Migraine Pathophysiology:Thalamus and Extended Allodynia

描述（由申请人提供）：偏头痛是一种单侧搏动性头痛，通常与限制性异常性疼痛（影响牵涉性疼痛区域）以及扩展性异常性疼痛（影响头部和身体的其他部位）相关。我们的电生理学研究表明，致敏的脑膜伤害感受器可以介导搏动，而延髓背角中的致敏的三叉神经血管神经元可以介导偏头痛侧面部的头部异常性疼痛，但在其他部位则没有。这项资助计划的目的是通过研究丘脑伤害性神经元的可塑性来获得对偏头痛过程中延长的异常性疼痛的病理生理学的新见解，丘脑伤害性神经元处理来自硬脑膜和头部及头外皮肤的感觉信息。将检验三个工作假设。假设1将测试是否腹后内侧（VPM）丘脑神经元可以介导的传播异常性疼痛从一侧的脸到另一侧后，他们的敏化。假设2将测试后（PO）丘脑神经元是否可以介导从一侧的脸到四肢和躯干的过敏性疼痛的蔓延后，他们的敏化。假设3将测试硬膜敏感的VPM和PO神经元是否投射到第一体感（SI）皮层和/或颗粒岛（GI）皮层。在具体目标1a-c和2a-c中，我们将绘制感受野，记录正在进行的活动，并确定VPM和PO神经元的生理反应特性之前和之后的局部应用'炎症汤'的硬脑膜-一种刺激，我们成功地用来诱导持久的敏化周围（三叉神经节）和中央（背角）硬脑膜敏感神经元在我们的颅内疼痛（如偏头痛）的动物模型。在具体目标3a、B中，我们将绘制硬脑膜敏感性VPM和PO神经元的皮质投射，以更深入地了解它们在偏头痛的定位、偏侧性、强度和情感方面可能发挥的不同作用。在我们的颅内疼痛动物模型中研究了三叉神经节和延髓背角神经元敏化的后果后，这项拨款提案是我们寻求更好地了解偏头痛病理生理学的自然“下一步”。通过研究偏头痛的扩展异常性疼痛-我们在患者中以科学严谨性为特征的临床症状-这项拨款提案为敏感丘脑神经元的活动和激活的生物学意义打开了一扇独特的窗户。

DESCRIPTION (provided by applicant): Migraine is a unilateral throbbing headache commonly associated with restricted allodynia (affecting the referred pain area) as well as extended allodynia (affecting other parts of the head and body). Our electrophysiological studies have shown that sensitized meningeal nociceptors can mediate the throbbing and that sensitized trigeminovascular neurons in the medullary dorsal horn can mediate cephalic allodynia on the migraine side of the face, but'not elsewhere. The objectives of this grant proposal are to gain novel insights into the pathophysiology of extended allodynia during migraine by studying neuronal plasticity of nociceptive thalamic neurons that process sensory information from the dura and from cephalic and extracephalic skin. Three working hypotheses will be tested. Hypothesis 1 will test whether ventral posteromedial (VPM) thalamic neurons can mediated the spread of allodynia from one side of the face to the other upon their sensitization. Hypothesis 2 will test whether posterior (PO) thalamic neurons can mediated the spread of allodynia from one side of the face to the limbs and trunk upon their sensitization. Hypothesis 3 will test whether dura-sensitive VPM and PO neurons project to the first somatosensory (SI) cortex and/or the granular insular (GI) cortex. In Specific Aims 1a-c and 2a-c we will map receptive fields, record ongoing activity and determine physiological response properties of VPM and PO neurons before and after local application of 'inflammatory soup' to the dura - a stimulus we used successfully to induce lasting sensitization in peripheral (trigeminal ganglion) and central (dorsal horn) dura-sensitive neurons in our animal model of intracranial pain (such as migraine). In Specific Aims 3a, b we will map cortical projections of dura-sensitive VPM and PO neurons in effort to gain more insight into the different role they may play in localization, laterality, intensity, and affective aspects of migraine headache. After studying the consequences of neuronal sensitization in the trigeminal ganglion and medullary dorsal horn in our animal model of intracranial pain, this grant proposal is a natural 'next step' in our quest to understand better the pathophysiology of migraine. By studying the extended allodynia of migraine - a clinical symptom we characterized with a scientific rigor in patients - this grant proposal opens a unique window into the biological meaning of activity and activation of sensitized thalamic neurons.