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

• 批准号: 7883677
• 负责人: DAVID J. CLARK
• 金额: $ 23.77万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 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/7883677
• 关键词: AR gene; Absence of pain sensation; Acute; Acute Pain; Address; Adverse effects; Afferent Neurons; Agonist; Alleles; Animal Model; Award; Binding; Biochemical; Biological Assay; Brain; Candidate Disease Gene; Characteristics; Chromosome Mapping; Chronic; Clinical; Complex; Computer Simulation; 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; 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; adverse outcome; beta-2 Adrenergic Receptors; chronic pain; cost; design; disability; drug efficacy; experience; improved; innovation; neurochemistry; novel; prevent; programs; receptor; receptor expression; research study; therapy development; trait; translational study; treatment strategy

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）：阿片类药物已成为中度至严重疼痛的治疗中的主要手段。疼痛治疗的直接医疗保健费用以及与疼痛有关的残疾每年花费数十亿美元的经济。虽然阿片类药物无疑对于由于恶性肿瘤而导致的急性疼痛和疼痛有效，但对于更慢性疼痛状态而言，使用这些药物通常是有问题的。滥用，依赖性，宽容和许多生理副作用可能会使长期阿片类药物管理复杂化。最近，在人类和动物模型中都证明了这一点，在持续的阿片类药物给药后，对疼痛刺激的敏感性发展，从而降低了药物在实现长期疼痛缓解效果方面的疗效。这种阿片类药物诱导的痛觉过敏（OIH）没有临床可用的治疗方法，也没有验证的策略来防止其发生。我们的长期目标是提供这种治疗方法和策略，从而提高我们控制严重疼痛的能力。作为我们阶段I CEBRA奖的一部分完成的工作已经记录了小鼠OIH的强大遗传组成部分，我们已经能够使用新的硅映射技术将这些遗传差异映射到特定基因。与OIH的机械维度最密切相关的基因是β-2肾上腺素能受体。作为本提案的一部分完成的研究将确认（或驳斥）该基因在OIH中的功能作用，记录该基因在OIH中的作用相关的表达的解剖位置，并确定该基因有助于支持OIH的机制。将采用许多选择性的药理学剂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有助于我们确定基础和吗啡诱导的该基因表达水平的变化，在特定的中枢和外周神经系统组织中。最后，我们将评估β-2肾上腺素能受体和已经建立的途径之间的假设相互作用，以调节啮齿动物中的OIH。这项研究在公共卫生方面的重要性在于解决一个基本问题，限制了我们最强大的疼痛药物，即阿片类药物的实用性。这样一来，我们将可以设计和测试可能限制OIH的策略。该研究所关注的分子特别适合将来可以完成的翻译研究。