Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Regulate Intraocular Pressure
Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Regulate Intraocular Pressure
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DOI：
10.1167/iovs.18-24838
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发表时间：
2018-12-01
影响因子：
4.4
通讯作者：
Straiker, Alex
中科院分区：
文献类型：
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作者：
Miller, Sally;Daily, Laura;Straiker, Alex
目的.近50年来，人们已经知道大麻和精神活性成分Delta（9）-四氢大麻酚（THC）可以降低眼内压（IOP）。眼压升高仍然是青光眼的主要标志和治疗目标，青光眼是致盲的主要原因。THC可能通过一种已知的大麻素相关受体（CB 1、CB 2、GPR 18、GPR 119、GPR 55）起作用，但这从未被明确确定。大麻二酚（CBD）是大麻的第二大主要成分，在大多数研究中发现其对IOP没有影响。通过使用眼压计和mRNA水平的测量在活小鼠中测试局部应用的THC和CBD的效果。此外，通过使用脂质分析测试CBD处理的脂质组学结果。我们现在报告，在雄性小鼠中，THC的单次局部应用显著降低IOP（类似于28%）8小时。这种效应是由于CB 1和GPR 18受体的联合激活，其中每一种都已被证明在激活时降低眼压。我们还发现，这种作用具有性别依赖性，雄性小鼠的作用更强，并且雄性小鼠中CB 1和GPR 18的mRNA水平更高。CBD被发现对眼压有两种相反的影响，其中之一涉及紧张性信号的拮抗作用。CBD阻止THC降低眼压。我们得出结论，THC通过激活两种受体CB 1和GPR 18降低IOP，但以性别依赖的方式。与预期相反，CBD对IOP有两种相反的影响，并且可以干扰THC的影响。
PURPOSE. It has been known for nearly 50 years that cannabis and the psychoactive constituent Delta(9)-tetrahydrocannabinol (THC) reduce intraocular pressure (IOP). Elevated IOP remains the chief hallmark and therapeutic target for glaucoma, a major cause of blindness. THC likely acts via one of the known cannabinoid- related receptors (CB1, CB2, GPR18, GPR119, GPR55) but this has never been determined explicitly. Cannabidiol (CBD) is a second major constituent of cannabis that has been found to be without effect on IOP in most studies.METHODS. Effects of topically applied THC and CBD were tested in living mice by using tonometry and measurements of mRNA levels. In addition the lipidomic consequences of CBD treatment were tested by using lipid analysis.RESULTS. We now report that a single topical application of THC lowered IOP substantially (similar to 28%) for 8 hours in male mice. This effect is due to combined activation of CB1 and GPR18 receptors each of which has been shown to lower ocular pressure when activated. We also found that the effect was sex- dependent, being stronger in male mice, and that mRNA levels of CB1 and GPR18 were higher in males. Far from inactive, CBD was found to have two opposing effects on ocular pressure, one of which involved antagonism of tonic signaling. CBD prevents THC from lowering ocular pressure.CONCLUSIONS. We conclude that THC lowers IOP by activating two receptors-CB1 and GPR18-but in a sex-dependent manner. CBD, contrary to expectation, has two opposing effects on IOP and can interfere with the effects of THC.