Direct and Indirect Nociceptive Inputs to Brainstem Pain-Modulating Neurons

项目总结 大脑通过从脑干到脊髓的下行投射来调节伤害性信息的处理。 和三叉神经背角。这是通过内源性疼痛调制电路实现的，该电路可以 放大或抑制疼痛相关信号，并正常保持促进和抑制疼痛信号之间的平衡 疼痛。在慢性疼痛条件下，系统调节失调，导致疼痛状态变得容易。输出 在这一痛觉调节系统中，通过延髓吻侧腹内侧部(RVM)的作用已被广泛研究。 来自该区域的双向疼痛控制是由两个生理上定义的细胞类别“on-cell”介导的。 和“离细胞”，分别促进和抑制伤害性信息的传递。然而，感官输入到 RVM现在才受到极大的关注。从背角通过臂旁神经的间接输入 Complex向RVM传递伤害性信息，参与RVM神经元的敏化。 持续性炎症性疼痛。然而，也有来自解剖学研究的证据表明， 后角通向右室。这一建议的假设是，RVM既接受间接功能又接受直接功能 来自三叉神经背角的有助于痛觉调制的输入，而直接输入在 持续的疼痛状态。这个项目将集中在三叉神经系统上，该系统调节来自 面部和头部，与慢性疼痛的沉重负担相关的区域，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 结合光遗传操作的直接(三叉神经到右室)和间接(三叉神经通过 臂旁复合体)投射，以测试每个连接对RVM的作用，并确定是否以及如何 在持续性疼痛中，直接通路的功能发生变化。总的来说，这些研究将加强我们的 了解三叉神经感觉输入对内在痛觉调制回路的作用并确定 伤害性输入如何获得对RVM的访问。通过识别前伤害性脑干输出的驱动因素， 我们可以获得新的见解，了解疼痛调节系统是如何在急性和慢性疾病中招募和调节的 疼痛，为我们提供了治疗的新靶点。该项目将补充一个全面和 我与我的导师Mary Heinricher博士合作制定的结构化培训计划。此外 为了进修光遗传学和活体电生理学，我将提高我的编程技能， 实验设计，定量分析。我还将获得对痛苦和 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。作为一个整体，拟议的 培训将使我成为一名独立的研究人员和学术疼痛研究的领导者。

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.