Topically administered CB2-receptor agonist, JWH-133, does not decrease intraocular pressure (IOP) in normotensive rabbits
Introduction
The intraocular pressure (IOP) -lowering effects of cannabinoids were first observed in humans smoking marijuana [1]. A number of studies have later confirmed that topically applied cannabinoids decrease IOP in experimental animals [2], [3], [4], [5] and humans [6].
Two cannabinoid receptor subtypes, CB1 and CB2, have been identified in mammalian tissues [7], [8]. While CB1 receptors are primarily distributed throughout the central nervous system (CNS), CB2 receptors are restricted to the immune system cells. A wide distribution of CB1 receptor protein has been detected from various human and bovine ocular tissues [9], [10], including the trabecular meshwork, Schlemm's canal and ciliary epithelium, which are the major eye structures that participate in maintaining IOP. While evidence of CB2 receptor mRNA has been obtained from rat retinal tissues [11], it is not clear whether CB2 receptors participate in the IOP-lowering actions of cannabinoids. To date, no studies have been conducted to determine if the topical administration of CB2 receptor agonists decrease IOP. Since CB2 agonists most probably lack the psychoactive CNS side-effects of CB1 agonists [12], they would offer an alternative approach to develop novel and more tolerable glaucoma therapeutics.
Recently, CB2 receptor specific ligands, such as JWH-133 (Fig. 1) have been developed. The binding affinity of JWH-133 is approximately 200 times superior towards the CB2 than CB1 receptors [13]. In this study, we investigated the IOP effects of topically administered JWH-133, and compared it to those of non-classical cannabinoid CP55,940, in normotensive rabbits.
Section snippets
Chemicals
The CB2 receptor agonist, 3-(1′,1′-dimethylbutyl)-1-deoxy-Δ8-THC (JWH-133), was purchased from Tocris Cookson Ltd. (Bristol, UK). CP55,940 [(−)-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclo-hexyl]-phenol] was kindly donated by Pfizer Inc. (Groton, CT, USA). Hydroxypropyl-β-cyclodextrin (HP-β-CD, Encapsin®; mw = 1297.4, degree of molar substitution 0.4) was purchased from Janssen Biotech (Olen, Belgium) and propylene glycol from Oriola Oy (Espoo, Finland). Poly(vinyl alcohol)
Results
Ocular administration of JWH-133 at the doses of 10 μg and 25 μg (25 μl) in 45% HP-β-CD vehicle did not decrease IOP in the treated eyes of normotensive rabbits when compared to plain vehicle treatment (Fig. 2A). In contrast, CP55,940 at the doses of 25 μg (in 5% HP-β-CD, 3% PVA) and 62.5 μg (in 10% HP-β-CD, 3% PVA) produced statistically significant IOP reductions in the treated eyes (Fig. 2A).
In order to achieve higher drug concentration in the eye drop solution, JWH-133 was formulated with
Discussion
Recent IOP and receptor localization studies suggest that the IOP effects of cannabinoids are mediated via ocular CB1 receptors. Cannabinoids acting via the CB2 receptors apparently lack the psychoactive CNS side-effects that are characteristic for CB1 receptor agonists [12]. Currently, it is discussed whether compounds acting via CB2 receptors are also able to decrease IOP. In this study, the IOP effects of the topically administered CB2 receptor agonist JWH-133 were studied in normotensive
Acknowledgements
This work was supported by grants from the Academy of Finland and the National Technology Agency of Finland.
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