically treated with opioids and the complementary use of selective pharmacological agents, gene knockout animals and tissue-specific gene expression studies. Our gene expression studies will target selected tissues and genes with strong evidence for participation in controlling each of the adaptations of interest. The tissues include the dorsal root ganglia (DRGs), spinal cord, locus coeruleus and extended amygdale. The experiments focused on gene X environment interaction will take advantage of a model of chronic inflammation well established in the laboratory and of particular relevance to clinical situations where chronic opioid administration is used. That model is the Freund's complete adjuvant (CFA) model of chronic inflammation. Finally, the proposed studies go well beyond simple descriptions of genetic and environmental effects as these studies are directed at identifying specific signaling pathways as convergence points for both genetic and environmental factors in controlling how animals respond to the relatively sustained administration of opioids. In the longer term we hope to design therapies based on the manipulation of these genetic and environmental factors to more successfully manage chronic pain and addiction in veterans.

描述（由申请人提供）：长期使用阿片类药物来控制慢性疼痛会因多种因素而变得复杂，这些因素限制了这种方法的功效，例如耐受性、阿片类药物诱发的痛觉过敏 (OIH)、身体依赖和滥用。近年来，人们已经清楚地看到，个体之间的遗传差异会影响这些问题发生的可能性。此外，遗传因素与环境条件的相互作用已被认为会影响疼痛的体验、发生阿片类药物成瘾的可能性以及对疼痛和成瘾治疗产生反应的可能性。退伍军人群体中疼痛、阿片类药物处方和药物滥用的普遍存在使得该主题与退伍军人事务部高度相关。对长期接受阿片类药物治疗的小鼠进行的遗传方法表明，5-阿片类药物、22-肾上腺素能受体和 5-HT3 受体控制着几种慢性阿片类药物反应“适应”（耐受性、OIH、身体依赖性和使用强化）。拟议工作的主要目标是，1）定义 5-阿片类药物、22-肾上腺素能和 5-HT3 受体控制每种适应的机制，2）以疼痛为关键和临床识别基因 X 环境相互作用。相关环境因素，3) 定义遗传因素和疼痛相互作用的机制，以控制临床相关的慢性阿片类药物反应适应。拟议的工作将使用一组垂直整合的实验，重点是仔细测量长期接受阿片类药物治疗的小鼠的行为，以及选择性药物制剂、基因敲除动物和组织特异性基因表达研究的补充使用。我们的基因表达研究将针对选定的组织和基因，并提供参与控制每种感兴趣的适应的有力证据。这些组织包括背根神经节（DRG）、脊髓、蓝斑和扩展杏仁核。专注于基因 X 环境相互作用的实验将利用实验室中建立的慢性炎症模型，该模型与长期使用阿片类药物的临床情况特别相关。该模型是慢性炎症的弗氏完全佐剂（CFA）模型。最后，拟议的研究远远超出了对遗传和环境影响的简单描述，因为这些研究旨在确定特定的信号通路作为遗传和环境因素的汇聚点，以控制动物对相对持续的阿片类药物的反应。从长远来看，我们希望设计基于操纵这些遗传和环境因素的疗法，以更成功地控制退伍军人的慢性疼痛和成瘾。