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 (CB1) 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 βARs. Cannabinoid agonists, βAR antagonists, and βAR agonists decreased IOP in wild-type mice and CB2(−/−) mice. In contrast, none of these compounds were found to reduce IOP in βAR(−/−) or CB1(−/−) mice. Desensitization of the βARs and depletion of catecholamines in wild-type mice also eliminated the ability of the cannabinoid agonist (R)-(+)-[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 βARs and catecholamines in the ocular hypotensive properties of cannabinoids. Finally, CB1 receptors were shown to colocalize with tyrosine hydroxylase, a marker for adrenergic neurons. Taken together, these findings suggest that βARs 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.
Footnotes
This work was supported by studentships from the Killam Trusts and Natural Sciences and Engineering Research Council of Canada (to B.D.H.); and a Canadian Institutes of Health operating grant (to M.E.M.K.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.185769.
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ABBREVIATIONS:
- IOP
- intraocular pressure
- CB
- cannabinoid
- AH
- aqueous humor
- AR
- adrenoceptor
- NE
- norepinephrine
- TH
- tyrosine hydroxylase
- ISO
- isoprenaline [1-(3′,4′-dihydroxyphenyl)-2-isopropylaminoethanol hydrochloride, N-isopropyl-dl-noradrenaline]
- WIN
- WIN 55,212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate]
- CP
- CP 55,940 [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol]
- AM281
- 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide
- AM630
- 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl(4-methoxyphenyl)methanone
- ACEA
- N-(2-chloroethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide.
- Received July 5, 2011.
- Accepted August 22, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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