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Research ArticleCellular and Molecular

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

Brian D. Hudson, Meggie Beazley, Anna-Maria Szczesniak, Alex Straiker and Melanie E. M. Kelly
Journal of Pharmacology and Experimental Therapeutics December 2011, 339 (3) 757-767; DOI: https://doi.org/10.1124/jpet.111.185769
Brian D. Hudson
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Meggie Beazley
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Anna-Maria Szczesniak
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Alex Straiker
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Melanie E. M. Kelly
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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.

  • 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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Journal of Pharmacology and Experimental Therapeutics: 339 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 3
1 Dec 2011
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Research ArticleCellular and Molecular

Cannabinoids and IOP

Brian D. Hudson, Meggie Beazley, Anna-Maria Szczesniak, Alex Straiker and Melanie E. M. Kelly
Journal of Pharmacology and Experimental Therapeutics December 1, 2011, 339 (3) 757-767; DOI: https://doi.org/10.1124/jpet.111.185769

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Research ArticleCellular and Molecular

Cannabinoids and IOP

Brian D. Hudson, Meggie Beazley, Anna-Maria Szczesniak, Alex Straiker and Melanie E. M. Kelly
Journal of Pharmacology and Experimental Therapeutics December 1, 2011, 339 (3) 757-767; DOI: https://doi.org/10.1124/jpet.111.185769
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