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.

项目摘要 大脑通过从脑干到脊髓的下行投射来调节伤害性感受过程 和三叉神经背角这是通过内源性疼痛调节回路来实现的， 放大或抑制疼痛相关信号，并在正常情况下保持促进和抑制之间的平衡。 痛苦在慢性疼痛条件下，该系统失调，有助于促进疼痛状态。输出 这种疼痛调节系统，通过延髓头端腹内侧（RVM）已被广泛研究。 该区域的双向疼痛控制由两种生理学上定义的细胞类别“ON细胞”介导。 和“OFF-细胞”，它们分别促进和抑制伤害感受传递。然而，感官输入 RVM直到现在才受到极大的关注。背角经臂旁间接传入 复合体向RVM传递伤害性信息，并参与RVM神经元的敏化， 持续性炎性疼痛。然而，解剖学研究也有证据表明， 背角到RVM。该建议的假设是，RVM接收间接和直接功能 三叉神经背角的输入有助于疼痛调制，并且直接输入在 持续性疼痛状态。这个项目将集中在三叉神经系统，它介导的感觉输入从 面部和头部，与慢性疼痛，包括偏头痛， 颞下颌关节紊乱和三叉神经痛。我将在RVM中使用单细胞记录的组合 结合直接（三叉神经到RVM）和间接（三叉神经中继通过RVM）的光遗传学操作， 臂旁复合体）投影，以测试每个连接到RVM的作用，并确定是否以及如何 直接通路的功能在持续性疼痛中改变。总的来说，这些研究将提高我们的 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。通过识别脑干前伤害性输出的驱动因素， 我们可以获得新的见解，疼痛调节系统是如何招募和调制急性和慢性， 疼痛，为我们提供了新的治疗目标。该项目将补充一个全面和 这是我和我的导师玛丽·海因里希博士合作制定的结构化培训计划。此外 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， 实验设计和定量分析。我也将获得更深入的理解疼痛， 疼痛研究，部分是通过暴露于慢性疼痛管理的临床挑战。最后，我希望 参与有助于提高科学交流技能的活动。总体而言，拟议的 培训将使我成为一名成功的独立研究人员和学术疼痛研究的领导者。