Dissecting the role of ethanol-induced plasticity in the PAG to BNST pathway in pain-related behaviors

剖析乙醇诱导的可塑性在 PAG 至 BNST 通路中在疼痛相关行为中的作用

• 批准号: 9763786
• 负责人: Thomas L. Kash
• 金额: $ 21.87万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-10 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763786
• 关键词: Acute; Address; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; American; Analgesics; Animal Model; Attenuated; Behavior; Brain; Brain region; Chronic; Comorbidity; Corticotropin-Releasing Hormone; Coupled; Dangerousness; Data; Development; Electrophysiology (science); Emotional; Ethanol; Future; Glutamates; Goals; Heavy Drinking; Hyperalgesia; Incidence; Investigation; Measures; Modeling; Molecular; Mus; Neurons; Outcome; Output; Pain; Pain management; Pathologic; Pathway interactions; Patients; Periodicity; Pharmacology; Physiological; Population; Property; Public Health; Recording of previous events; Regulation; Research; Role; Scanning; Signal Transduction; Site; Slice; Stimulus; Structure of terminal stria nuclei of preoptic region; Testing; United States; Viral; Withdrawal; Work; alcohol behavior; alcohol exposure; alcohol use disorder; chronic alcohol ingestion; chronic pain; chronic pain patient; disability; dopaminergic neuron; effective therapy; experimental study; in vivo; in vivo calcium imaging; insight; interest; male; membrane-associated placental tissue protein 1; midbrain central gray substance; neuronal circuitry; neurotransmission; novel; optogenetics; pain reduction; pain relief; pain sensitivity; recruit; side effect; stem; transmission process

The high incidence of alcohol abuse that occurs in patients with chronic pain underscores the importance of continued research towards effective treatments for both pain and alcohol use disorders. It has been found in animal models that chronic alcohol exposure can drive adaptations in the brain, which drive increased pain- related behaviors. Our long-term goal is to understand how chronic alcohol exposure can alter the neuronal circuits that regulate pain-related behavior in order to develop more effective approaches to treat alcohol induced pain. One region of particular interest for these studies is the periaqueductal gray (PAG). We have previously shown that a subpopulation of dopamine neurons in the ventrolateral PAG (PAGDA) are activated by acute alcohol and activation of these same neurons induces an anti-nociceptive effect in the hot-plate test. Furthermore, in our preliminary data, we found that activation of the outputs to the bed nucleus of the stria terminalis (BNST) could replicate this anti-nociceptive effect. These findings are noteworthy, as they identify a novel ascending anti-nociceptive pathway (PAGDA to BNST) distinct from the well-characterized descending anti-nociceptive pathway (PAG to Medulla). In keeping with the critical role of the PAGDA to BNST pathway, we found that viral deletion of CRF from the BNST can alter pain related behaviors. In addition, we have found that intermittent alcohol drinking can drive changes in pain-related behavior in mice. Taken together, these studies support the testable hypothesis that intermittent alcohol drinking drives alterations in pain related behavior, in part through disruptions in the PAGDA to BNST pathway, and that in vivo activation of this pathway can ameliorate alcohol- induced hyperalgesia.

慢性疼痛患者酗酒的高发病率强调了以下方面的重要性： 继续研究对疼痛和酒精使用障碍的有效治疗方法。已经发现 动物模型表明，慢性酒精暴露可以驱动大脑的适应性，从而增加疼痛， 相关行为。我们的长期目标是了解慢性酒精暴露如何改变神经元的功能。 调节疼痛相关行为的回路，以开发更有效的方法来治疗酒精诱导的 痛苦这些研究中特别感兴趣的一个区域是中脑导水管周围灰质（PAG）。我们先前已经 表明急性酒精激活腹外侧PAG（PAGDA）中的多巴胺神经元亚群 并且这些相同神经元的激活在热板试验中诱导抗伤害感受效应。更以 我们的初步数据，我们发现，激活输出到床核的终纹（BNST） 可以复制这种抗伤害效应。这些发现是值得注意的，因为他们确定了一个新的提升， 抗伤害性通路（PAGDA至BNST），不同于特征明确的下行抗伤害性通路 途径（PAG到髓质）。与PAGDA到BNST通路的关键作用一致，我们发现病毒 从BNST中删除CRF可以改变疼痛相关行为。此外，我们还发现， 饮酒可以改变小鼠的疼痛相关行为。总之，这些研究支持了 间歇性饮酒会导致疼痛相关行为的改变，部分原因是 PAGDA到BNST通路的中断，并且该通路的体内激活可以改善酒精- 诱发痛觉过敏