Identification of gene variants for alcohol analgesia

酒精镇痛基因变异的鉴定

• 批准号: 10380160
• 负责人: M. Imad Damaj
• 金额: $ 46.03万
• 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/10380160
• 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; 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; conditional knockout; genetic approach; genetic variant; genomic locus; midbrain central gray substance; mouse genetics; 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存的证据是 正在浮现。也有迹象表明，酒精可以通过交叉作用诱导急性镇痛。 部分证据表明，一些人可能有动机使用酒精来应对 疼痛。然而，潜在的主持人和行动机制在很大程度上仍然 没有特征，也很难理解。这项提案将侧重于审查潜在的 乙醇-痛觉联系的药理学和遗传学机制 小鼠BXD重组近交系(RI)板。这项提议的主要目标是 确定导致酒精急性止痛作用的新的遗传因素，并 小鼠的耐受性发展。我们第一次观察到菌株的差异 C57BL6/J和DBA/2J对酒精性痛觉过敏的影响 口服后进行平板试验。在目标1中，我们将检查和描述酒精的 小鼠口服急性疼痛模型的止痛特性。在目标2中，我们 将使用BXD RI系来定位因果关联的基因组区域或QTL 对酒精的敏感性和耐受性的影响和耐受性的发展 在电热板测试中。在目标3中，我们将确定相关转录组的变化 具有急性止痛表型和酒精耐受性。我们将衡量以下变化 相关神经元组织(杏仁核、中脑导水管周围灰质和 前额叶皮质)与极端RI的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 根据AIMS 2-3确定和排序的变种。