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

项目摘要/摘要 腹外侧导水管周围灰质(VlPAG)在下行痛觉调制中起重要作用。这个 GABA去抑制假说认为，强直性GABA能神经传递在vlPAG水平 抑制输出兴奋性投射，调节下行止痛机制。解除抑制 投射到延髓头端腹内侧(RVM)的vlPAG兴奋性神经元被认为允许 将投射到脊髓背角并抑制伤害性信息的RVM细胞的激活 加工，产生止痛作用。改变的vlPAG神经传递，以低谷氨酸能为特征 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。为了了解vlPAG的这一回路、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的特异性， 负责下行镇痛的神经元的身份和确切作用尚不清楚。技术 例如化学遗传学和光遗传学，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，并最终询问它们在伤害性信息处理中的作用。 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 在天真的条件下巡回。我们的发现支持局部强直性GABA能控制 VlPAG神经元。我们假设vlPAG GABA能音调降低或刺激输出 投射到右室的谷氨酸能神经元将导致热和机械衰减。 在持续性炎症性疼痛模型下，除了减轻自发性疼痛外，还有痛觉过敏。 初步结果表明，局部GABA能(Vgat)或光发生的化学发生抑制 刺激血管紧张素Ⅱ受体投射的vlPAG神经元可减弱炎症诱导的热反应 和机械性痛觉过敏。简而言之，拟议的研究旨在描述PAG下降的特征 在解剖学和分子水平上的电路，并将确定vlPAG，GABA和谷氨酸的作用 持续性炎症性疼痛的神经传递和vlPAG-RVM投射。对…的准确理解 VlPAG-RVM通路、神经元亚群和vlPAG的调节机制 持续性炎性疼痛可能会指导未来专注于新的慢性炎症性疼痛靶向治疗的研究 炎症性疼痛。

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.