A GPR18-based signalling system regulates IOP in murine eye

Area of Science:

• Ophthalmology
• Pharmacology
• Neuroscience

Background:

• The G protein-coupled receptor 18 (GPR18) is activated by N-arachidonoyl glycine (NAGly) and abnormal cannabidiol (Abn-CBD).
• The role of GPR18 in ocular signaling remains largely uninvestigated.

Purpose of the Study:

• To determine the presence and location of GPR18 receptors and ligands in the anterior part of the murine eye.
• To investigate the effect of GPR18 activation on intraocular pressure (IOP) in mice, including those lacking CB₁, CB₂, or GPR55 receptors.

Main Methods:

• Intraocular pressure (IOP) was measured after topical application of GPR18 agonists (Abn-CBD, NAGly) and an antagonist (O-1918).
• GPR18 protein expression was analyzed using immunohistochemistry.
• Endocannabinoid levels were quantified via liquid chromatography-tandem mass spectrometry (LC/MS-MS).

Main Results:

• GPR18 protein was prominently expressed in the ciliary epithelium, corneal epithelium, and trabecular meshwork of the mouse eye.
• The GPR18 ligand NAGly was detected in the mouse eye.
• Topical application of Abn-CBD and NAGly significantly reduced IOP in mice, an effect blocked by the GPR18 antagonist O-1918.

Conclusions:

• Evidence supports a functional GPR18 signaling system within the anterior murine eye.
• GPR18 agonists (Abn-CBD, NAGly) lower IOP independently of CB₁, CB₂, or GPR55.
• GPR18 presents a potential therapeutic target for developing novel ocular hypotensive medications.