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: 10386925
• 负责人: Thomas L. Kash
• 金额: $ 41.73万
• 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/10386925
• 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; Pharmacology; 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; 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; 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，影响着7000多万人 美国人和全球15亿人。疼痛的一线治疗一直是阿片类药物，然而他们的 使用与上瘾、依赖和过量有关。减少对阿片类药物依赖的战略 慢性疼痛的治疗是为了更好地了解介导慢性疼痛不同方面的回路和 确定非阿片能机制以恢复正常的电路功能和行为。促肾上腺皮质激素释放 终纹床核(BNST)中的因子(CRF)信号已被证明调节两者 与疼痛相关的伤害性和情感/动机行为，然而， 针对CRF系统的药理作用仍有待探索。鉴于开发治疗方法的迫切需要 针对慢性疼痛的情感和动机方面，这可能是一条重要的前进道路。我们 假设持续性炎性疼痛导致BNST导联CRF信号的激活增加 扰乱情感行为，降低积极性。我们假设BNST的调节器的功能是相反的 CRF信号转导可以为研究和治疗伤害性和动机/情感性提供一种新的途径 疼痛的方方面面。与此相关的是，我们在初步研究中发现，中脑导水管周围的灰色种群 多巴胺(PAGDA)神经元投射到BNST，在激活时表现出抗伤害性特性， 突显了BNST中的多巴胺是疼痛相关行为的关键抑制因素的可能性。上一首 研究发现，这些PAGDA神经元在阿片类药物诱导的抗伤害性反应中起关键作用。目标是 这一建议的目的是严格和机械地确定PAGDA到BNSTCRF电路在 炎症性疼痛驱动的行为变化，长期目标是确定新的治疗方法 炎症性疼痛。我们已经收集了强有力的数据，表明急性疼痛与这一环路有关，并假设 这种最初的接触导致了有助于炎症性疼痛持续的可塑性，并且 与炎症性疼痛相关的情绪行为的发展。这将通过以下三个途径实现 目标趋同