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.

项目总结/摘要 腹外侧导水管周围灰质（vlPAG）在下行性痛觉调制中起重要作用。的 GABA去抑制假说提出，在vlPAG水平的紧张性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。的抑制解除 投射到延髓头端腹内侧（RVM）的vlPAG兴奋性神经元被认为允许随后的 激活RVM细胞，其将投射到脊髓背角并抑制伤害性信息 加工，导致镇痛。改变的vlPAG神经传递，特征在于低血压性 和增强的GABA能神经传递，被认为有助于发展和维持 慢性疼痛为了理解这个回路，我们尝试了vlPAG的药理学和电刺激， 已经部分描述了它在下行疼痛调节中的作用，但由于缺乏细胞类型特异性， 负责下行镇痛的神经元的身份和确定的作用仍然不清楚。技术 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神经元群体，并最终询问这些在伤害性处理中的作用。 初步数据表明，我们可以双向调节感觉阈值，通过操纵这个 在天真的条件下。我们的研究结果支持局部紧张性GABA能控制 vlPAG神经元。我们假设vlPAG GABA能紧张度的降低或输出的刺激 投射到RVM的突触能神经元将导致热和机械传导的衰减。 在持续性炎性疼痛模型下，除了减弱自发性疼痛之外，还可以抑制痛觉过敏。 初步结果表明，局部GABA能（Vgat）或光遗传学的化学遗传学抑制 刺激VIP 2 RVM投射的vlPAG神经元导致炎症诱导的热传导减弱， 和机械性痛觉过敏简而言之，拟议的研究旨在表征下行PAG 电路在解剖和分子水平，并将确定的作用vlPAG GABA和谷氨酸 神经传递和vIPAG-RVM投射。准确了解 vIPAG-RVM回路、神经元亚群和vIPAG可调节VIPAG的机制 持续性炎症性疼痛可能会指导未来的研究，重点是慢性炎症性疼痛的新型靶向治疗。 炎性疼痛。