Migraine pathophysiology: neural basis of photophobia

描述（由申请人提供）：大约85%的偏头痛患者在黑暗环境中寻求庇护，以减轻环境光引起的头痛加剧。这种避光反应的神经机制仍然是一个谜。目前关于偏头痛的神经基础的观点涉及颅硬脑膜中的三叉神经疼痛纤维和髓背角、丘脑和皮层中的中枢伤害神经元。我们对硬脑膜敏感的丘脑神经元作为脑外异常性疼痛的介质的研究使我们非常偶然地评估了这些神经元是否可能在偏头痛畏光症中发挥作用。在一项临床研究中，我们了解到偏头痛畏光症发生在感知光（完整的黑视素光感受器）的盲人（锥体/杆状变性）中，但不发生在完全失明的偏头痛患者中。我们假设偏头痛通路上的活动可能是通过视神经从视网膜传递到大脑的会聚信号来调节的。在大鼠丘脑中，我们发现了硬脑膜敏感神经元，其持续活动受到光的强烈调节。神经束示迹表明，这些丘脑神经元的细胞体和树突受到许多起源于视网膜的传入事件的影响，它们自己的轴突广泛地分支到初级体感觉皮层。在这里，我们将重点研究脑膜伤害感觉和视网膜光接受通过丘脑皮质神经元作为偏头痛畏光的候选机制的独特整合。研究1将测试硬脑膜/光敏丘脑神经元的活动受到经典光感受器（杆状、锥状）和黑素能光感受器的差异调节的假设，因为它与偏头痛畏光症的定性和定量特征有关。研究2将验证硬脑膜敏感丘脑神经元的光调节是由视神经介导的，而不是由眼睛的三叉神经支配。研究3将验证一种假设，即丘脑中硬脑膜/光敏神经元的细胞体和树突与黑色素能视网膜神经节细胞的轴突相结合，为将视网膜光接受纳入盲性偏头痛伴视锥/杆变性的脑膜伤害感觉通路提供了一种候选神经基质。研究4将验证一种假设，即丘脑中硬脑膜/光敏神经元的细胞体和树突富含含有特定神经调节分子的轴突，作为偏头痛畏光药物截获的潜在靶点。研究5将测试丘脑神经元整合来自硬脑膜和视网膜的感觉信息的假设，并投射到涉及疼痛感知（例如，体感和岛状皮质）或/和光觉（视觉皮质）的皮质区域。我们的工作假设是，非图像形成的视网膜输入汇聚到硬脑膜敏感的丘脑皮质神经元上，可以加剧偏头痛，这代表了偏头痛病理生理学领域的一个新概念。因此，我们提交这个项目作为一个新的应用程序，可能会打开一个独特的窗口，了解数百万头痛患者所描述的不良现象的生物学。

DESCRIPTION (provided by applicant): About 85% of people experiencing a migraine attack seek sanctuary in a dark environment in order to lessen headache intensification brought on by ambient light. The neural mechanism of this photophobic reaction remains a puzzle. Current views on the neural basis of migraine headache implicate trigeminal pain fibers in cranial dura mater, and central nociceptive neurons in the medullary dorsal horn, thalamus, and cortex. Our studies on dura-sensitive thalamic neurons as mediators of extracephalic allodynia led us, quite fortuitously, to evaluate if such neurons may play a role in migraine photophobia. In a clinical study leading up to this grant proposal, we learned that migraine photophobia occurs in blind persons (cone/rod degeneration) that perceive light (intact melanopsin photoreceptors), but not in migraineurs who are totally blind. We postulate that activity along migraine pain pathways may be modulated by converging signals transmitted from the retina to the brain through the optic nerve. In the rat thalamus, we identified dura-sensitive neurons whose ongoing activity was strongly modulated by light. Neural tract-tracing indicated that the cell bodies and dendrites of these thalamic neurons were apposed by many afferents of retinal origin, and that their own axons branched extensively into the primary somatosensory cortex. Here we will focus on this unique integration of meningeal nociception and retinal photoreception by thalamocortical neurons as a candidate mechanism for migraine photophobia. Study 1 will test the hypothesis that activity of dura/light-sensitive thalamic neurons is differentially modulated by classical photoreceptors (rods, cones) and melanopsinergic photoreceptors as it relates to qualitative and quantitative characteristics of migraine photophobia. Study 2 will test the hypothesis that photomodulation of dura-sensitive thalamic neurons is mediated by the optic nerve rather than by trigeminal innervation of the eye. Study 3 will test the hypothesis that cell bodies and dendrites of dura/light-sensitive neurons in the thalamus are apposed by axons of melanopsinergic retinal ganglion cells, providing a candidate neural substrate for incorporating retinal photoreception into a pathway of meningeal nociception in blind migraineurs with cone/rod degeneration. Study 4 will test the hypothesis that cell bodies and dendrites of dura/light-sensitive neurons in the thalamus are richly apposed by axons containing specific neuromodulating molecules as potential targets for pharmacological interception of migraine photophobia. Study 5 will test the hypothesis that thalamic neurons that integrate sensory information from the dura and retina project to cortical areas involved in the pain perception (e.g., somatosensory and insular cortices) or/and photoperception (visual cortices). Our working hypothesis that migraine headache can be exacerbated by non-image-forming retinal input converging upon dura-sensitive thalamocortical neurons represents a new concept in the field of migraine pathophysiology. As such, we submit this project as a new application that could potentially open a unique window into the biology of an adverse phenomenon described by millions of headache sufferers. PUBLIC HEALTH RELEVANCE: Almost every person undergoing a migraine attack seeks sanctuary in a dark environment in order to lessen the intensification of headache caused by exposure to light. This grant proposal will test a novel hypothesis that migraine headache is exacerbated by non-image-forming signals from the retina that are incorporated in the thalamus by nociceptive neurons that project to cortical areas involved in pain perception. This application could potentially open a unique window into the biology of an adverse phenomenon described by millions of headache sufferers.