Direct and Indirect Nociceptive Inputs to Brainstem Pain-Modulating Neurons

脑干疼痛调节神经元的直接和间接伤害性输入

• 批准号: 10520013
• 负责人: Caitlynn De Preter
• 金额: $ 4.85万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10520013
• 关键词: Absence of pain sensation; Acute; Acute Pain; Anatomy; Animals; Area; Attention; Attenuated; Behavioral; Brain; Brain Stem; Brain region; Cells; Chronic; Clinical; Collaborations; Communication; Complement; Complex; Data; Development; Electrophysiology (science); Equilibrium; Exhibits; Experimental Designs; Exposure to; Face; Freund' s Adjuvant; Functional disorder; Goals; Head; Hyperalgesia; Hypersensitivity; In Vitro; Inflammation; Injections; Link; Maps; Masseter Muscle; Mechanical Stimulation; Mediating; Mentors; Migraine; Neurons; Nociception; Orofacial Pain; Output; Pain; Pain Research; Pain management; Pathway interactions; Persistent pain; Physiological; Positioning Attribute; Research Personnel; Role; Signal Transduction; Spinal; Spinal cord posterior horn; Structure; System; Temporomandibular Joint Disorders; Testing; Training; Trigeminal Neuralgia; Trigeminal System; Vertebral column; Withdrawal; Work; adeno-associated viral vector; central pain; chronic pain; chronic pain management; chronic painful condition; craniofacial; dorsal horn; experimental study; in vivo; inflammatory pain; insight; new therapeutic target; optogenetics; orofacial; pain inhibition; recruit; response; sensory input; skills; transmission process

PROJECT SUMMARY The brain regulates nociceptive processing through descending projections from the brainstem to the spinal and trigeminal dorsal horns. This is accomplished through endogenous pain-modulating circuits that can amplify or suppress pain-related signals, and normally maintain a balance between facilitation and inhibition of pain. In chronic pain conditions, the system is dysregulated, contributing to a facilitated pain state. The output of this pain-modulating system, via the rostral ventromedial medulla (RVM) has been extensively studied. Bidirectional pain control from this region is mediated by two physiologically defined cell classes, “ON-cells” and “OFF-cells,” that respectively facilitate and inhibit nociceptive transmission. However, sensory inputs to RVM are only now receiving significant attention. Indirect inputs from the dorsal horn via the parabrachial complex convey nociceptive information to RVM and contribute to the sensitization of RVM neurons in persistent inflammatory pain. However, there also is evidence from anatomical studies for a direct input from the dorsal horn to RVM. The hypothesis of this proposal is that RVM receives both indirect and direct functional inputs from the trigeminal dorsal horn that contribute to pain-modulation, and that the direct input is altered in a persistent pain state. This project will focus on the trigeminal system, which mediates sensory input from the face and head, regions associated with a heavy burden of chronic pain, including migraine headache, temporomandibular disorder, and trigeminal neuralgia. I will use a combination of single-cell recording in RVM combined with optogenetic manipulation of the direct (trigeminal-to-RVM) and indirect (trigeminal relay through parabrachial complex) projections to test the role of each connection to RVM and determine whether and how the function of the direct pathway changes in persistent pain. Collectively, these studies will enhance our understanding of the contribution of trigeminal sensory inputs to the intrinsic pain-modulatory circuit and define how nociceptive inputs gain access to the RVM. By identifying the drivers of pro-nociceptive brainstem outputs, we can gain new insights into how pain-modulating systems are recruited and modulated in acute and chronic pain, providing us with novel targets for therapies. This project will complement a comprehensive and structured training plan that I have developed in collaboration with my mentor, Dr. Mary Heinricher. In addition to advanced training in optogenetics and in vivo electrophysiology, I will enhance my skills in programming, experimental design, and quantitative analysis. I will also gain increased depth of understanding of pain and pain research, in part by exposure to the clinical challenges of chronic pain management. Finally, I expect to engage in activities that will support increased skills in scientific communication. As a whole, the proposed training will position me to succeed as an independent researcher and leader in academic pain research.

项目概要 大脑通过从脑干到脊柱的下降投射来调节伤害感受处理 这是通过内源性疼痛调节回路来实现的。 放大或抑制与疼痛相关的信号，并通常在促进和抑制之间保持平衡 在慢性疼痛情况下，系统失调，导致疼痛状态的输出。 这种疼痛调节系统通过延髓头端腹内侧 (RVM) 的作用已得到广泛研究。 该区域的双向疼痛控制由两种生理学定义的细胞类别“ON-细胞”介导 和“OFF-细胞”，分别促进和抑制伤害性传递。 RVM 现在才受到了来自背角通过臂旁肌的间接输入的广泛关注。 复合体向 RVM 传递伤害性信息，并有助于 RVM 神经元的敏化 然而，解剖学研究也有证据表明来自于持续性炎症疼痛。 该提案的假设是 RVM 接收间接和直接功能。 来自三叉神经背角的输入有助于疼痛调节，并且直接输入是在 该项目将重点关注三叉神经系统，该系统介导来自大脑的感觉输入。 面部和头部，与慢性疼痛（包括偏头痛）沉重负担相关的区域， 颞下颌关节紊乱病和三叉神经痛我将在 RVM 中结合使用单细胞记录。 结合直接（三叉神经到 RVM）和间接（三叉神经中继）的光遗传学操作 臂旁复合体）投影来测试每个 RVM 连接的作用并确定是否以及如何 总的来说，这些研究将增强我们对持续性疼痛中直接通路变化的功能的认识。 了解三叉神经感觉输入对内在疼痛调节回路的贡献并定义 伤害性输入如何进入 RVM 通过识别促伤害性脑干输出的驱动因素， 我们可以获得关于如何在急性和慢性疾病中招募和调节疼痛调节系统的新见解 疼痛，为我们提供了新的治疗靶标，该项目将补充全面且有效的治疗方法。 此外，我与导师 Mary Heinricher 博士合作制定了结构化培训计划。 通过光遗传学和体内电生理学的高级培训，我将提高我的编程技能， 我还将加深对疼痛和疼痛的理解。 最后，我希望通过接触慢性疼痛管理的临床挑战来进行疼痛研究。 参与有助于提高科学传播技能的活动 总体而言，拟议的。 培训将使我成为一名成功的独立研究员和学术疼痛研究的领导者。