Migraine pathophysiology: neural basis of photophobia

描述(申请人提供)：大约85%的偏头痛患者在黑暗的环境中寻求庇护，以减轻环境光引起的头痛加剧。这种恐光反应的神经机制仍然是个谜。目前关于偏头痛神经基础的观点认为，三叉神经痛纤维位于硬脑膜，中枢伤害性神经元位于延髓背角、丘脑和皮质。我们对硬脑膜敏感的丘脑神经元作为头外痛觉异常的媒介的研究，非常幸运地让我们评估了这种神经元是否可能在偏头痛恐光中发挥作用。在这项拨款提案之前的一项临床研究中，我们了解到偏头痛恐光症发生在感知光线(完整的黑色素感受器)的盲人(视锥/视杆变性)中，而不是发生在完全失明的偏头痛患者中。我们推测，偏头痛疼痛通路上的活动可能受到汇聚的信号的调节，这些信号通过视神经从视网膜传递到大脑。在大鼠丘脑中，我们发现了对硬脑膜敏感的神经元，其持续活动受到光的强烈调制。神经束追踪显示，这些丘脑神经元的胞体和树突被许多视网膜来源的传入神经元对置，它们自己的轴突广泛地分支到初级体感皮质。在这里，我们将专注于丘脑皮质神经元脑膜伤害性感受和视网膜光接收的独特整合，作为偏头痛畏光的候选机制。研究1将验证硬脑膜/光敏丘脑神经元的活动受经典光感受器(视杆细胞、视锥细胞)和黑素能光感受器的不同调制的假说，因为它与偏头痛畏光的定性和定量特征有关。研究2将验证这样一种假设，即硬脑膜敏感的丘脑神经元的光调制是由视神经而不是眼睛的三叉神经神经介导的。研究3将验证丘脑硬脑膜/光敏神经元的胞体和树突与黑素能视网膜神经节细胞的轴突相对的假说，为视锥/视杆变性的盲性偏头痛患者将视网膜光接收纳入脑膜伤害性通路提供候选神经底物。研究4将验证这样一种假设，即丘脑中硬脑膜/光敏神经元的胞体和树突与含有特定神经调节分子的轴突丰富地相对，是药物拦截偏头痛畏光的潜在靶点。研究5将测试这样一种假设，即整合了来自硬脑膜和视网膜的感觉信息的丘脑神经元投射到与疼痛感知有关的皮质区域(例如，躯体感觉和岛叶皮质)或/和光感知(视觉皮质)。我们的工作假设，偏头痛可以通过非成像视网膜输入汇聚到硬脑膜敏感的丘脑皮质神经元而加剧，这代表了偏头痛病理生理学领域的一个新概念。因此，我们将这个项目作为一项新的申请提交，它可能会打开一扇独特的窗口，了解数百万头痛患者所描述的不良现象的生物学。 公共卫生相关性：几乎每个偏头痛发作的人都在黑暗的环境中寻求庇护，以减轻因暴露在阳光下而加剧的头痛。这项拨款提案将检验一个新的假设，即偏头痛是由来自视网膜的非成像信号加剧的，这些信号由投射到涉及疼痛感知的皮质区域的伤害性神经元合并到丘脑中。这项应用可能会为数百万头痛患者描述的不良现象的生物学打开一扇独特的窗口。

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.