The cannabinoid signaling system regulates intraocular pressure (IOP) in the mouse via a complex system that includes three receptors: CB1, GPR18 and GPR119. In each case, activating the receptor lowers IOP, but CB1 receptors are found both at sites of aqueous humor inflow and outflow. As such, knockout mice for any of these receptors would be expected to have higher-than average, or at least unchanged, intraocular pressure. The current study investigates the unexpected observation that CB1 knockout mice have lower pressure than wild type counterparts by testing various regulators of cannabinoid signaling in murine models of IOP. We now report that a CB1 antagonist has differential effects on IOP: SR141716 raises IOP in standard light cycle (SLC) but lowers IOP in reverse light cycle (RLC). This is mimicked by ABD1085, a negative allosteric modulator of CB1. CB1 inhibitors lower IOP in both normotensive and hypertensive mouse eyes. The pressure-lowering effect is absent in CB1 knockout mice. IOP rebounds after the end of treatment but shows no sign of desensitization with daily treatment for a week. Unlike the positive cannabinoid effect, antagonist effects are not sex-dependent. We propose that there are two mechanisms of action for CB1, one that lowers IOP upon activation and a second with inverse sign that lowers IOP when CB1 is antagonized. The relatively lower pressure in CB1 knockout mouse eyes suggests that this second negative regulation of IOP is dominant.

大麻素信号系统通过一个复杂的系统调节小鼠的眼内压 (IOP)，该系统包括三个受体：CB1、GPR18 和 GPR119。在每种情况下，激活受体都会降低眼压，但在房水流入和流出部位都发现了 CB1 受体。因此，预计任何这些受体的基因敲除小鼠的眼压都高于平均水平，或至少保持不变。目前的研究通过在 IOP 小鼠模型中测试大麻素信号传导的各种调节因子来调查意外观察结果，即 CB1 基因敲除小鼠的压力低于野生型小鼠。我们现在报告 CB1 拮抗剂对 IOP 有不同的影响：SR141716 在标准光周期 (SLC) 中提高 IOP，但在逆光周期 (RLC) 中降低 IOP。这是由 ABD1085 模仿的，CB1 的负变构调节剂。CB1 抑制剂降低血压正常和高血压小鼠眼的 IOP。CB1 基因敲除小鼠不存在降压作用。治疗结束后眼压会反弹，但在一周内每天治疗后没有出现脱敏的迹象。与积极的大麻素效应不同，拮抗剂效应不依赖于性别。我们提出CB1有两种作用机制，一种在激活时降低IOP，另一种在CB1被拮抗时降低IOP。CB1 基因敲除小鼠眼压相对较低表明眼压的第二种负调节占主导地位。治疗结束后眼压会反弹，但在一周内每天治疗后没有出现脱敏的迹象。与积极的大麻素效应不同，拮抗剂效应不依赖于性别。我们提出CB1有两种作用机制，一种在激活时降低IOP，另一种在CB1被拮抗时降低IOP。CB1 基因敲除小鼠眼压相对较低表明眼压的第二种负调节占主导地位。治疗结束后眼压会反弹，但在一周内每天治疗后没有出现脱敏的迹象。与积极的大麻素效应不同，拮抗剂效应不依赖于性别。我们提出CB1有两种作用机制，一种在激活时降低IOP，另一种在CB1被拮抗时降低IOP。CB1 基因敲除小鼠眼压相对较低表明眼压的第二种负调节占主导地位。