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.

项目摘要/摘要 腹外侧周围灰色（VLPAG）在降低疼痛调节中起重要作用。这 GABA抑制假设提案提案，即在VLPAG水平上进行补品GABA能神经传递 用于抑制输出兴奋的预测，调节降级机制。抑制 VLPAG兴奋性神经元将投射到延髓腹膜髓质（RVM）被认为允许随后的序列 RVM细胞的激活将投射到脊髓背角并抑制伤害性信息 处理，导致镇痛。 VLPAG神经传播的改变，其特征是低谷氨酸能 并增强了GABA能神经传递，被认为有助于发展和维护 慢性疼痛。为了了解该电路，药理学和VLPAG的电刺激 部分描述了其在降低疼痛调节中的作用，但由于缺乏细胞类型的特异性， 负责降低镇痛的神经元的身份和确切的作用尚不清楚。技术 例如化学和光生遗传学，结合遗传小鼠模型，使我们能够选择性地 操纵VLPAG神经元种群，并最终询问这些神经元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一点在双向调节感觉阈值 在幼稚条件下电路。我们的发现支持局部补品GABA能控制的假设 VLPAG神经元。我们假设降低VLPAG GABA能音调或刺激输出 向RVM投射的谷氨酸能神经元将导致热和机械的衰减 在持续的炎症疼痛模型下，除了减轻了赞助疼痛之外，痛风。 初步结果表明，化学发生抑制局部GABA能（VGAT）或光遗传学 刺激VGLUT2 RVM射击VLPAG神经元导致炎症诱导的热衰减 和机械痛觉过敏。简而言之，拟议的研究旨在表征下降的PAG 在解剖和分子水平上的电路，将确定VLPAG GABA和谷氨酸的作用 神经传递和VLPAG-RVM在持续的炎症性疼痛中项目。对 VLPAG-RVM电路，神经元亚群和VLPAG可以调节的机制 持续性炎症性疼痛可能会指导未来的研究，重点是针对慢性的新型靶向疗法 炎症性疼痛。