Migraine pathophysiology: neural basis of photophobia

偏头痛病理生理学：畏光的神经基础

基本信息

批准号：
8418737
负责人：
Rami Burstein
金额：
$ 36万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/8418737
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 intravitreal injection 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

项目摘要

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.

描述（由申请人提供）：大约 85% 的偏头痛发作患者会在黑暗环境中寻求庇护，以减轻环境光引起的头痛加剧。这种畏光反应的神经机制仍然是一个谜。目前关于偏头痛神经基础的观点表明，颅硬脑膜中的三叉神经疼痛纤维以及髓质背角、丘脑和皮质中的中枢伤害性神经元。我们对硬脑膜敏感丘脑神经元作为头外异常性疼痛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，偏头痛畏光症发生在感知光（完整的黑视蛋白感光器）的盲人（视锥细胞/视杆细胞退化）中，但不会发生在完全失明的偏头痛患者中。我们假设偏头痛路径上的活动可以通过从视网膜通过视神经传输到大脑的汇聚信号来调节。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。神经束追踪表明，这些丘脑神经元的细胞体和树突被许多视网膜起源的传入神经并列，并且它们自己的轴突广泛分支到初级体感皮层。在这里，我们将重点关注丘脑皮质神经元脑膜伤害感受和视网膜感光的独特整合，作为偏头痛畏光的候选机制。研究 1 将检验以下假设：硬脑膜/光敏感丘脑神经元的活动受到经典光感受器（视杆细胞、视锥细胞）和黑视神经光感受器的差异调节，因为它与偏头痛畏光的定性和定量特征有关。研究 2 将检验硬脑膜敏感丘脑神经元的光调制是由视神经而不是眼睛的三叉神经支配介导的假设。研究3将检验这样的假设：丘脑中硬脑膜/光敏神经元的细胞体和树突由黑视神经视网膜神经节细胞的轴突并列，为将视网膜感光纳入盲人偏头痛患者脑膜伤害感受通路提供候选神经基质。视锥/视杆变性。研究 4 将检验这样的假设：丘脑中硬脑膜/光敏神经元的细胞体和树突与含有特定神经调节分子的轴突大量并列，作为药物拦截偏头痛畏光的潜在靶标。研究 5 将检验以下假设：整合来自硬脑膜和视网膜的感觉信息的丘脑神经元投射到参与疼痛感知（例如体感和岛叶皮质）或/和光感知（视觉皮质）的皮质区域。我们的工作假设是，非成像视网膜输入汇聚到硬脑膜敏感的丘脑皮质神经元上会加剧偏头痛，这代表了偏头痛病理生理学领域的一个新概念。因此，我们将这个项目作为一个新的应用程序提交，它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。