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：
8198373
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/8198373
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. PUBLIC HEALTH RELEVANCE: Opioids are medications very commonly used to provide relief from pain of many types including chronic pain. Veterans suffer from very high rates of pain and are often treated with these drugs. Unfortunately opioid therapy for pain is limited by tolerance to these drugs, increased pain sensitivity resulting from use of these medications and physical dependence after chronic use. Opioids are also drugs of abuse, and the rate of abuse of prescription opioids has escalated dramatically in recent years. Making matters more complex, the existence of pain in patients treated with opioids or abusing opioids likely alters how quickly they develop adverse responses such as those mentioned. In the proposed work we seek to understand the mechanism by which genes recently discovered to regulate some of these adverse reactions actually accomplish that regulation. Furthermore, we will determine how genetic factors interact with pain in controlling adaptations to the chronic administration of these drugs.

描述（由申请人提供）：多种因素限制了这种方法的功效，例如耐受性，阿片类药物引起的痛觉过敏（OIH），身体依赖和虐待。近年来，很明显，个体之间的遗传差异会影响这些问题的可能性。此外，已经确认遗传因素与环境条件的相互作用会影响疼痛的经历，发展阿片类药物成瘾的可能性以及对疼痛和成瘾疗法的反应可能性。在退伍军人人口中，疼痛，阿片类药物处方和药物滥用的高度流行使该主题与VA具有很高的相关性。应用于阿片类药物长期治疗的小鼠的遗传方法表明，5-阿片类药物，22-肾上腺素能和5-HT3受体控制了几种慢性阿片类药物反应“适应”（耐受性，OIH，身体依赖性和使用增强）。提议的工作的主要目标是：1）定义5-阿片类药物22-肾上腺素能和5-HT3受体控制的机制，每个适应性控制，2）使用疼痛识别基因x环境相互作用，作为疼痛和临床上的疼痛相关的环境因素，以及3）定义遗传因素和疼痛以控制临床相关的慢性阿片类药物反应适应的机制。拟议的工作将使用一组垂直整合的实验集，重点是仔细测量接受阿片类药物长期治疗的小鼠的行为以及选择性药理剂，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，并具有强大的证据参与控制每个感兴趣的适应。组织包括背根神经节（DRG），脊髓，层层层和延伸的杏仁核。集中于基因X环境相互作用的实验将利用实验室中良好确定的慢性炎症模型，并与使用慢性阿片类药物给药的临床情况特别相关。该模型是Freund的完整辅助（CFA）模型的慢性炎症模型。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，因为这些研究旨在将特定的信号通路作为遗传和环境因素的收敛点，以控制动物如何应对阿片类药物的相对持续施用。从长远来看，我们希望根据对这些遗传和环境因素的操纵来设计疗法，以更成功地管理退伍军人的慢性疼痛和成瘾。公共卫生相关性：阿片类药物是非常常用的药物，以减轻许多类型的疼痛，包括慢性疼痛。退伍军人患有很高的疼痛率，并且经常接受这些药物治疗。不幸的是，阿片类药物治疗疼痛受到对这些药物的耐受性的限制，由于使用这些药物而导致的疼痛敏感性增加，并且在长期使用后的身体依赖性。阿片类药物也是滥用药物，近年来，处方阿片类药物的滥用率显着升级。使事情变得更加复杂，接受阿片类药物治疗或滥用阿片类药物的患者的疼痛存在可能会改变他们产生不良反应的速度，例如提到的反应。在拟议的工作中，我们试图理解基因最近发现调节这些不良反应的机制实际上实现了该调节。此外，我们将确定遗传因素如何与疼痛相互作用，以控制对这些药物的长期给药的适应。