Identification of gene variants for alcohol analgesia

酒精镇痛基因变异的鉴定

• 批准号: 10598056
• 负责人: M. Imad Damaj
• 金额: $ 45.88万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598056
• 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; Mus; Neurons; Oral; Oral Administration; Pain; Pattern; 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; antinociception; behavioral response; behavioral study; behavioral tolerance; candidate validation; catalyst; chronic pain; conditional knockout; coping; genetic approach; genetic variant; genomic locus; midbrain central gray substance; mouse genetics; mouse model; neural; novel; pain model; pain sensitivity; pharmacologic; progenitor; 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.

疼痛和饮酒之间显着同时发生的证据是 新兴。还迹象表明，酒精可以通过交叉诱导急性镇痛 部分证据表明，某些人可能会使用酒精来应对 疼痛。但是，潜在的主持人和行动机制在很大程度上仍然是 未经表征和知之甚少。该建议将重点介绍潜力 使用的药理学和遗传机制使用使用酒精饮食连接的药理和遗传机制 小鼠BXD重组亲（RI）面板。该提议的主要目的是 确定有助于酒精急性镇痛作用的新型遗传因素和 小鼠耐受性的发展。我们在首次应变差异观察 在C57BL6/J和DBA/2J之间，用于酒精引起的抗伤害感受效应 口服给药后的板测试。在AIM 1中，我们将检查并描述酒精的 小鼠口服给药后急性疼痛模型中的镇痛特性。在AIM 2中，我们 将使用BXD RI线绘制有时关联的基因组区域或QTL 具有易感性与对酒精效应的韧性和耐受性的发展 在热板测试中。在AIM 3中，我们将确定相关转录组相关的变化 具有急性镇痛表型和酒精的耐受性。我们将衡量变更 相关神经元组织中的基因表达（杏仁核，周围灰色和 与酒精初始敏感性和极端RI的耐受性相关的前额叶皮层） 菌株。在AIM 4中，我们将验证候选定量性状基因和功能 用目标2-3识别和排名的变体。

项目成果

Thermal antinociceptive responses to alcohol in DBA/2J and C57BL/6J inbred male and female mouse strains.

• DOI: 10.1016/j.bbr.2022.114087
• 发表时间: 2023-01-05
• 期刊: BEHAVIOURAL BRAIN RESEARCH
• 影响因子: 2.7
• 作者: White, Alyssa;Caillaud, Martial;Carper, Moriah;Poklis, Justin;Miles, Michael F.;Damaj, M. Imad
• 通讯作者: Damaj, M. Imad