Determining the impact of BNST CRF systems on inflammatory pain-induced disruptions of behavior

确定 BNST CRF 系统对炎性疼痛引起的行为破坏的影响

• 批准号: 10608985
• 负责人: Thomas L. Kash
• 金额: $ 39.54万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608985
• 关键词: Acute; Acute Pain; Affect; Affective; American; Automobile Driving; Behavior; Behavioral; Brain; CRISPR/Cas technology; Calcium; Clinical; Corticotropin-Releasing Hormone; Data; Dependence; Development; Dopamine; Dopamine Receptor; Exhibits; Genetic; Goals; Image; Link; Measurement; Mediating; Motivation; Mus; Neurons; Nociception; Opioid; Overdose; Pain; Pain management; Persons; Physiological Adaptation; Physiology; Play; Population; Property; Rewards; Role; Signal Transduction; Signaling Molecule; Site; Slice; Structure of terminal stria nuclei of preoptic region; System; Testing; United States; addiction; antinociception; chronic pain; chronic pain management; disability; dopaminergic neuron; emotional behavior; heat stimulus; in vivo; in vivo calcium imaging; inflammatory pain; insight; midbrain central gray substance; nociceptive response; novel; novel strategies; pharmacologic; receptor; receptor function

Pain is currently the most common cause of long-term disability in the United States, affecting over 70 million Americans and 1.5 billion people worldwide. The first line of treatment for pain has been opioids, however their use is associated with addiction, dependence and overdose. A strategy for reducing the reliance on opioids for treatment of chronic pain is to better understand the circuits that mediate different aspects of chronic pain and identify non-opioidergic mechanisms to restore normal circuit function and behavior. Corticotropin releasing factor (CRF) signaling in the bed nucleus of the stria terminalis (BNST) has been shown to regulate both nociceptive and affective/motivational behaviors associated with pain, however the clinical utility of pharmacologically targeting the CRF system has yet to be explored. Given the critical need to develop treatments to target affective and motivational aspects of chronic pain, this could be an important path forward. We hypothesize that persistent inflammatory pain leads to increased activation of CRF signaling in the BNST leading to disrupted affective behaviors and reduced motivation. We posit that modulators of BNST function that oppose CRF signaling could provide a novel approach to investigate and treat both nociceptive and motivational/affective aspects of pain. Relevant to this, we have found in preliminary studies, a population of periaqueductal gray dopamine (PAGDA) neurons that project to the BNST that exhibit anti-nociceptive properties when activated, highlighting the possibility that dopamine in the BNST is a critical suppressor of pain-related behaviors. Previous studies have found that these PAGDA neurons play a key role in opioid induced anti-nociception. The objective of this proposal is to rigorously and mechanistically determine the role of the PAGDA to BNSTCRF circuit in inflammatory pain-driven changes in behavior, with the long term goal of identifying new treatments for inflammatory pain. We have collected strong data showing that acute pain engages this circuit, and hypothesize that this initial engagement leads to plasticity contributing to the persistence of inflammatory pain, and the development of emotional behaviors associated with inflammatory pain. This will be accomplished via three convergent aims

疼痛目前是美国长期残疾的最常见原因，影响超过7000万 美国人和全球15亿人。疼痛的第一道治疗是阿片类药物，但是 使用与成瘾，依赖性和过量相关。减少对阿片类药物的依赖的策略 慢性疼痛的治疗方法是更好地了解介导慢性疼痛和 识别非阿片机制以恢复正常电路功能和行为。皮质激素释放 已证明了质子末端（BNST）床核中的因子（CRF）信号传导可以调节这两者 与疼痛相关的伤害性和情感/动机行为，但是 在药理学上针对CRF系统尚未探索。考虑到开发治疗的迫切需要 为了靶向慢性疼痛的情感和动机方面，这可能是前进的重要途径。我们 假设持续性炎症性疼痛会导致BNST领先的CRF信号传导的激活增加 破坏情感行为并减少动力。我们认为BNST功能的调节器反对 CRF信号传导可以提供一种新颖的方法来调查和治疗伤害性和动机/情感 疼痛的各个方面。与此相关的是，我们在初步研究中发现了灰色周围的人群 激活后向BNST投射的多巴胺（PAGDA）神经元，该神经元在BNST上表现出抗伤害性特性 强调BNST中多巴胺是与疼痛相关行为的关键抑制剂的可能性。以前的 研究发现，这些PAGDA神经元在阿片类药物诱导的抗伤害感受中起着关键作用。目标 该提议的严格和机械师确定PAGDA在BNSTCRF电路中的作用 炎症性疼痛驱动的行为变化，其长期目标是确定新的治疗方法 炎症性疼痛。我们收集了强大的数据，表明急性疼痛与该电路相关，并假设 最初的参与导致可塑性导致炎症性疼痛的持续性，以及 与炎症性疼痛相关的情绪行为的发展。这将通过三个 融合目标