Mechanisms of Pain and Photophobia in Migraine and Dry Eye

项目摘要 眼痛和眼恐怖症是与偏头痛和干眼症相关的常见和使人衰弱的病症 疾病（DED）。近40%的患者还经历了持续疼痛、干眼和/或恐惧症 接受过屈光手术的人偏头痛、DED和屈光不正的共同神经解剖学基础 手术是三叉神经，特别是眼分支，这是参与反射稳态 调节角膜和硬脑膜。众所周知，对这些反射回路的损伤会导致明显的 疼痛的感觉，但其潜在的机制知之甚少，有效的非阿片类药物治疗 缺乏。我们假设投射到角膜和硬脑膜的三叉神经元受到 来自眼睛中感光细胞的反馈，以及与浸润免疫细胞的相互作用， 反射通路失调和感觉反应放大-引起对 触摸和光（恐惧症）。我们将在偏头痛、DED和屈光不正的啮齿动物模型中检验这一假设。 通过识别三种疼痛模型共有的分子机制和神经通路， 神经解剖学、生理学和行为学方法。实验将包括潜在的调查 治疗靶点，包括CGRP、TRPM 3和黑视素，所有这些都与先前的研究有关。 恐惧症。这些研究将阐明关键的细胞和分子变化的发展， 在偏头痛、DED和屈光手术中的眼痛和眼恐怖症，并将指导治疗发展。

Project Summary Ocular pain and photophobia are common and debilitating conditions associated with migraine and dry eye disease (DED). Persistent pain, dry eye, and/or photophobia are also experienced by nearly 40% of patients who have received refractive surgery. A common neuroanatomical substrate in migraine, DED, and refractive surgery is the trigeminal nerve, specifically the ophthalmic branch, which is involved in reflex homeostatic regulation of the cornea and dura. It is well known that damage to these reflex circuits leads to overt sensations of pain, yet the underlying mechanisms are poorly understood and effective non-opioid treatments are lacking. We hypothesize that the trigeminal neurons projecting to the cornea and dura are modulated by feedback from light-sensing cells in the eye, as well as by interaction with infiltrating immune cells leading to dysregulation of the reflex pathways and amplification of sensory responses – causing hypersensitivities to touch and light (photophobia). We will test this hypothesis in rodent models of migraine, DED, and refractive surgery by identifying molecular mechanisms and neural pathways common to the three pain models, using neuroanatomical, physiological, and behavioral approaches. Experiments will include investigation of potential therapeutic targets, including CGRP, TRPM3, and melanopsin, all of which have been previously implicated in photophobia. These studies will elucidate key cellular and molecular changes underlying the development of ocular pain and photophobia in migraine, DED, and refractive surgery, and will guide therapeutic development.