Investigation of the endogenous opioid neural circuitry in pain

疼痛中内源性阿片类神经回路的研究

• 批准号: 10646973
• 负责人: Erin Nicole Bobeck
• 金额: $ 7.3万
• 依托单位: UTAH STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646973
• 关键词: Affect; American; Amygdaloid structure; Anterior; Automobile Driving; Behavioral; Binding; Biomedical Research; Brain; Brain region; Cell Nucleus; Central Nervous System; Chronic; Communication; Communities; Dynorphins; Endorphins; Enkephalins; Female; Gene Expression; In Vitro; Investigation; Knowledge; Label; Lead; Maps; Measures; Medial; Mediating; Molecular; Morphine; Mus; Neurons; Nucleus Accumbens; Opioid; Opioid Analgesics; Opioid Peptide; Opioid Receptor; Opioid agonist; Output; Pain; Pain Measurement; Pain management; Pathway interactions; Peptides; Pharmaceutical Preparations; Play; Prefrontal Cortex; Pro-Opiomelanocortin; Process; Property; Quantitative Reverse Transcriptase PCR; Receptor Activation; Research; Rewards; Role; Sex Differences; Specificity; Spinal Cord; Spinal cord posterior horn; Synapses; System; Therapeutic; Time; Tracer; Viral; Work; abuse liability; addiction; allostatic load; antinociception; chronic pain; cingulate cortex; delta opioid receptor; endogenous opioids; experimental study; fighting; genetic approach; kappa opioid receptors; mRNA Expression; male; midbrain central gray substance; mu opioid receptors; neural; neural circuit; neuromechanism; nociceptive response; opioid epidemic; opioid exposure; pain behavior; pain signal; prodynorphin; proenkephalin; receptor; receptor expression; response; sex; sexual dimorphism; side effect

PROJECT SUMMARY The opioid epidemic has encouraged the biomedical research community to explore new pain targets and further study opioid’s most famous target, the mu opioid receptor. One underexplored arena is the study of the endogenous opioid peptide system, which we know very little especially in comparison to our knowledge of the receptors they activate. This is despite the commonsense understanding that the endogenous peptides must change as a result of the allostatic load imposed by chronic pain, opioids, and chronic opioid exposure. There are well established sex differences in the actions of opioids at the mu opioid receptor, but it is unknown whether there are also differences in the endogenous opioid peptides. The experiments outlined here lay the necessary and long overdue groundwork to understand the neural mechanisms of one class of the endogenous opioids, called enkephalins, and how they contribute to pain. In the first aim, we will quantify enkephalin mRNA expression in regions of the brain known to play a role in top-down pain modulation. Next, we will use a viral retrograde tracer to map the enkephalin containing neurons that synapse in the PAG, something that has never been done before. In Aim 2 we will probe the behavioral effects of activating enkephalin containing neurons that synapse in the PAG using excitatory and inhibitory chemogenetic approaches followed by assessment on pain assays. We expect that increasing activation of all enkephalin neurons that synapse in the PAG will result in increased antinociception. Further, we expect that inhibition will lower the endogenous opioid release and therefore produce pain. We will further isolate certain neural projections from one brain region at a time to elucidate which brain regions are driving the enkephalin mediated antinociceptive responses. This research will allow us to better understand how the endogenous opioid system facilitates pain control and whether there are underlying differences that lead to differences in pain modulation in males and females.

项目摘要 阿片类药物的流行鼓励生物医学研究界探索新的疼痛 目标和进一步研究阿片类药物最著名的目标，μ阿片受体。一个探索不足的 竞技场是对内源性阿片肽系统的研究，尤其是对这一系统的研究，我们所知甚少 与我们对它们激活的受体的了解相比。这是不顾常识 理解内源性肽必须作为非稳态负荷的结果而改变 由慢性疼痛、阿片类药物和慢性阿片类药物暴露引起。有很好的性别 阿片类药物在μ阿片受体上的作用存在差异，但尚不清楚是否存在 内源性阿片肽也有差异。这里概述的实验奠定了 必要的和长期拖延的基础，以了解神经机制的一类， 内源性阿片类物质，称为脑啡肽，以及它们如何导致疼痛。第一个目标，我们 将量化脑啡肽mRNA在大脑区域的表达，这些区域已知在自上而下的 疼痛调节接下来，我们将使用病毒逆行示踪剂来绘制脑啡肽， 在PAG中形成突触的神经元，这是以前从未做过的。在目标2中， 探索激活PAG中突触的含脑啡肽神经元的行为效应 使用兴奋性和抑制性化学发生方法，然后通过疼痛测定进行评估。 我们预计，增加激活所有脑啡肽神经元的突触在PAG将导致 增加抗伤害感受。此外，我们预计抑制将降低内源性阿片样物质 释放，从而产生疼痛。我们将进一步分离出某些神经投射 大脑区域，以阐明哪些大脑区域驱动脑啡肽介导的 抗伤害性反应这项研究将使我们更好地了解内源性 阿片样物质系统促进疼痛控制，以及是否存在导致 男性和女性疼痛调节的差异。