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Alex Straiker, Meggie Beazley, Suresh Viswanathan, Heather Bradshaw, Shu-jung Hu, Melanie Kelly; Evidence That A Functional Gpr18-based Signaling System In The Anterior Murine Eye Modulates Intraocular Pressure. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5093.
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© ARVO (1962-2015); The Authors (2016-present)
GPR18 is a recently deorphanized lipid receptor that is activated by the chief psychoactive ingredient of marijuana, THC, as well as behaviorally-inactive cannabinoids (e.g. abnormal cannabidiol (Abn-CBD)). This G protein-coupled receptor is related to CB1/CB2 and GPR55 receptors. Strong evidence now supports N-arachidonoyl glycine (NAGly) as the endogenous ligand of GPR18. The presence and/or function of any GPR18-based ocular signaling system remains essentially unstudied. The objectives of this research are: 1) to determine the disposition of GPR18 receptors and ligands in anterior murine eye, 2) examine the effect on intraocular pressure (IOP) by GPR18 and GPR55 in a murine model, including knockout mice for CB1 (CB1-/-), CB2 (CB2-/-) or GPR55 (GPR55-/-).
IOP was measured by rebound tonometry in C57Bl/J6 (C57), CB1-/-, and GPR55-/- anesthetized mice (isoflurane 2-3%) following a 5 μl topical application of 2% Abn-CBD, 1% 0-1602, 1% NAGly or vehicle (Tocrisolve®). O-1918, an antagonist at both GPR55 and GPR18, was injected i.p at 2 mg/kg. GPR18 protein localization was assessed with immunohistochemistry in frozen sections of mouse eye using an antibody developed against GPR18 protein. Endo-cannabinoids were measured using LC-MS.
GPR18 protein is expressed most prominently in the ciliary epithelium and the corneal epithelium though it is also expressed elsewhere at lower levels. Interestingly, GPR18 staining is detected in the trabecular meshwork. The GPR18 ligand NAGly is also detected in mouse eye at levels comparable to the brain. Abn-CBD (2%) significantly reduced IOP in C57, CB1-/-, CB2-/- and GPR55-/- mice, with decreases of 1.17±0.15, 1.37±0.16, 0.68±0.08 and 0.85±0.15 mmHg, respectively. NAGly (1%) produced similar decreases in IOP of 0.72±0.18, 1.41±0.08, 1.22±0.23 and 0.86±0.18, respectively, when tested in all four groups of mice. The GPR55 receptor agonist, 0-1602 (1%) failed to decrease IOP in WT mice (p > 0.05). Abn-CBD and NAGly did not significantly reduce IOP when co-administered with 0-1918, in C57, CB1-/-, or GPR55-/- mice (p > 0.05 per respective group).
We present evidence for a functional GPR18-based signaling system in the murine anterior eye, including receptors and ligands. GPR18 agonists, Abn-CBD and NAGly reduce IOP independently of CB1, CB2, or GPR55. These findings suggest that GPR18 may serve as a desirable target for the development of novel ocular hypotensive medications.
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