Involvement of cannabinoid receptors in the intraocular pressure-lowering effects of WIN55212-2.
It is known that marijuana smoking and administration of natural cannabinoids reduce intraocular pressure. However, it has not been established whether the intraocular pressure-lowering effects of cannabinoids are mediated by cannabinoid receptors. Aminoalkylindoles are a new class of cannabimimetics with structures entirely different from those of natural cannabinoids. WIN55212-2, a prototypic aminoalkylindole, has been shown to bind cannabinoid receptors and to exhibit cannabinoid-like activities. The objective of this study was to determine whether aminoalkylindoles lower intraocular pressure and whether the effects of aminoalkylindoles are mediated by ocular cannabinoid receptors. The intraocular pressure of New Zealand White rabbits was measured with the use of applanation pneumatonography. After the measurement of baseline intraocular pressure, drugs were applied topically and the intraocular pressure was monitored. The topical application of WIN55212-2 significantly reduced intraocular pressure in the treated eyes. The intraocular pressure-lowering effects of WIN55212-2 were time and dose dependent, and the maximal reduction was 4.7 +/- 0.5 mm Hg at a dose of 100 microg. In contrast to treated eyes, the intraocular pressure on the contralateral eyes was not significantly affected. The topical application of WIN55212-3, the enantiomer of WIN55212-2, had no effect on intraocular pressure. Furthermore, the intraocular pressure-lowering effects of WIN55212-2 were significantly reduced by topically administered SR141716A, a selective antagonist for the CB1 cannabinoid receptor. The dose-response curve of WIN55212-2 is shifted parallel to the right by SR141716A. These data demonstrate that like natural cannabinoids, WIN55212-2 also reduces intraocular pressure, and the effects of WIN55212-2 are mediated at least in part by the CB1 cannabinoid receptors in the eye.
Song
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ZH
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, USA. zhsong@louisville.edu
Slowey
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CA
D000287:Administration, Topical; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D048588:Benzoxazines; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011817:Rabbits; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D000077285:Rimonabant; D013237:Stereoisomerism; D013997:Time Factors; D014065:Tonometry, Ocular
D000700:Analgesics; D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant