Evidence that cannabinoid CB1 receptors regulate intraocular pressure via two opposing mechanisms.
Evidence that cannabinoid CB1 receptors regulate intraocular pressure via two opposing mechanisms.
复制标题
大麻素CB1受体通过两种相反机制调节眼内压的证据。
DOI：
10.1016/j.exer.2020.108241
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发表时间：
2020-11
影响因子：
3.4
通讯作者：
Straiker A
中科院分区：
文献类型：
--
作者：
Miller S;Daily L;Ploss M;Greig I;Ross R;Rayana NP;Dai J;Sugali CK;Mao W;Straiker A
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），该系统包括三种受体：CB1，GPR18和GPR119。在每种情况下，激活受体降低IOP，但CB1受体在房水流入和流出部位都有发现。因此，这些受体中的任何一种的敲除小鼠预期具有高于平均值或至少不变的眼内压。目前的研究调查了意外的观察结果，即CB1基因敲除小鼠通过测试IOP小鼠模型中大麻素信号的各种调节剂，比野生型小鼠具有更低的压力。我们现在报告CB 1拮抗剂对IOP具有不同的作用：SR 141716在标准光周期（SLC）中升高IOP，但在反向光周期（RLC）中降低IOP。这是模仿ABD1085，CB1的负变构调节剂。CB1抑制剂降低正常血压和高血压小鼠眼中的IOP。在CB1基因敲除小鼠中不存在降压效应。IOP在治疗结束后反弹，但在一周的每日治疗中没有显示脱敏的迹象。与大麻素的正效应不同，拮抗剂效应不依赖于性别。我们认为CB1有两种作用机制，一种是激活后降低IOP，另一种是拮抗CB1后降低IOP。CB1基因敲除小鼠眼睛中相对较低的压力表明，IOP的第二种负调节占主导地位。
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.
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影响因子：
2.3
作者：
Beilin, M;Neumann, R;Bar-Ilan, A
通讯作者：
Bar-Ilan, A
影响因子：
64.8
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MUNRO, S;THOMAS, KL;ABUSHAAR, M
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影响因子：
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Miller S;Leishman E;Hu SS;Elghouche A;Daily L;Murataeva N;Bradshaw H;Straiker A
通讯作者：
Straiker A
影响因子：
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作者：
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通讯作者：
Clark, Abbot F.
影响因子：
4.4
作者：
Miller, Sally;Daily, Laura;Straiker, Alex
通讯作者：
Straiker, Alex