Delta-opioid agonist SNC-121 protects retinal ganglion cell function in a chronic ocular hypertensive rat model

This study examined if the delta-opioid (δ-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. 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-α and p38 mitogen-activated protein (MAP) kinase was measured by immunohistochemistry and Western blotting. PERG amplitudes in ocular hypertensive eyes were significantly reduced (14.3 ± 0.60 μvolts) when compared with healthy eyes (18.0 ± 0.62 μvolts). PERG loss in hypertensive eyes was inhibited by SNC-121 treatment (17.20 ± 0.1.3 μvolts; 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-α 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-α induced increase in p38 MAP kinase activation in astrocytes was inhibited in the presence of SNC-121. These data provide evidence that activation of δ-opioid receptors inhibited the loss of PERG amplitudes and rate of RGC loss during glaucomatous injury. Mechanistic data provided clues that TNF-α 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 δ-opioidergic activity in the eye may provide retina neuroprotection against glaucoma.