Dissecting active neural circuits regulating sensory and affective pain

剖析调节感觉和情感疼痛的活跃神经回路

• 批准号: 10206401
• 负责人: Akihiko Ozawa
• 金额: $ 67.28万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206401
• 关键词: Acute; Acute Pain; Address; Affective; Analgesics; Animals; Anterior; Anxiety; Applications Grants; Attention; Automobile Driving; Behavior; Brain; Brain region; Cells; Clinical; Cognition; Cognitive; Communication; Contralateral; DNA; Data; Development; Dimensions; Emotional; Emotions; Empathy; Enterobacteria phage P1 Cre recombinase; FOS gene; Fiber; Future; Genetic; Genetic Recombination; Genetically Engineered Mouse; Goals; Immediate-Early Genes; Individual; Ipsilateral; Knowledge; Light; Link; Mechanics; Mediating; Mental Depression; Modality; Molecular; Motor; Mus; Neuraxis; Neuroanatomy; Neurons; Neurosciences; Nociception; Nociceptive Stimulus; Opioid; Pain; Pain management; Painless; Patients; Peripheral; Pharmacology Study; Photometry; Process; Quality of life; Research Proposals; Role; Sensory; Side; Signal Transduction; Spinal; Spinal Cord; Spinal nerve structure; Stimulus; Structure; System; Tamoxifen; Technology; Tissues; Touch sensation; addiction; chronic neuropathic pain; chronic pain; chronic painful condition; cingulate cortex; expectation; genetic approach; in vivo imaging; injured; mouse genetics; neural circuit; novel; opioid abuse; opioid misuse; optimal treatments; optogenetics; pain behavior; pain sensation; pain signal; psychologic; recombinase; relating to nervous system; response; side effect; somatosensory; tool; transmission process

Project Summary Opioids as a pain medication has been the most preferred pain treatments in order to provide quick relief from severe pain. Decades of opioid abuse have triggered negative impact on pain therapies. Understanding of neural circuits that are actually driving pain is essential in order to develop more effective and safer pain therapies. Neuroanatomical studies have allowed us to define the regions and subsets of neurons that are important for pain. However, there is very limited understanding of neural circuits that are activated by each pain modality; i.e. how all of the pain-dependently activated neuronal subsets communicate to transmit nociceptive signals derived by distinct pain conditions as well as to distinguish the transition of acute and chronic pain. In addition, recent attention has also tuned into mechanisms underlying emotional dimension of pain such as depression, anxiety, and loss of cognition, especially associated with chronic pain. The anterior cingulate cortex (ACC) is a brain structure known to drive aversion associated with chronic pain. The functional changes in the ACC neurons caused by chronic pain have yet to be clearly explained at the molecular and neural circuit levels. Our preliminary studies have demonstrated that a larger number of neurons are pain specifically activated in the ipsilateral side of the spinal cord in SNL mice compared to those of sham. Similarly, neurons in the contralateral side of the ACC are also selectively activated under a chronic pain condition, which is also consistent with the previous studies describing aversive response associated with chronic pain due to the hyperexcitability of ACC neurons. Here, we therefore focus on two representative regions for pain-related behaviors: the ACC as a key brain structure in the affective pain; and the spinal cord for sensory using mouse genetics combined with neuroanatomy, chemogenetics, and neural recording in order to obtain a better understanding of the mechanisms underlying pain-related behaviors by shedding light on active neural circuits under specific pain conditions. In Specific Aim 1, we will identify the neuronal subsets activated by distinct pain stimuli (acute heat and mechanical pain, and chronic pain) in the spinal cord, and chemogenetically manipulate the activity of pain specifically-activated neurons in order to validate that these neurons are directly regulating the specific pain modalities. In Specific Aim 2, we will investigate the role of chronic pain dependently activated ACC neurons in order to obtain a better understanding of the mechanism by which the ACC discriminates the affective and sensory pain behavior associated with chronic pain. We will use neuroanatomical tracing to identify the ACC neuronal subsets and their projection neurons communicating with other pain-related brain regions. Our proposed studies will enable us to collect feasibility data for a future Targeted BRAIN Circuits Projects R01 research proposal, which will help to further understand the active neural circuits regulating the transmission of pain sensory signals elicited by different pain modalities at the spinal cord and also the expression of affective and sensory pain behavior mediated by the ACC circuits in chronic pain.

项目摘要 阿片类药物作为止痛药是最喜欢的疼痛治疗方法，以便快速缓解 严重的疼痛。数十年的阿片类药物滥用已经引发了对疼痛疗法的负面影响。对神经的理解 实际上正在驱动疼痛的电路对于开发更有效，更安全的疼痛疗法至关重要。 神经解剖学研究使我们能够定义对神经元的区域和亚集，这些区域和子集对 疼痛。但是，对每种疼痛方式激活的神经回路的理解非常有限。 IE。 所有疼痛依赖性激活的神经元子集如何通信发射伤害性信号 通过不同的疼痛条件以及区分急性和慢性疼痛的过渡。此外，最近 注意还调整了疼痛的情绪维度的机制，例如抑郁，焦虑， 和认知的丧失，尤其是与慢性疼痛有关。前扣带回皮层（ACC）是大脑 已知的结构可以驱动与慢性疼痛相关的厌恶。 ACC神经元的功能变化 由慢性疼痛引起的尚未在分子和神经回路水平上清楚地解释。我们的初步 研究表明，较大的神经元在同侧特别激活了疼痛 与假的小鼠相比，SNL小鼠的脊髓的脊髓。同样，在对侧的神经元 在慢性疼痛状态下，ACC也被选择性地激活，这也与以前的 由于ACC神经元的过度兴奋性，描述与慢性疼痛相关的厌恶反应的研究。 因此，我们专注于两个与疼痛相关行为的代表性区域：ACC作为关键大脑 情感疼痛中的结构；以及使用小鼠遗传学结合使用的感觉的脊髓 神经解剖学，化学遗传学和神经记录，以便更好地了解 通过在特定疼痛下阐明主动神经回路的启示，与疼痛相关行为的机制 状况。在特定的目标1中，我们将识别由不同的疼痛刺激激活的神经元子集（急性热量 脊髓中的机械疼痛和慢性疼痛），并在化学上操纵疼痛的活性 特定激活的神经元以验证这些神经元直接调节特定疼痛 方式。在特定的目标2中，我们将研究慢性疼痛依赖于激活的ACC神经元在 为了更好地理解ACC歧视情感的机制和 与慢性疼痛有关的感觉疼痛行为。我们将使用神经解剖学跟踪来识别ACC 神经元亚群及其投射神经元与其他与疼痛相关的大脑区域进行通信。我们的 拟议的研究将使我们能够为未来的目标脑电路项目收集可行性数据R01 研究建议将有助于进一步了解调节传播的主动神经回路 脊髓处不同的疼痛方式引起的疼痛感官信号，也表达了情感 慢性疼痛中的ACC电路介导的感觉疼痛行为。

项目成果

Functional and anatomical analyses of active spinal circuits in a mouse model of chronic pain.

• DOI: 10.1097/j.pain.0000000000003068
• 发表时间: 2023-10
• 期刊: Pain
• 影响因子: 7.4
• 作者: Katarzyna M Targowska-Duda;Darian Peters;Jason L. Marcus;Gilles Zribi;L. Toll;Akihiko Ozawa