Migraine pathophysiology: neural basis of photophobia

描述（由申请人提供）：大约85%的偏头痛发作患者在黑暗的环境中寻求庇护，以减轻环境光线引起的头痛加剧。这种恐惧反应的神经机制仍然是一个谜。目前偏头痛的神经基础的观点涉及硬脑膜中的三叉神经痛纤维，以及延髓背角、丘脑和皮质中的中枢伤害感受神经元。我们对硬膜敏感的丘脑神经元作为脑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恐惧症中发挥作用。在一项导致这项拨款申请的临床研究中，我们了解到偏头痛恐惧症发生在盲人（视锥/视杆细胞变性）中，这些盲人可以感知光线（完整的黑视蛋白光感受器），但不发生在完全失明的偏头痛患者中。我们推测，活动沿沿着偏头痛的途径可能是调制的汇聚信号从视网膜通过视神经传输到大脑。在大鼠丘脑中，我们发现了持续活动受到光强烈调制的硬脑膜敏感神经元。神经束示踪表明，这些丘脑神经元的细胞体和树突由许多视网膜起源的传入神经并置，并且它们自己的轴突广泛地分支到初级躯体感觉皮层。在这里，我们将集中在这种独特的整合脑膜伤害性和视网膜光感受丘脑皮质神经元作为一个候选机制偏头痛恐惧症。研究1将检验以下假设：硬脑膜/光敏感丘脑神经元的活性受经典光感受器（视杆细胞、视锥细胞）和黑素能光感受器的差异调节，因为它与偏头痛恐惧症的定性和定量特征有关。研究2将测试这一假设，即视神经介导的视神经，而不是三叉神经支配的眼睛的硬脑膜敏感的丘脑神经元的光调制。研究3将测试这一假设，即丘脑中的硬脑膜/光敏神经元的细胞体和树突与黑视素能视网膜神经节细胞的轴突并列，为将视网膜光感受纳入患有视锥/视杆变性的盲偏头痛患者的脑膜伤害感受通路提供候选神经基质。研究4将检验以下假设：丘脑中硬脑膜/光敏神经元的细胞体和树突被含有特定神经调节分子的轴突丰富地并置，作为偏头痛恐惧症的药理学拦截的潜在靶点。研究5将测试以下假设：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的皮质区域（例如，躯体感觉和岛叶皮层）或/和光感知（视觉皮层）。我们的工作假设，偏头痛可以加剧非图像形成视网膜输入汇聚在硬脑膜敏感的丘脑皮质神经元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，进入数百万头痛患者描述的不良现象的生物学。 公共卫生相关性：几乎每一个经历偏头痛发作的人都在黑暗的环境中寻求庇护，以减轻因暴露于光线而引起的头痛加剧。这项拨款提案将测试一个新的假设，即偏头痛是由来自视网膜的非图像形成信号加剧的，这些信号通过投射到参与疼痛感知的皮层区域的伤害感受神经元并入丘脑。这一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户。

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.