Recent IOP and receptor localization studies suggest that the IOP effects of cannabinoids are mediated via ocular CB(1) receptors. However, it is not yet known whether CB(2) receptor agonists decrease IOP. In this study, the IOP-lowering effects of the CB(2) receptor agonist JWH-133 were studied in normotensive rabbits, and compared with CP55,940. JWH-133 and CP55,940 were dissolved in aqueous hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solutions and propylene glycol. The eye drops (25 microl) were administered unilaterally to the rabbit eye, and IOPs were measured at fixed time intervals. JWH-133, dissolved in either HP-beta-CD (doses = 10 microg and 25 microg) or propylene glycol (dose = 62.5 microg), did not have any effect on IOP when compared to vehicle treatments. In contrast, CP55,940 formulated in HP-beta-CD (doses = 25 microg and 62.5 microg) or propylene glycol (dose = 62.5 microg) reduced IOP significantly compared to vehicle treatments. The results suggest that topically administered CB(2) receptor agonist, JWH-133, does not decrease IOP in normotensive rabbits at the doses and formulations used, and thus, CB(2) receptor agonists may not be useful as cannabinoid-based IOP-lowering therapeutics.