Role of the non-neuronal cholinergic system in the eye: a review

Pharmacologically active preparations directed towards modulating muscarinic receptor activity in the eye have been used for over 2000 years when extracts from Atropa belladonna were first applied to enhance eye appearance through pupillary dilation. The first clinically active drugs targeting a specific eye disease were anticholinesterases (e.g. ecothiophate) applied as eye drops to treat glaucoma in the 1960's. However, cataract was soon detected as a relatively frequent side effect and such drugs are now only used to treat glaucoma as a last resort. As muscarinic agonists have been found to reduce intraocular pressure both by decreasing aqueous humour production (through Na,K-ATPase pump inhibition) and increasing outflow (by muscle contraction), it is likely that treatments will be developed that target specific muscarinic subtypes. Recently, it has been shown that the M1 receptor subtype predominates in the lens. It is therefore important that this subtype is not targeted in future ocular therapies so that the side-effect of cataract is avoided. Form-deprived myopia resulting from an increased axial length in the affected eye can be reduced by the application of atropine. This effect has been achieved both in a chick model system and in human clinical trials, and in the former system atropine has been shown to reduce the production of scleral extracellular proteins. Carbachol stimulates tear fluid production through the activation of muscarinic receptors. Interestingly, at least part of the stimulation occurs via epidermal growth factor (EGF) receptors and although the precise signalling mechanisms are not completely understood, it has been shown that calcium mobilisation plays a critical role in both muscarinic and EGF receptor activity. It should be noted that in the four examples described above, the cell types responsible for producing the physiological output are non-neuronal in origin. Therefore cholinergic receptor activation plays diverse roles in the eye and pharmacological intervention based on specific receptor sub-types has potential benefit in a number of ocular problems. However, potential side effects have also recently been identified.