Involvement of cannabinoid receptors in the intraocular pressure-lowering effects of WIN55212-2

It is known that marijuana smoking and administration of natural cannabinoi ds reduce intraocular pressure. However, it has not been established whethe r the intraocular pressure-lowering effects of cannabinoids are mediated by cannabinoid receptors. Aminoalkylindoles are a new class of cannabimimetic s with structures entirely different from those of natural cannabinoids. WI N55212-2, a prototypic aminoalkylindole, has been shown to bind cannabinoid receptors and to exhibit cannabinoid-like activities. The objective of thi s study was to determine whether aminoalkylindoles lower intraocular pressu re and whether the effects of aminoalkylindoles are mediated by ocular cann abinoid receptors. The intraocular pressure of New Zealand White rabbits wa s measured with the use of applanation pneumatonography. After the measurem ent of baseline intraocular pressure, drugs were applied topically and the intraocular pressure was monitored. The topical application of WIN55212-2 s ignificantly reduced intraocular pressure in the treated eyes. The intraocu lar pressure-lowering effects of WIN55212-2 were time and dose dependent, a nd the maximal reduction was 4.7 +/- 0.5 mm Hg at a dose of 100 mu g. In co ntrast 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. Furthermor e, the intraocular pressure-lowering effects of WIN55212-2 were significant ly reduced by topically administered SR141716A, a selective antagonist for the CB1 cannabinoid receptor. The dose-response curve of WIN55212-2 is shif ted parallel to the right by SR141716A. These data demonstrate that like na tural cannabinoids, WIN55212-2 also reduces intraocular pressure, and the e ffects of WIN55212-2 are mediated at least in part by the CB1 cannabinoid r eceptors in the eye.