Coupling activation of primary sensory neurons as a novel plasticity mechanism for chronic pain

初级感觉神经元的耦合激活作为慢性疼痛的新型可塑性机制

• 批准号: 9219773
• 负责人: Yu Shin Kim
• 金额: $ 36.81万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9219773
• 关键词: Acute Pain; Adult; Adverse effects; Affect; Afferent Neurons; Amyloid beta-Protein; Analgesics; Animal Genetics; Animals; Area; Attenuated; Behavioral; Brain; Caliber; Cell Communication; Cells; Chemicals; Connexins; Coupling; Data; Development; Economic Burden; Electrophysiology (science); Employee Strikes; Event; Fiber; Gap Junctions; Genetic; Hyperalgesia; Hypersensitivity; Image; Imagery; Imaging Techniques; Individual; Inflammation; Injury; Label; Link; Mechanical Stimulation; Mechanics; Mechanoreceptors; Mediating; Mediator of activation protein; Medical; Methodology; Methods; Microscopy; Modality; Modeling; Molecular; Molecular Genetics; Monitor; Mus; Neuroglia; Neuronal Plasticity; Neurons; Nociceptors; Non-Steroidal Anti-Inflammatory Agents; Opiates; Pain; Pathologic; Patients; Pharmacology; Physiological; Population; Public Health; Quality of life; Resolution; Role; Sensory; Signaling Molecule; Skin; Spinal Cord; Spinal Ganglia; Stimulus; Techniques; Testing; Therapeutic; Transgenic Mice; Up-Regulation; base; chronic pain; ganglion cell; genetic approach; imaging genetics; improved; in vivo; in vivo imaging; multiphoton imaging; nerve injury; novel; novel strategies; pain inhibition; painful neuropathy; patch clamp; response; sensor; temporal measurement; tool

Chronic pain is affecting over 100 millions of U.S. adults with its debilitating medical problems, inadequate treatment, and severe economic burdens (over $600 billion). This is due to limited efficacy or intolerable side effects of available analgesic options. In order to better serve chronic pain patients, it is better to have clearer understanding of how chronic pain is generated. We don’t know exactly how innocuous stimuli (i.e. normal input to Aβ-fiber activation) become painful, leading to chronic pain after injury. And it remains unclear how the encoding of mechanosensory information to brain area is conveyed after it is sensitized at the level of primary sensory neuron and spinal cord. Although the mechanisms of hyperexcitability of individual DRG neurons have been extensively studied, how DRG neurons function at a populational level as an ensemble under physiological and pathological conditions is unclear due to the lack of suitable tools and techniques. Here, we developed an imaging technique that allowed us to simultaneously monitor the activation of >1,600 neurons/DRG in response to mechanical stimulation applied to the skin in live mice. And we now acquired and obtained mouse genetic tools that allow visualization of all four major Low Threshold Mechanoreceptor (LTMR) subtypes; Aβ, SA-LTMRs, Aβ, RA-LTMRs, Aδ-LTMRs, and C-LTMRs. Specific labeling of distinct sensory neuron subtypes provide an unprecedented opportunity to determine whether the activity of each subtype is altered during chronic pain after nerve injury. Using this powerful techniques and tools, we discovered a striking neuronal coupling phenomenon as a novel pain mechanism that adjacent neurons activate together following inflammation or nerve injury, although this rarely happens in naïve animals. This is the first demonstration that coupling phenomenon of primary sensory neurons after nerve injury contributes to new mechanisms underlying chronic pain conditions. This coupling activation occurs among various sizes of neurons including small-diameter nociceptors and large-diameter low-threshold mechanoreceptors. Combining the imaging technique with pharmacological and genetic approaches, we found that the coupling is, in part, mediated by an injury-induced upregulation of gap junction in satellite glial cells surrounding DRG neurons. Blocking gap junctions significantly attenuated neuronal coupling in the DRG and also reduced mechanical hyperalgesia. Therefore, neuronal coupling represents a new form of neuronal plasticity in the DRG and by “hijacking” neighboring neurons through gap junction it contributes to pain hypersensitivity. Our studies suggest a new strategy to alleviate neuropathic pain by inhibiting gap junction connection between DRG neurons.

慢性疼痛正在影响超过1亿的美国成年人，其使人衰弱的医疗问题， 治疗和严重的经济负担（超过6000亿美元）。这是由于疗效有限或不能耐受的副作用 现有镇痛剂的效果。为了更好地服务于慢性疼痛患者，最好有更清晰的 了解慢性疼痛是如何产生的。我们不知道无害刺激（即正常刺激） Aβ-纤维激活的输入）变得疼痛，导致损伤后的慢性疼痛。目前尚不清楚， 机械感觉信息的编码是在初级水平上被敏化后传递到脑区的 感觉神经元和脊髓。尽管单个DRG神经元的过度兴奋机制有 已经被广泛研究，DRG神经元如何在群体水平上作为一个整体发挥作用， 由于缺乏适当的工具和技术，生理和病理条件尚不清楚。这里我们 开发了一种成像技术，使我们能够同时监测> 1，600的激活 在活体小鼠中，神经元/DRG响应于施加到皮肤的机械刺激。我们现在获得了 获得了小鼠遗传工具，允许可视化所有四个主要的低阈值机械感受器（LTMR） 亚型; Aβ、SA-LTMR、Aβ、RA-LTMR、Aδ-LTMR和C-LTMR。不同感觉器官的特异性标记 神经元亚型提供了一个前所未有的机会，以确定是否每个亚型的活动， 在神经损伤后的慢性疼痛中改变。利用这些强大的技术和工具，我们发现了一个 神经元耦合现象是一种新的疼痛机制，相邻神经元共同激活 炎症或神经损伤后，虽然这很少发生在幼稚动物。这是第一 证明神经损伤后初级感觉神经元的耦合现象有助于新的 慢性疼痛的潜在机制。这种耦合激活发生在各种尺寸的 神经元包括小直径的伤害感受器和大直径的低阈值机械感受器。结合 成像技术与药理学和遗传学的方法，我们发现，耦合是，部分， 通过损伤诱导的DRG神经元周围卫星神经胶质细胞间隙连接上调介导。 阻断缝隙连接显著减弱了DRG中的神经元偶联， 痛觉过敏因此，神经元耦合代表了DRG中神经元可塑性的新形式， 它通过缝隙连接“劫持”邻近的神经元，导致疼痛超敏反应。我们的研究表明 通过抑制DRG神经元之间的缝隙连接来减轻神经病理性疼痛的新策略。