Migraine Pathophysiology:Thalamus and Extended Allodynia

描述(申请人提供)：偏头痛是一种单侧跳动性头痛，通常伴有局限性异位痛(影响牵涉的疼痛区域)和广泛性异位痛(影响头部和身体的其他部位)。我们的电生理学研究表明，致敏的脑膜伤害性感受器可以介导搏动，延髓背角的致敏的三叉神经血管神经元可以介导偏头痛一侧的头痛症，但不能在其他地方。这项拨款提案的目的是通过研究处理来自硬脑膜以及头和头外皮肤的感觉信息的丘脑伤害性神经元的神经元可塑性，获得对偏头痛期间延长的超常痛觉的病理生理学的新见解。三个有效的假设将会被检验。假设1将测试丘脑腹后内侧(VPM)神经元是否可以在敏化后介导痛觉异常从面部一侧扩散到另一侧。假设2将测试丘脑后部(PO)神经元是否能在敏化后介导痛觉异常从面部一侧扩散到四肢和躯干。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躯体感觉(SI)皮质和/或颗粒岛叶(GI)皮质。在特定的目标1a-c和2a-c中，我们将绘制VPM和PO神经元的感受野图，记录正在进行的活动，并确定在我们的颅内疼痛(如偏头痛)动物模型中，VPM和PO神经元在对硬脑膜局部应用“炎性汤”之前和之后的生理反应特性-我们成功地用来在外周(三叉神经节)和中央(背角)硬脑膜敏感神经元诱导持久敏化。在具体的目标3a，b中，我们将绘制对硬脑膜敏感的VPM和PO神经元的皮质投射图，以努力更深入地了解它们在偏头痛的定位、偏侧性、强度和情感方面所起的不同作用。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的下一步。通过研究偏头痛的延迟性异位痛症--我们以患者的科学严谨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，揭示致敏丘脑神经元的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.