Since 1923 when marijuana was first placed on Canada’s banned substances list there have been people calling for the legalization of what is, to many, more than just a recreational drug. However, marijuana’s place as an illegal substance means that criminal charges can be laid, and jail time and a permanent record received if a person is caught possessing, growing, or trafficking marijuana -- even if the amount of marijuana found is miniscule (less than 30 grams). Then, in July 2000 the Ontario Court of Appeal ruled that “banning marijuana for medicinal purposes violates the Canadian Charter of Rights and Freedoms” (Khoo). Almost exactly a year later Canada became the first nation to legalize the use of marijuana for medicinal purposes with the Marijuana Medical Access Regulations which allows individuals suffering from terminal illnesses or severe chronic diseases, such as epilepsy and arthritis, to use cannabis if it eases their symptoms, particularly if they do not respond to conventional therapies. Only last week Prime Minister Jean Chrétien announced that legislation decriminalizing the possession of marijuana in Canada would soon be announced, although he cautioned listeners “Don’t start smoking yet, we’re legalizing, not decriminalizing, so you will have another ticket; for losing your senses, or something like that” (“PM says”).
This legalization of marijuana may be good news for sufferers of glaucoma, a chronic eye disease that can damage sight quickly with few warning symptoms. It is estimated that there are 65 million suspected cases of glaucoma worldwide, and that glaucoma accounts for 9% - 12% of the cases of blindness in the United States (“Learn”). Vision loss is due to damage of the optic nerve, and it is now known that elevated intraocular pressure (IOP) is a major risk factor for the development of glaucoma. This increase in IOP results from an inability of the eye to drain the aqueous humor properly. Aqueous humor plays an important role in the physiology of the eye; it supplies the retina and the cornea with nutrients, removes waste, and is indispensable for the maintenance of the optical properties of the eye.
The ciliary body epithelium (CBE), which is composed of two layers, one of pigmented ciliary epithelial (PCE) and the other of non-pigment ciliary epithelial cells (NPCE), secretes the aqueous humor into the posterior chambers of the eye. The rate and quantity of aqueous humor production, along with the outflow of the aqueous humour through the trabecular meshwork and Schlemm’s canal are the determining factors of IOP (Figure 1). Part of the regulatory process of aqueous humour production is looked after by volume-sensitive Cl- channels which are themselves controlled by a cell volume regulatory mechanism and G-protein coupled receptors (GPCRs) (Civan, 1998; Jacob & Civan, 1996). Agonists for these receptors have been reported to alter intraocular pressure.
Currently there are a number of drugs available that have been used in the management of patients with glaucoma. These drugs work by targeting different molecular pathways within the eye tissues with the aim of reducing the IOP. The drugs target receptors on the ciliary body processes, inhibit aqueous humor secretion, and act on the aqueous humor outflow pathway to achieve this goal. However, occasionally these agents are ineffective, or they cause side effects which are intolerable for a subpopulation of patients. Therefore, there is a constant search for new ways to ease the suffering of these patients.
It is known that the cannabinoids exert their action through the activation of CB1 and CB2 receptors, which are members of the G-proteincoupled receptor superfamily (Figure 2) (Matsuda et al., 1990). Both CB1 and CB2 receptor mRNA is expressed in the brain, spinal cord, and certain peripheral tissues. CB1 receptors are also present in the mammalian ciliary body epithelium and appear to be localized to NPCE cells (Stamer et al., 2001; Straiker et al., 1999). Cannabinoid receptors normally respond to endogenous ligands such as anandamide (AEA), 2arachidonolyl glycerol (2AG), and palmitylethanolamide (PEA) (Devan et al., 1992). In the recent years several selective receptor agonists (CP55940, WIN 55212.2) and antagonists (SR 141716A) have been developed. Both endogenous cannabinoid receptor ligands and synthetic cannabinoid receptor agonists have been shown to decrease the intraocular pressure. Recent studies in the Retina and Optic Nerve Laboratory at Dalhousie University have confirmed the fact that cannabinoid compounds, including the active ingredient of the marijuana leaf ∆9THC, have been shown to decrease intraocular pressure (IOP) in human and animals (Figures 3,4). Furthermore, cannabinoid receptors (CB1) have been identified in the anterior portion of the eye. However, the precise mechanism of cannabinoid action has yet to be determined, although it is suspected that it occurs either through the activation of cannabinoid receptors expressed in the ciliary epithelium and/or possibly in the trabecular meshwork.
Cannabinoids have been suggested to possess therapeutic benefits in the treatment of a number of pathological conditions. What has limited the pharmacological study of the assessment of tetrahydrocannabinol (THC), the active ingredient in marijuana leaves, is the problem of reliably delivering known concentrations of THC via the ingestion of inhaled smoke. Furthermore, the quantification of the degree of postoperative nausea and pain is difficult and subjective and the sites and mechanisms of THC and other endogenous cannabinoid agonists remain relatively unclear. Although it is possible to measure intraocular pressure more definitely, the mechanisms of THC and other endogenous cannabinoid agonists remain unclear in this area of research as well.
By examining the expression of cannabinoid receptors in the different structures of rat eyes, as well as the intracellular pathways involved in the lowering effect of cannabinoids on IOP upon activation of the CB1 receptor it is hoped that further understanding of the phenomenon that is the reduction of IOP by cannabinoids will be gained.