Genetic Determinants of Opioid-Induced Hyperalgesia

阿片类药物引起的痛觉过敏的遗传决定因素

基本信息

批准号：
7313573
负责人：
DAVID J. CLARK
金额：
$ 24.5万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7313573
关键词：
AR gene Absence of pain sensation Acute Acute Pain Address Adverse effects Afferent Neurons Agonist Alleles Analgesics Animal Model Award Binding Biochemical Biological Assay Brain Candidate Disease Gene Characteristics Chromosome Mapping Chronic Class Clinical Complex Computer Simulation Condition Constipation Data Dependence Dimensions Drug usage Event Exposure to Fostering Funding Future Gene Expression Genes Genetic Genetic Determinism Goals Hand Haplotypes Health Care Costs Human Hyperalgesia Immunoblotting Immunohistochemistry Inbred Mouse Inbred Strains Mice Individual Intervention Investigation Laboratories Ligands Link Literature Location Malignant Neoplasms Maps Measures Mechanics Mediating Messenger RNA Methodology Morphine Mus Mutant Strains Mice Neurotransmitters Nociception Nociceptors Operative Surgical Procedures Opioid Opioid Analgesics P-Glycoprotein P-Glycoproteins Pain Pathway interactions Peripheral Peripheral Nervous System Pharmaceutical Preparations Physiological Play Polymerase Chain Reaction Positioning Attribute Procedures Production Proteins Protocols documentation Public Health Publishing Reporting Research Research Personnel Rodent Role Scheme Science Sedation procedure Site Spinal Cord Spinal Ganglia Staging Stimulus Syndrome Techniques Technology Testing Therapeutic Intervention Time Tissues Transgenic Animals United States National Institutes of Health Work beta-2 Adrenergic Receptors chronic pain cost day design disability drug efficacy experience human study improved innovation neurochemistry novel prevent programs receptor receptor expression research study therapy development trait translational study

项目摘要

DESCRIPTION (provided by applicant): Opioids have become a mainstay of treatment for moderate to severe pain. Direct healthcare costs of pain treatment together with pain-related disability cost the US economy tens of billions annually. While opioids are indisputably effective for acute pain and pain due to malignancies, the use of these drugs is often problematic for more chronic pain states. Abuse, dependence, tolerance and a host of physiological side effects may complicate long-term opioid management. Recently it has been demonstrated both in humans and in animal models that sensitization to painful stimuli develops after the sustained administration of opioids thereby reducing the efficacy of the drugs in achieving long term pain relief. This opioid-induced hyperalgesia (OIH) has no clinically available treatments, and there exist no validated strategies to prevent its occurrence. Our long term goals are to provide such treatments and strategies thus improving our ability to control serious pain. Work completed as part of our Stage I CEBRA award has documented a strong heritable component to OIH in mice, and we have been able to map these genetic differences to specific genes using new in silico mapping techniques. The gene most strongly associated with the mechanical dimension of OIH was the beta-2 adrenergic receptor. The studies to be completed as part of this proposal will confirm (or refute) a functional role for this gene in OIH, document the anatomical location of expression of this gene relevant to its role in OIH and determine the mechanism by which this gene helps to support OIH. A host of selective pharmacological agents as well as transgenic animals and biochemical assays will be employed. In addition, quantitative PCR, immunoblotting, immunohistochemistry and other techniques will assist us in determining basal and morphine-induced changes in levels of expression of this gene in specific central and peripheral nervous system tissues. Finally, we will evaluate hypothesized interactions between the beta-2 adrenergic receptor and pathways already well established to modulate OIH in rodents. The importance of this research with respect to public health is in addressing a fundamental problem limiting the utility of our most powerful pain relieving medications, the opioids. In doing so, we will be in position to design and test strategies which may limit OIH. The molecules on which this research focuses are particularly amenable to translational studies which could be completed in the future.

描述（由申请人提供）：阿片类药物已成为治疗中度至重度疼痛的主要药物。疼痛治疗的直接医疗费用以及与疼痛相关的残疾每年给美国经济造成数百亿美元的损失。虽然阿片类药物无疑对急性疼痛和恶性肿瘤引起的疼痛有效，但对于慢性疼痛状态，使用这些药物通常会出现问题。滥用、依赖性、耐受性和一系列生理副作用可能会使长期阿片类药物管理变得复杂。最近，在人类和动物模型中都证明，持续施用阿片类药物后会对疼痛刺激产生敏感性，从而降低药物实现长期疼痛缓解的功效。这种阿片类药物引起的痛觉过敏 (OIH) 尚无临床可用的治疗方法，也没有有效的策略来预防其发生。我们的长期目标是提供此类治疗和策略，从而提高我们控制严重疼痛的能力。作为第一阶段 CEBRA 奖的一部分完成的工作记录了小鼠 OIH 的强大遗传成分，并且我们已经能够使用新的计算机绘图技术将这些遗传差异映射到特定基因。与 OIH 机械尺寸最密切相关的基因是 β2 肾上腺素受体。作为该提案的一部分，将完成的研究将证实（或反驳）该基因在 OIH 中的功能作用，记录该基因与其在 OIH 中的作用相关的表达的解剖位置，并确定该基因帮助支持奥伊哈。将采用大量选择性药物以及转基因动物和生化测定。此外，定量PCR、免疫印迹、免疫组织化学和其他技术将帮助我们确定特定中枢和周围神经系统组织中该基因表达水平的基础和吗啡诱导的变化。最后，我们将评估 β2 肾上腺素受体与已经建立的调节啮齿动物 OIH 途径之间的假设相互作用。这项研究对公共卫生的重要性在于解决限制我们最强大的止痛药物阿片类药物的使用的基本问题。在此过程中，我们将能够设计和测试可能限制 OIH 的策略。这项研究重点关注的分子特别适合于未来完成的转化研究。