Cannabinoids are part of an endogenous signaling system found throughout the body, including the eye. Hepler and Frank showed in the early 1970s that plant cannabinoids can lower intraocular pressure (IOP), an effect since shown to occur via cannabinoid CB1 and GPR18 receptors. Endocannabinoids are synthesized and metabolized enzymatically. Enzymes implicated in endocannabinoids breakdown include monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), but also ABHD12, NAAA, and COX-2. Inhibition of MAGL activity raises levels of the endocannabinoid 2-arachidonoyl glycerol and substantially lowers IOP. Blocking other cannabinoid metabolizing enzymes or cannabinoid transporters may similarly contribute to lowering IOP and so serve as therapeutic targets for treating glaucoma. We have tested blockers for several cannabinoid-metabolizing enzymes and transporters (FABP5 and membrane reuptake) for their ability to alter ocular pressure in a murine model of IOP. Of FAAH, ABHD12, NAAA, and COX2, only FAAH was seen to play a role in regulation of IOP. Only the FAAH blocker URB597 lowered IOP, but in a temporally, diurnally, and sex-specific manner. We also tested two blockers of cannabinoid transport (SBFI-26 and WOBE437), finding that each lowered IOP in a CB1-dependent manner. Though we see a modest, limited role for FAAH, our results suggest that MAGL is the primary cannabinoid-metabolizing enzyme in regulating ocular pressure, thus pointing towards a role of 2-arachidonoyl glycerol. Interestingly, inhibition of cannabinoid transport mechanisms independent of hydrolysis may prove to be an alternative strategy to lower ocular pressure.

大麻素是整个身体（包括眼睛）内源性信号系统的一部分。赫普勒和弗兰克在1970年代初证明，植物大麻素可以降低眼内压（IOP），自从证明通过大麻素CB1和GPR18受体发生这种作用以来，这种作用就产生了。内源性大麻素是通过酶合成和代谢的。与内源性大麻素分解有关的酶包括单酰基甘油脂肪酶（MAGL）和脂肪酸酰胺水解酶（FAAH），还包括ABHD12，NAAA和COX-2。抑制MAGL活性会提高内源性大麻素2-花生四烯酰基甘油的水平，并显着降低IOP。阻断其他大麻素代谢酶或大麻素转运蛋白可能同样有助于降低IOP，因此可作为治疗青光眼的治疗靶标。我们已经测试了几种大麻素代谢酶和转运蛋白（FABP5和膜再摄取）的阻滞剂在IOP鼠模型中改变眼压的能力。在FAAH，ABHD12，NAAA和COX2中，仅FAAH被认为在IOP的调节中起作用。仅FAAH阻滞剂URB597降低了IOP，但以时间，昼夜和性别特定的方式降低了IOP。我们还测试了两种大麻素转运阻滞剂（SBFI-26和WOBE437），发现每种阻滞剂均以CB1依赖性方式降低了IOP。尽管我们发现FAAH的作用有限，但我们的结果表明MAGL是调节眼压的主要大麻素代谢酶，因此指向2-花生四烯酸甘油酯。有趣的是