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Abstract #47581 Published in IGR 13-4
Indirect sympatholytic actions at (beta)-adrenoceptors account for the ocular hypotensive actions of cannabinoid receptor agonists
Hudson BD; Beazley M; Szczesniak A-M; Straiker A; Kelly MEMJournal of Pharmacology and Experimental Therapeutics 2011; 339: 757-767
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 (beta)ARs. Cannabinoid agonists, (beta)AR antagonists, and (beta)AR agonists decreased IOP in wild-type mice and CB(2)(-/-) mice. In contrast, none of these compounds were found to reduce IOP in (beta)AR(-/-) or CB(1)(-/-) mice. Desensitization of the (beta)ARs 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 (beta)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 (beta)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. Copyright (copyright) 2011 by The American Society for Pharmacology and Experimental Therapeutics.
M.E.M. Kelly. Department of Pharmacology, Sir Charles Tupper Building, Dalhousie University, 5850 College St., Halifax, NS B3H1X5, Canada. Email: Melanie.Kelly@Dal.ca
Classification:
3.8 Pharmacology (Part of: 3 Laboratory methods)
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)