Indirect Sympatholytic Actions at β-Adrenoceptors Account for the Ocular Hypotensive Actions of Cannabinoid Receptor Agonists

Abstract

Intraocular pressure (IOP) is the primary risk factor for glaucoma, a blinding eye disease. Cannabinoid agonists have long been known to decrease IOP, suggesting they may be useful in glaucoma treatment. However, the specific mechanism by which cannabinoids generate this ocular hypotensive effect remains unknown. The current evidence suggests the cannabinoids reduce IOP through actions at cannabinoid 1 (CB 1 ) receptors within the eye, and adrenergic receptors (ARs) may also contribute to this action of cannabinoids. Considering this, the present study aimed to elucidate the mechanism behind the ocular hypotensive properties of cannabinoids through the use of mice genetically lacking either cannabinoid receptors or ␤ARs. Cannabinoid agonists, ␤AR antagonists, and ␤AR agonists decreased IOP in wild-type mice and CB 2 (Ϫ/Ϫ) mice. In contrast, none of these compounds were found to reduce IOP in ␤AR(Ϫ/Ϫ) or CB 1 (Ϫ/Ϫ) mice. Desensitization of the ␤ARs and depletion of catecholamines in wild-type mice also eliminated the ability of the cannabinoid agonist (R)-(ϩ)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212-2) to reduce IOP, strongly implicating a role for both ␤ARs and catecholamines in the ocular hypotensive properties of cannabinoids. Finally, CB 1 receptors were shown to colocalize with tyrosine hydroxylase, a marker for adrenergic neurons. Taken together, these findings suggest that ␤ARs are required for the ocular hypotensive properties of cannabinoids, and cannabinoids reduce IOP by acting as indirect sympatholytics and inhibiting norepinephrine release within the eye.

Evidence for a GPR18 Role in Diurnal Regulation of Intraocular Pressure

“…We previously reported that this diurnal variation in IOP persists in CB 1 , CB 2 , and GPR55 knockout animals, indicating that these receptors are not involved. 9,10 Several of the candidate molecules have been linked to GPR119 or GPR18: GPR119 may be a target for N -oleoyl ethanolamine (OEA) and N -palmitoyl ethanolamine (PEA), 35 whereas GPR18 has been proposed as the endogenous partner for NAGly. Notably, activation of GPR18 by NAGly lowers IOP in the eye.…”

“…9,10 More recently, we reported that activation of GPR18 also lowers IOP and that the receptors are present in multiple tissues in the anterior eye. 10 GPR18 is a lipid receptor that is activated by a metabolite of endocannabinoids as described in greater detail below.…”

New Therapeutic Targets for Intraocular Pressure Lowering

“…The ocular hypotensive properties of cannabinoids are dependent on the β -adrenergic receptors stimulation. The cannabinoids reduce IOP by acting as indirect sympatholytics [126]. Cannabinoids can induce COX-2 expression, resulting in higher levels of PGE2 and MMPs, which modulates aqueous outflow resistance [127].…”

A GPR119 Signaling System in the Murine Eye Regulates Intraocular Pressure in a Sex-Dependent Manner

“…Although the increase was modest, this suggests that MBX2982 has a second target that is coupled to an increase in pressure, not unlike our findings for WIN55212 and CB 1 . 29 The other two compounds may have suffered from limited penetration of the cornea, an issue we encountered for MAGL blockers. 22 …”

“…Women are not at greater risk of open angle glaucoma. Women outnumber men in cases of glaucoma (although likely substantially because women outlive men 30 ), meaning that there is a greater need for glaucoma medication among women than men, and the longevity of women leaves them at greater risk of developing tolerance to one or more of the available drugs.…”