Hewitt Laboratory of the Ola B. Williams Glaucoma Center, Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, 29425, USA.
Curr Pharm Des. 2012;18(37):6101-8. doi: 10.2174/138161212803582441.
Inadequate blood flow in the retina (ischemia) is a common cause of visual impairment and blindness. Retinal ischemia plays a pivotal role in a number of ocular degenerative diseases such as diabetic retinopathy, glaucoma, and retinal artery occlusion. The sequence of events by which ischemia leads to retinal degeneration are not completely understood, but likely involve both necrotic and apoptotic processes. A variety of diverse chemical mediators (e.g., glutamate, oxygen free-radical, nitric oxide, and proinflammatory cytokines) have been implicated as participants in ischemic retinal injury. In the eye, experimental and/or clinical evidence has suggested roles for endogenous opioids and their receptors in the regulation of iris function, aqueous humor dynamics, corneal wound healing, and retinal development and neuroprotection. In numerous vital organs, opioid receptor activation prior to ischemia or severe hypoxia is neuroprotective. Recently, activation of opioid-receptors, particularly δ-opioid-receptors (DOR), has been demonstrated to suppress several steps in the deleterious cascade of events during ischemic/hypoxic stress. In providing neuroprotection against ischemia, opioid-receptor activation appears to block proinflammatory cytokines, such as TNF-α, and glutamate excitotoxicity. Depending on duration and severity of cellular stress, DOR activation can trigger different mechanisms at multiple levels to preserve neuronal survival, including: stabilized ionic homeostasis, augmented pro-survival signaling (e.g., PKC, ERK, PI3K/Akt) and enhanced anti-oxidative capacity. This review will summarize the potential roles of opioids in protecting the viability of ocular tissues. Special emphasis will be focused on enhancing the understanding of the molecular mechanisms of opioid actions in protecting the retina against ischemic/hypoxic injury.
视网膜血流不足（缺血）是视力障碍和失明的常见原因。视网膜缺血在许多眼部退行性疾病中起着关键作用，如糖尿病视网膜病变、青光眼和视网膜动脉阻塞。缺血导致视网膜变性的事件顺序尚不完全清楚，但可能涉及坏死和凋亡过程。多种不同的化学介质（如谷氨酸、氧自由基、一氧化氮和促炎细胞因子）被认为参与了缺血性视网膜损伤。在眼睛中，实验和/或临床证据表明内源性阿片样物质及其受体在调节虹膜功能、房水动力学、角膜伤口愈合以及视网膜发育和神经保护中发挥作用。在许多重要器官中，缺血或严重缺氧前阿片受体的激活具有神经保护作用。最近，阿片受体（特别是 δ-阿片受体（DOR））的激活已被证明可抑制缺血/缺氧应激过程中有害级联反应的几个步骤。阿片受体的激活在提供对缺血的神经保护方面似乎可以阻断促炎细胞因子，如 TNF-α 和谷氨酸兴奋性毒性。根据细胞应激的持续时间和严重程度，DOR 激活可以在多个水平触发不同的机制来维持神经元存活，包括：稳定的离子动态平衡、增强的生存信号（例如 PKC、ERK、PI3K/Akt）和增强的抗氧化能力。这篇综述将总结阿片类药物在保护眼部组织活力方面的潜在作用。特别强调的是，要增强对阿片类药物在保护视网膜免受缺血/缺氧损伤方面的作用机制的理解。
