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 也有迹象表明，酒精可引起交叉性的急性镇痛。 部分证据表明，某些人可能会被迫使用酒精来应对 然而，潜在的调节因素和作用机制在很大程度上仍然存在。 该提案将侧重于审查潜力。 介导酒精-疼痛关系的药理学和遗传机制 小鼠 BXD 重组近交 (RI) 小组 该提案的主要目标是。 识别导致急性酒精镇痛作用的新遗传因素，以及 我们首次观察到小鼠的耐受性差异。 C57BL6/J 和 DBA/2J 之间对酒精诱导的热应激作用的影响 在目标 1 中，我们将检查并表征酒精的含量。 在目标 2 中，我们研究了小鼠口服给药后急性疼痛模型的镇痛特性。 将使用 BXD RI 系来绘制因果相关的基因组区域或 QTL 对酒精影响的敏感性与抵抗力以及耐受性的发展 在热板测试中，我们将识别相关转录组的变化。 我们将测量急性镇痛表型和酒精耐受性的变化。 相关神经组织（杏仁核、导水管周围灰质和 前额皮质）与极端 RI 中初始酒精敏感性和耐受性相关 在目标 4 中，我们将验证候选数量性状基因和功能。 按目标 2-3 确定并排序变体。

项目成果

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

DBA/2J 和 C57BL/6J 近交雄性和雌性小鼠品系对酒精的热镇痛反应。

• 发表时间: 2023-01-05
• 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

Pharmacological mechanisms of alcohol analgesic-like properties in mouse models of acute and chronic pain.

急性和慢性疼痛小鼠模型中酒精镇痛样特性的药理学机制。

• 发表时间: 2019
• 影响因子: 4.7
• 作者: Neddenriep, Bradley;Bagdas, Deniz;Contreras, Katherine M;Ditre, Joseph W;Wolstenholme, Jennifer T;Miles, Michael F;Damaj, M Imad
• 通讯作者: Damaj, M Imad

Surgical incision pain induced an increase in alcohol consumption in mice.

手术切口疼痛导致小鼠饮酒量增加。

• 发表时间: 2024-06
• 作者: Ghani, Sofia;Alkhlaif, Yasmin;Mann, Jared;Moncayo, Lauren;Ulker, Esad;Caillaud, Martial;Barik, Mitali;Ditre, Joseph W;Miles, Michael F;Damaj, M Imad
• 通讯作者: Damaj, M Imad