Defining the descending pain modulatory circuit

定义下行疼痛调节回路

• 批准号: 10712085
• 负责人: Mary Magdalen Heinricher
• 金额: $ 53.17万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712085
• 关键词: Defining; descending; pain; modulatory; circuit

PROJECT SUMMARY The central nervous system has an intrinsic pain modulatory system that regulates nociceptive processing through descending projections from the brainstem to the spinal cord dorsal horn. The ventrolateral periaqueductal gray (vlPAG) integrates sensory information with input from higher cortical and subcortical areas, and sends projections to the rostral ventromedial medulla (RVM) that are relayed to the dorsal horn of the spinal cord. Both the vlPAG and RVM are heterogenous with respect to participating in multiple behavioral circuits. The proposed studies build on extensive previous work from the Heinricher laboratory that has defined the output from the RVM, showing that bidirectional pain control from this region is mediated by two physiologically defined cell classes, “ON-cells” and “OFF-cells,” that respectively facilitate and inhibit dorsal horn nociceptive transmission under different conditions. The Ingram laboratory has expertise studying opioid actions within the PAG and RVM, as well as adaptations in both areas with persistent inflammation. Proposed viral optogenetic strategies will map and define the vlPAG circuit that regulates RVM ON-cells involved in the facilitation of pain and elucidate underlying cellular mechanisms that shift the balance of RVM output from inhibition of pain to facilitation of pain with persistent inflammation. The combined expertise of the two laboratories will focus on identified PAG-RVM synapses using optogenetic stimulation of RVM terminals originating from the PAG. In vitro brain-slice recordings (Ingram lab) will examine the heterogeneity of PAG output to the RVM and PAG-RVM synapses, as well as cellular mechanisms of synaptic plasticity induced in persistent inflammation. These studies will use a fluorescent label for the μ-opioid receptor to differentiate presumed ON-cells from other classes in the slice to determine whether PAG terminals directly synapse on ON-cells, OFF-cells, or both, as well as what neurotransmitters are released. In vivo single-cell recording studies (Heinricher lab) will determine how inflammation-induced changes in PAG-RVM synapses control excitability of specific populations of RVM neurons and establish the link between these changes and pain behaviors. A better understanding of molecular, cellular, and circuit-level mechanisms that underlie pain is essential if we are to develop better treatments. By carefully mapping the descending projections from PAG to RVM during the development of persistent inflammation, and by tying these to defined RVM outputs and behavior, we can begin to determine the interactions in this complex network, and gain new insights into how pain-modulating systems are recruited and modulated in acute and chronic pain.

项目概要 中枢神经系统具有调节伤害性处理的内在疼痛调节系统 通过从脑干到脊髓背角的下降投射。腹外侧 导水管周围灰质（vlPAG）将感觉信息与来自更高皮质和皮质下的输入整合起来 区域，并将投射发送到延髓头侧腹内侧（RVM），然后再转发到背角 脊髓。 vlPAG 和 RVM 在参与多种行为方面都是异质的 电路。拟议的研究建立在 Heinricher 实验室之前的大量工作的基础上，该实验室定义了 RVM 的输出，表明该区域的双向疼痛控制是由两个介导的 生理学上定义的细胞类别，“ON-细胞”和“OFF-细胞”，分别促进和抑制背侧 不同条件下喇叭伤害性传播。英格拉姆实验室拥有研究阿片类药物的专业知识 PAG 和 RVM 内的活动，以及两个持续炎症区域的适应。建议的 病毒光遗传学策略将绘制和定义调节 RVM ON 细胞的 vlPAG 回路，该回路参与 促进疼痛并阐明改变 RVM 输出平衡的潜在细胞机制 抑制疼痛以促进持续炎症引起的疼痛。两者的专业知识相结合 实验室将重点利用 RVM 末端的光遗传学刺激来识别 PAG-RVM 突触 源自 PAG。体外脑切片记录（英格拉姆实验室）将检查 PAG 的异质性 RVM 和 PAG-RVM 突触的输出，以及诱导的突触可塑性的细胞机制 持续性炎症。这些研究将使用 μ-阿片受体的荧光标记来区分 假定切片中其他类的 ON-cell 以确定 PAG 终端是否直接突触 ON 细胞、OFF 细胞或两者，以及释放的神经递质。体内单细胞记录 研究（Heinricher 实验室）将确定炎症引起的 PAG-RVM 突触变化如何控制 特定 RVM 神经元群的兴奋性，并建立这些变化与疼痛之间的联系 行为。更好地理解疼痛背后的分子、细胞和回路水平机制是 如果我们要开发更好的治疗方法，这一点至关重要。通过仔细映射从 PAG 到 持续性炎症发展过程中的 RVM，并将这些与定义的 RVM 输出和 行为，我们可以开始确定这个复杂网络中的相互作用，并获得关于如何进行的新见解 疼痛调节系统在急性和慢性疼痛中被募集和调节。