In Vivo Patch Clamp Studies of Dorsal Horn Neurons in Relation to Headache

背角神经元与头痛相关的体内膜片钳研究

• 批准号: 7751919
• 负责人: Andrew Mark Strassman
• 金额: $ 18.41万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751919
• 关键词: Brain Stem; Classification; Clinical; Cornea; Cutaneous; Data; Development; Dura Mater; Equilibrium; Event; Face; Frequencies; Headache; In Vitro; Inflammation Mediators; Injection of therapeutic agent; Investigation; Label; Lead; Location; Maps; Measurement; Measures; Mechanics; Mediating; Mediation; Migraine; Morphology; Mus; Neurons; Nociception; Pain; Pathogenesis; Pattern; Peripheral; Pharmaceutical Preparations; Posterior Horn Cells; Process; Property; Research; Sensory; Site; Slice; Staining method; Stains; Stimulus; Synapses; Techniques; Testing; Time; Tissues; Trigeminal System; Urethane; allodynia; base; central sensitization; dorsal horn; extracellular; in vivo; insight; novel; patch clamp; public health relevance; receptive field; research study; response; transmission process; voltage; voltage clamp

DESCRIPTION (provided by applicant): Nociceptive neurons in the medullary dorsal horn that receive convergent input from dural and facial receptive fields have been implicated in mediating the pain of some types of headache, including migraine. These neurons can be induced into a prolonged state of sensitization, or abnormally heightened responsiveness, following an initial noxious sensory input from the dura. The phenomenon of central sensitization of dorsal horn nociceptive neurons is thought to contribute to clinical pain conditions, and has now been implicated as a critical factor in the pain and allodynia of migraine. Consequently, the study of central sensitization and the resulting allodynia has become a major focus of current headache research. However, our understanding of the electrophysiological mechanisms of central sensitization is derived in large part from in vitro slice studies, which have the limitation that it is not possible to characterize responses to natural forms of peripheral stimulation, or stimulate specific types of peripheral tissues. As a result, there is a gap that must be bridged in trying to relate the information obtained from in vitro studies to the phenomenon of central sensitization as observed in vivo. The novel technique of in vivo patch clamp recording has the potential to help bridge this gap, and in so doing have a major impact on our understanding of central nociceptive processing. Among the advantages of this technique over extracellular recording are the ability to directly detect inhibitory and subthreshold excitatory synaptic inputs, and the ability to separately measure inhibitory and excitatory inputs in isolation. We propose to establish this technique for the first time in the brainstem trigeminal system, and use it to examine receptive field properties and sensitization of nociceptive medullary dorsal horn neurons that receive input from the intracranial dura. We propose that the responsiveness of these neurons represents a balance between the strength of inhibitory and excitatory inputs, and that this balance is altered during central sensitization. We also propose that conversion of subthreshold to suprathreshold inputs represents an important underlying mechanism of sensitization. We hypothesize that the modulatory mechanisms that operate in these neurons differ from those in neurons that receive input only from a superficial site such as cornea, and these differences will be important for understanding the distinctive qualities of headache pain and the pathogenesis of migraine. PUBLIC HEALTH RELEVANCE This project will give new insight into the cellular mechanisms underlying the phenomenon of central sensitization of pain-transmitting neurons, which is now thought to be an important component of migraine as well as many other pain conditions. This information will lead to better understanding of migraine headache, and will be important for devising strategies for development of new drug treatments.

描述（由申请人提供）：髓质角中的伤害感受神经元，这些神经元接收来自硬脑膜和面部接受场的收敛输入，这与介导某些类型的头痛的疼痛（包括偏头痛）有关。这些神经元可以在最初的硬脑膜输入后，将这些神经元转变为长时间的敏化状态，也可以异常提高反应性。背角伤害神经元的中央敏化现象被认为有助于临床疼痛状况，现在已被视为偏头痛疼痛和异常性的关键因素。因此，对中央敏感性和由此产生的异常性疾病的研究已成为当前头痛研究的主要重点。但是，我们对中央敏化的电生理机制的理解在很大程度上是由于体外切片研究而得出的，这些研究的局限性是无法表征对周围刺激的自然形式的反应，或刺激特定类型的外周组织。结果，在试图将体外研究获得的信息与体内观察到的中央敏化现象相关联时，必须弥合一个差距。体内斑块夹记录的新技术具有帮助弥合这一差距的潜力，因此，对我们对中央伤害性处理的理解产生了重大影响。在该技术比细胞外记录的优点中，有能力直接检测抑制性和阈值兴奋性突触输入，以及分别测量抑制性和兴奋性输入的能力。我们建议在脑干三叉神经系统中首次建立该技术，并使用它来检查接受田间特性和对接收颅内硬脑膜输入的伤害性髓质角神经元的敏感性。我们建议这些神经元的响应能力代表了抑制性和兴奋性输入的强度之间的平衡，并且在中央敏化期间这种平衡发生了变化。我们还建议将子阈值转换为跨质量投入代表着一种重要的敏化机制。我们假设在这些神经元中起作用的调节机制与仅从浅层部位（例如角膜）输入的神经元中的调节机制不同，这些差异对于理解头痛疼痛的独特品质和偏头痛的发病机理至关重要。公共卫生相关性该项目将对疼痛传播神经元的中心敏化现象的基础的细胞机制提供新的见解，该现象现在被认为是偏头痛以及许多其他疼痛状况的重要组成部分。这些信息将使人们更好地了解偏头痛的头痛，对于制定新药物治疗的策略至关重要。