Migraine pathophysiology: neural basis of photophobia

偏头痛病理生理学：畏光的神经基础

• 批准号: 8013547
• 负责人: Rami Burstein
• 金额: $ 36.35万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013547
• 关键词: Ablation; Animals; Applications Grants; Area; Axon; Behavioral; Biology; Brain; Cephalic; Characteristics; Chemicals; Circadian Rhythms; Clinical; Clinical Research; Data; Dendrites; Dopamine; Dorsal; Dura Mater; Environment; Exhibits; Exposure to; Eye; Fiber; Figs - dietary; Functional disorder; Goals; Headache; Histamine; Image; Immunohistochemistry; Individual; Injection of therapeutic agent; Label; Lateral posterior nucleus of thalamus; Lead; Learning; Life; Light; Light Exercise; Manuscripts; Maps; Mediating; Mediator of activation protein; Meningeal; Methodology; Methyl Green; Migraine; Molecular; Nerve; Neurologic; Neuromodulator; Neurons; Nociception; Nociceptors; Optic Nerve; Pain; Pathway interactions; Pattern; Perception; Peripheral; Persons; Photophobia; Photoreceptors; Photosensitivity; Play; Positioning Attribute; Posterior Thalamic Nuclei; Presynaptic Terminals; Pupil light reflex; Rattus; Reaction; Relative (related person); Resolution; Response Latencies; Retina; Retinal; Retinal Cone; Retinal Ganglion Cells; Role; Sensory; Serotonin; Severities; Signal Transduction; Sleep; Somatosensory Cortex; Stimulus; Symptoms; Synapses; Testing; Thalamic structure; Time; Tracer; Trigeminal Neuralgia; Trigeminal System; Vertebrate Photoreceptors; Visible Radiation; Visual; Visual Cortex; Visually Impaired Persons; Work; allodynia; base; blind; central sensitization; cone-rod degeneration; dorsal horn; experience; hypocretin; in vivo; insight; light intensity; melanopsin; nerve supply; neural tract; neuromechanism; neuronal cell body; neuronal patterning; noradrenergic; novel; photoactivation; public health relevance; relating to nervous system; response; retinal axon; retinal rods; sensory cortex; somatosensory; transmission process

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.

描述（由申请人提供）：大约85％的人经历偏头痛攻击的人在黑暗的环境中寻求保护区，以减少周围光线带来的头痛加剧。这种嗜恐惧反应的神经机制仍然是一个难题。当前关于偏头痛神经基础的观点暗示了颅硬脑膜的三叉神经疼痛纤维，以及髓质背角，丘脑和皮质的中央伤害性神经元。我们对硬脑膜敏感的丘脑神经元作为脑外痛的介体的研究非常幸运地评估了这种神经元是否在偏头痛恐惧症中起作用。在这项赠款提案的一项临床研究中，我们了解到，偏头痛发生在盲人（锥/杆变性）中，感知光（完整的黑色素蛋白光感受器），但在完全盲目的偏头痛中没有。我们假设沿偏头痛途径的活性可以通过通过视神经从视网膜传播到大脑的融合信号来调节。在大鼠丘脑中，我们确定了对硬脑膜敏感的神经元的持续活性受到光的强烈调节。神经道追踪表明，这些丘脑神经元的细胞体和树突是由许多视网膜来源传入的，并且它们自己的轴突将其自身的轴突广泛分支到主要的体体皮质中。在这里，我们将重点关注脑膜伤害感受和视网膜光感受的独特整合，作为偏头痛恐惧症的候选机制。研究1将检验以下假设：硬脑膜/光敏丘脑神经元的活性是由经典的光感受器（杆，锥体）和黑素蛋白能光感受器差异调节的，因为它与偏头痛的定性和定量特征有关。研究2将检验以下假设：硬脑膜敏感的丘脑神经元的光调节是由视神经介导的，而不是通过眼睛的三叉神经神经介导的。研究3将检验丘脑中硬脑膜/光敏感性神经元的细胞体和树突的假设，由黑色素能视网膜神经节细胞的轴突提出，为候选神经底物提供了视网膜光感受，将视网膜光摄取掺入盲属偏移率cone/rodeneration的脑膜偏移率的途径。研究4将检验丘脑中硬脑膜/光敏感神经元的细胞体和树突，并由含有特定神经调节分子作为偏头痛的药理学拦截的潜在靶标。研究5将检验以下假设：将Dura和Retina项目的感觉信息整合到疼痛感知的皮质区域（例如，体感和岛状皮层）或/和/和光疗法（视觉皮层）。我们的工作假设是，通过对硬脑膜敏感的丘脑皮层神经元收敛的非图像形成的视网膜输入可以加剧偏头痛，这代表了偏头痛病理生理学领域的一个新概念。因此，我们将该项目提交为一个新应用程序，它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个独特的窗口。 公共卫生相关性：几乎每个受到偏头痛攻击的人都在黑暗环境中寻求保护区，以减少暴露于光线导致的头痛的加剧。该赠款提案将检验一个新的假设，即偏头痛会因视网膜的非图像形成信号而加剧，这些信号由对疼痛感知的皮质区域的伤害感受性神经元纳入丘脑。该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个独特的窗口。