Muscarinic Antagonist Control of Myopia: Evidence for M4 and M1 Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew

PURPOSE. The broadband muscarinic antagonist atropine is effective in stopping the progression of myopia in animals and humans. The partially selective M-1/M-4 antagonist pirenzepine also slows progression of myopia, although not as effectively as atropine. Due to the supra maximal doses utilized in these studies, it is unclear if this antimyopia effect occurs through a receptoral-based mechanism, and if so, which receptors are involved. Studies in chicks indicate the involvement of the M-4 muscarinic receptor. The current study investigated the effect of the highly selective muscarinic antagonists Muscarinic Toxin 3 (MT3) (M-4 selective) and Muscarinic Toxin 7 (MT7) (M-1 selective) on experimental myopia in a mammalian model. METHODS. Tree shrews (n = 23) underwent daily intravitreal injections of MT3, MT7, or vehicle (phosphate buffered saline) for five days in the treated eye, combined with deprivation of vision with a translucent occluder (MD). The contralateral eye was unocccluded and underwent intravitreal injections of vehicle for the same period. Two additional groups (n = 10) underwent daily intravitreal injections of MT7 or vehicle for 10 days in the treated eye combined with negative lens (-9.5 diopter [D]) defocus (LIM). The control eye was injected with saline and wore a plano lens. RESULTS. Both MT3 and MT7 treatment reduced the development of deprivation-induced myopia (treated-control eye [T-C]; vehicle-MD; -4.3 +/- 0.6 D versus MT3-MD; -0.7 +/- 0.2 D and MT7-MD; -0.7 +/- 0.4 D; P < 0.001). MT7 treatment was effective at inhibiting lens-induced myopia (T-C; vehicle-LIM; -4.6 +/- 0.5 D versus MT7-LIM; 0.2 +/- 0.2 D; P < 0.05). CONCLUSIONS. The findings demonstrate that inhibition of form-deprivation myopia by muscarinic antagonists involves both M-4 and M-1 muscarinic receptor signaling pathways in mammals. (Invest Ophthalmol Vis Sci. 2012;53:5827-5837) DOI: 10.1167/iovs.12-9943