Identification of gene variants for alcohol analgesia

酒精镇痛基因变异的鉴定

• 批准号: 9758078
• 负责人: M. Imad Damaj
• 金额: $ 39.3万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-20 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9758078
• 关键词: Absence of pain sensation; Acute; Acute Pain; Alcohol Phenotype; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcohols; Alleles; American; Amygdaloid structure; Analgesics; Animal Model; Bioinformatics; CRISPR/Cas technology; Candidate Disease Gene; Complex; Data; Databases; Development; Dose; Drug abuse; Ethanol; Future; Gene Delivery; Gene Expression; Genes; Genetic; Genetic study; Genomic Segment; Genomic approach; Goals; Heritability; Human; Hyperalgesia; Hypersensitivity; Inbred Mouse; Inbreeding; Individual; Knock-out; Link; Lumbar spinal cord structure; Maps; Measures; Mechanics; Mediating; Molecular Genetics; Mus; Neurons; Oral; Oral Administration; Pain; Pattern; Pharmacology; Phenotype; Population Study; Predisposition; Prefrontal Cortex; Process; Property; Quantitative Trait Loci; Recombinant Inbred Strain; Recombinants; Sex Differences; Testing; Time; Tissues; Variant; Viral Vector; Withdrawal; Work; alcohol abstinence; alcohol effect; base; behavioral response; behavioral study; behavioral tolerance; candidate validation; catalyst; chronic pain; genetic approach; genetic variant; midbrain central gray substance; mouse model; novel; pain model; pain sensitivity; progenitor; relating to nervous system; resilience; sex; trait; transcriptome; transcriptome sequencing

Evidence of significant co-occurrence between pain and alcohol consumption are emerging. There is also indication that alcohol can induce acute analgesia with cross- sectional evidence that some individuals may be motivated to use alcohol to cope with pain. However, potential moderators and mechanisms of action remain largely uncharacterized and poorly understood. This proposal will focus on examining potential pharmacological and genetic mechanisms mediating the alcohol-pain connection using the mouse BXD recombinant inbred (RI) panel. The primary objective of this proposal is to identify novel genetic factors that contribute to alcohol acute analgesic effects and development of tolerance in mice. We observed for the first time strain differences between C57BL6/J and DBA/2J for alcohol-induced antinociceptive effects in the hot- plate test after oral administration. In Aim 1, we will examine and characterize alcohol’s analgesic properties in acute pain models after oral dosing in the mouse. In Aim 2, we will use BXD RI lines to map genomic regions, or QTLs, that are causally associated with susceptibility versus resilience to alcohol effects and the development of tolerance in the hot-plate test. In Aim 3, we will identify changes in the transcriptome associated with acute analgesic phenotype and tolerance of alcohol. We will measure changes in gene expression in relevant neuronal tissues (amygdala, periaqueductal grey and prefrontal cortex) associated with alcohol initial sensitivity and tolerance in extreme RI strains. In Aim 4, we will validate candidate quantitative trait genes and functional variants identified and ranked by Aims 2-3.

疼痛和饮酒之间显著共同发生的证据是 正在浮现也有迹象表明，酒精可以诱导急性镇痛与交叉- 部分证据表明，一些人可能有动机使用酒精来科普 痛苦然而，潜在的调节剂和作用机制仍然主要是 没有特征也不太了解这项提案将侧重于审查潜在的 药理学和遗传机制介导的酒精疼痛连接使用 小鼠BXD重组近交系（RI）组。这项建议的主要目的是 确定新的遗传因素，有助于酒精急性镇痛作用， 在小鼠中产生耐受性。我们第一次观察到 C57 BL 6/J和DBA/2 J之间的酒精诱导的抗伤害性作用，在热- 经口给药后平板试验。在目标1中，我们将检查和表征酒精的 在小鼠中口服给药后急性疼痛模型中的镇痛特性。在目标2中， 将使用BXD RI系来定位基因组区域或QTL，这些区域与 对酒精影响的敏感性和恢复力以及耐受性的发展 在热板测试中。在目标3中，我们将确定与转录组相关的变化， 具有急性镇痛表型和酒精耐受性。我们将衡量 在相关神经元组织（杏仁核、导水管周围灰质和海马体）中的基因表达 前额叶皮层）与极端RI中酒精初始敏感性和耐受性相关 菌株在目标4中，我们将验证候选数量性状基因和功能基因， 通过目标2-3识别和排序的变体。