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

描述（由申请人提供）：髓背角中的伤害性神经元接收来自硬脑膜和面部感受野的会聚输入，涉及介导某些类型的头痛，包括偏头痛。这些神经元可以被诱导进入一种长时间的敏化状态，或者在硬脑膜最初的有害感觉输入后异常地提高反应性。背角痛觉神经元的中枢致敏现象被认为有助于临床疼痛状况，并且现在已被认为是偏头痛疼痛和异常性疼痛的关键因素。因此，中枢致敏及其引起的异常性疼痛的研究已成为当前头痛研究的主要焦点。然而，我们对中枢致敏的电生理机制的理解在很大程度上来自体外切片研究，其局限性在于不可能表征对自然形式的外周刺激或刺激特定类型的外周组织的反应。因此，在试图将体外研究获得的信息与体内观察到的中枢致敏现象联系起来时，必须弥合差距。在体内膜片钳记录的新技术有可能帮助弥合这一差距，并因此对我们对中枢伤害性加工的理解产生重大影响。与细胞外记录相比，该技术的优点之一是能够直接检测抑制性和阈下兴奋性突触输入，并且能够单独测量抑制性和兴奋性突触输入。我们首次提出在脑干三叉神经系统中建立这种技术，并利用它来检测从颅内硬脑膜接收输入的伤害性髓背角神经元的感受野特性和敏化。我们提出，这些神经元的反应性代表了抑制性和兴奋性输入强度之间的平衡，这种平衡在中枢敏化过程中被改变。我们还提出阈下到阈上输入的转换代表了敏感化的重要潜在机制。我们假设这些神经元的调节机制不同于那些只从表面部位（如角膜）接收输入的神经元，这些差异将对理解头痛的独特性质和偏头痛的发病机制很重要。该项目将为疼痛传递神经元中枢致敏现象背后的细胞机制提供新的见解，这一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。这些信息将有助于更好地了解偏头痛，并将对制定新的药物治疗策略具有重要意义。

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.