GENETIC DISSECTION OF BRAINSTEM CIRCUITS AND THEIR ROLE IN PERSISTENT INFLAMMATORY PAIN

脑干回路的基因解剖及其在持续性炎症性疼痛中的作用

• 批准号: 9470677
• 负责人: Jose G Grajales Reyes
• 金额: $ 3万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9470677
• 关键词: Absence of pain sensation; Accounting; Adult; Adverse effects; Analgesics; Anatomy; Animal Behavior; Attenuated; Brain; Brain Stem; Cells; Chemosensitization; Chronic inflammatory pain; Data; Development; Disinhibition; Dissection; Electric Stimulation; Excision; Exhibits; Expenditure; Fellowship; Fiber; Genetic; Glutamates; Goals; Hyperalgesia; Hypersensitivity; Inflammation; Injection of therapeutic agent; Left; Maintenance; Mechanics; Mediating; Modality; Modeling; Molecular; Neuronal Plasticity; Neurons; Nociception; Output; Pain; Pain management; Pathway interactions; Patient Care; Pharmacological Treatment; Pharmacology; Play; Population; Process; Property; Regulation; Research; Role; Sensory; Sensory Thresholds; Signal Transduction; Specificity; Spinal; Spinal cord posterior horn; Stimulus; Synaptic Transmission; System; Techniques; Testing; Thermal Hyperalgesias; Training; United States; attenuation; cell type; chronic pain; designer receptors exclusively activated by designer drugs; excitatory neuron; experience; gamma-Aminobutyric Acid; in vivo; inflammatory pain; information processing; inhibitory neuron; insight; intersectionality; midbrain central gray substance; mouse model; multidisciplinary; neural circuit; neurotransmission; new therapeutic target; novel; novel therapeutics; optogenetics; relating to nervous system; spontaneous pain; transmission process

PROJECT SUMMARY/ABSTRACT The ventrolateral periaqueductal gray (vlPAG) plays an important role in descending pain modulation. The GABA disinhibition hypothesis proposes that tonic GABAergic neurotransmission at the level of the vlPAG serves to inhibit output excitatory projections, regulating descending analgesic mechanisms. Disinhibition of vlPAG excitatory neurons that project to the rostral ventromedial medulla (RVM) is thought to allow subsequent activation of RVM cells that will project to the dorsal horn of the spinal cord and inhibit nociceptive information processing, resulting in analgesia. Altered vlPAG neural transmission, characterized by a hypoglutamatergic and enhanced GABAergic neurotransmission, is thought to contribute to the development and maintenance of chronic pain. In an attempt to understand this circuit, pharmacology and electrical stimulation of the vlPAG have partially described its role in descending pain modulation, but due to the lack of cell-type specificity, the identity and definitive role of the neurons responsible for descending analgesia remains unclear. Techniques such as chemo- and opto-genetics, in combination with genetic mouse models, allow us to selectively manipulate vlPAG neuronal populations and finally interrogate the role of these in nociceptive processing. Preliminary data demonstrates that we can bidirectionally modulate sensory thresholds via manipulation of this circuit under naïve conditions. Our findings support the hypothesis of a local tonic GABAergic control over vlPAG neurons. We hypothesize that reduction of the vlPAG GABAergic tone or stimulation of output glutamatergic neurons that project to the RVM will result in attenuation of thermal and mechanical hyperalgesia, in addition to attenuating spontaneous pain, under a persistent inflammatory pain model. Preliminary results demonstrate that chemogenetic inhibition of local GABAergic (Vgat) or optogenetic stimulation of Vglut2 RVM-projecting vlPAG neurons results in attenuation of inflammation-induced thermal and mechanical hyperalgesia. In brief, the proposed research aims to characterize the descending PAG circuitry at both an anatomical and molecular level and will identify the role of vlPAG GABA and glutamate neurotransmission and vlPAG-RVM projections in persistent inflammatory pain. A precise understanding of vlPAG-RVM circuitry, neuronal subpopulations and the mechanism by which the vlPAG can modulate persistent inflammatory pain may direct future research focused on novel targeted therapies for chronic inflammatory pain.

项目概要/摘要 导水管周围灰质腹外侧区（vlPAG）在下行疼痛调节中发挥着重要作用。 GABA 去抑制假说提出，vlPAG 水平的强直 GABA 能神经传递 用于抑制输出兴奋性投射，调节下行镇痛机制。 vlPAG 兴奋性神经元投射到延髓头侧腹内侧 (RVM)，被认为允许随后的 激活 RVM 细胞，投射到脊髓背角并抑制伤害性信息 处理，导致镇痛作用改变，其特征是谷氨酸能低下。 和增强的 GABA 能神经传递，被认为有助于发育和维持 试图了解 vlPAG 的这一回路、药理学和电刺激。 部分描述了其在下行疼痛调节中的作用，但由于缺乏细胞类型特异性， 负责下行镇痛技术的神经元的身份和明确作用仍不清楚。 例如化学和光遗传学，与遗传小鼠模型相结合，使我们能够选择性地 操纵 vlPAG 神经群体并最终询问它们在伤害性处理中的作用。 初步数据表明，我们可以通过操纵这个来双向调节感觉阈值 我们的研究结果支持局部强直 GABA 能控制的假设。 我们追踪 vlPAG GABA 能神经元的减少或输出的刺激。 投射到 RVM 的谷氨酸能神经元将导致热力和机械力的衰减 在持续性炎性疼痛模型下，除了减轻自发性疼痛外，还存在痛觉过敏。 初步结果表明，局部 GABA 能 (Vgat) 的化学遗传学抑制或光遗传学抑制 刺激 Vglut2 RVM 投射的 vlPAG 神经元会导致炎症诱导的热减弱 简而言之，本研究旨在描述下降 PAG 的特征。 在解剖学和分子水平上分析电路，并将确定 vlPAG GABA 和谷氨酸的作用 对持续性炎症疼痛的神经传递和 vlPAG-RVM 预测的精确理解。 vlPAG-RVM 电路、神经亚群以及 vlPAG 调节机制 持续性炎症疼痛可能会指导未来的研究重点关注慢性炎症的新型靶向疗法 炎症性疼痛。