Migraine Pathophysiology:Thalamus and Extended Allodynia

描述（由申请人提供）：偏头痛是一种单侧悸动性头痛，通常与限制性异常性痛（影响所指疼痛区域）以及延伸性异常性痛（影响头部和身体的其他部位）相关。我们的电生理研究表明，致敏的脑膜伤害感受器可以介导悸动，髓背角致敏的三叉神经血管性神经元可以介导面部偏头痛一侧的头性异常痛，但在其他地方没有。本基金提案的目的是通过研究处理硬脑膜、头侧和头外皮肤感觉信息的丘脑痛觉神经元的神经元可塑性，对偏头痛期间延长的异常性疼痛的病理生理学获得新的见解。将测试三个可行的假设。假设1将测试腹侧后内侧（VPM）丘脑神经元是否可以在其致敏后介导异常性疼痛从面部一侧扩散到另一侧。假设2将测试丘脑后丘神经元在敏化后是否能介导异常性疼痛从面部一侧向四肢和躯干的扩散。假设3将测试硬脑膜敏感的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，我们将绘制接受野图，记录正在进行的活动，并确定在硬脑膜局部应用“炎症汤”之前和之后VPM和PO神经元的生理反应特性-我们成功地使用这种刺激诱导外周（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）动物模型中持久致敏。在Specific Aims 3a和b中，我们将绘制硬脑膜敏感的VPM和PO神经元的皮质投影，以进一步了解它们在偏头痛的定位、偏侧、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髓质背角的神经元致敏的后果后，这项拨款提案是我们寻求更好地理解偏头痛病理生理学的自然“下一步”。通过研究偏头痛的延展性异常性疼痛——我们以患者的科学严密性为特征的一种临床症状——这项拨款提案打开了一扇独特的窗口，让我们了解致敏丘脑神经元活动和激活的生物学意义。

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.