Evidence that cannabinoid CB1 receptors regulate intraocular pressure via two opposing mechanisms. (November 2020)

• Record Type: Journal Article
• Authors: Miller, Sally; Daily, Laura; Ploss, Maya; Greig, Iain; Ross, Ruth; Rayana, Naga Pradeep; Dai, Jiannong; Sugali, Chenna Kesavulu; Mao, Weiming; Straiker, Alex
• Is Part Of: Experimental eye research. Volume 200(2020)
• Publication Date: 2020-11
• Subjects: Cannabinoid -- CB1 -- Ocular pressure -- Glaucoma -- Antagonist; C57 C57BL/6J -- FAAH fatty acid amide hydrolase -- IOP intraocular pressure -- MAGL monoacylglycerol lipase -- NAM negative allosteric modulators -- NAPE-PLD N-acyl phosphatidylethanolamine-specific phospholipase D -- OHT ocular hypertension -- RLC reversed light dark cycle -- SLC standard light dark cycle -- THC tetrahydrocannabinol. -- TM trabecular meshwork; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2020.108241
• Languages: English
• ISSNs: 0014-4835

Abstract

Abstract: 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. Highlights: Cannabinoid CB1 receptor activation and antagonism can each lower ocular pressure. CB1 antagonism appears to be dominant in terms of its effects on ocular pressure. Both CB1 antagonists and negative allosteric modulators can lower ocular pressure. Unlike CB1 agonist effects, CB1 antagonist action is not sex-dependent.