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: 9393998
• 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/9393998
• 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); 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; Opioid; 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; chronic pain patient; chronic painful condition; ganglion cell; genetic approach; imaging genetics; improved; in vivo; in vivo imaging; multiphoton imaging; nerve injury; novel; novel strategies; pain inhibition; pain model; pain sensitivity; 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1亿美国成年人，其令人衰弱的医疗问题，不充分 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无法忍受的副作用。 可供选择的止痛药的效果。为了更好地服务于慢性疼痛患者，最好有更明确的 了解慢性疼痛是如何产生的。我们不知道无害的刺激(即正常的 Aβ纤维的输入)变得疼痛，导致受伤后的慢性疼痛。目前还不清楚 机械感觉信息在初级水平被敏化后，被传递到大脑区域 感觉神经元和脊髓。尽管单个DRG神经元的超兴奋性机制 已被广泛研究，背根神经节神经元如何在种群水平上作为一个整体在 由于缺乏合适的工具和技术，生理和病理条件尚不清楚。在这里，我们 开发了一种成像技术，使我们能够同时监测&gt；1,600的激活 对活体小鼠皮肤施加机械刺激的神经元/背根神经节。我们现在获得了 获得了可以可视化所有四种主要的低阈值机械感受器(LTMR)的小鼠遗传工具 亚型：Aβ、SA-LTMRs、Aβ、RA-LTMRs、Aδ-LTMRs和C-LTMRs。不同感官的特殊标记 神经元亚型提供了一个前所未有的机会来确定每种亚型的活动是否 在神经损伤后的慢性疼痛期间发生改变。使用这种强大的技术和工具，我们发现了一个 突显的神经元耦合现象--相邻神经元共同激活的一种新的疼痛机制 在炎症或神经损伤之后，尽管这种情况很少发生在幼稚的动物身上。这是第一次 神经损伤后初级感觉神经元的偶联现象有助于新的 慢性疼痛的潜在机制。这种耦合激活发生在不同大小的 神经元包括小直径伤害性感受器和大直径低阈值机械感受器。组合 结合药理学和遗传学方法的成像技术，我们发现这种耦合在一定程度上 通过损伤诱导背根节神经元周围卫星神经胶质细胞缝隙连接的上调。 阻断缝隙连接显著减弱背根神经节中神经元的耦合，也降低了机械性 痛觉过敏。因此，神经元耦合代表了背根神经节中神经元可塑性的一种新形式。 通过缝隙连接“劫持”邻近神经元，导致痛觉过敏。我们的研究表明 通过抑制背根节神经元之间的缝隙连接来缓解神经病理性疼痛的新策略。