Delta-Opioid Agonist SNC-121 Protects Retinal Ganglion Cell Function in a Chronic Ocular Hypertensive Rat Model

PURPOSE. This study examined if the delta-opioid (delta-opioid) receptor agonist, SNC-121, can improve retinal function and retinal ganglion cell (RGC) survival during glaucomatous injury in a chronic ocular hypertensive rat model. METHODS. IOP was raised in brown Norway rats by injecting hypertonic saline into the limbal venous system. Rats were treated with 1 mg/kg SNC-121 (intraperitoneally [IP]) once daily for 7 days. Pattern-electroretinograms (PERGs) were obtained in response to contrast reversal of patterned visual stimuli. RGCs were visualized by fluorogold retrograde labeling. Expression of TNF-alpha and p38 mitogen-activated protein (MAP) kinase was measured by immunohistochemistry and Western blotting. RESULTS. PERG amplitudes in ocular hypertensive eyes were significantly reduced (14.3 +/- 0.60 mu volts) when compared with healthy eyes (18.0 +/- 0.62 mu volts). PERG loss in hypertensive eyes was inhibited by SNC-121 treatment (17.20 +/- 0.1.3 mu volts; P < 0.05). There was a 29% loss of RGCs in the ocular hypertensive eye, which was inhibited in the presence of SNC-121. TNF-a production and activation of p38 MAP kinase in retinal sections and optic nerve samples were upregulated in ocular hypertensive eyes and inhibited in the presence of SNC-121. Furthermore, TNF-a induced increase in p38 MAP kinase activation in astrocytes was inhibited in the presence of SNC-121. CONCLUSIONS. These data provide evidence that activation of delta-opioid receptors inhibited the loss of PERG amplitudes and rate of RGC loss during glaucomatous injury. Mechanistic data provided clues that TNF-a is mainly produced from glial cells and activates p38 MAP kinase, which was significantly inhibited by SNC-121 treatment. Overall, data indicate that enhancement of delta-opioidergic activity in the eye may provide retina neuroprotection against glaucoma. (Invest Ophthalmol Vis Sci. 2013;54:1816-1828) DOI:10.1167/iovs.12-10741