Novel role for the δ-opioid receptor in hypoxic preconditioning in rat retinas

Abstract δ‐Opioid receptor (DOR) is an oxygen‐sensitive protein whose function in the rat retina is unknown. We examined whether DOR is involved in hypoxic preconditioning (HPC)‐mediated retinoprotection following intraocular pressure (IOP) elevation. Rats were exposed to intermittent hypoxia (10% oxygen) to induce HPC. Unilateral retinal ischemia/reperfusion injury was induced by elevating IOP to 100 mmHg for 1 h. HPC attenuated the loss of neuronal marker expression and increased pro‐apoptotic caspase 3 activity in the IOP retina. Excess superoxide production and 8‐iso‐prostaglandin F2α accumulation caused by enhanced oxidant protein expression and reduced antioxidant enzyme level after IOP elevation were largely abrogated by HPC. HPC markedly increased the expression of hypoxia‐inducible factor‐1α (HIF‐1α) and DOR, but intravitreal administration of HIF‐1α‐specific small interfering RNA abrogated the up‐regulation of DOR. This suggested that DOR functions downstream of HIF‐1α. However, the endogenous content of leucine enkephalin in retinas was not affected by HPC or IOP. Treatment of retinas with the DOR antagonist naltrindole attenuated the HPC‐induced protection and activation of extracellular signal‐regulated kinase. These results suggest a novel mechanism of HPC‐mediated retinoprotection whereby HIF‐1α induces the expression of DOR, and DOR‐mediated activation of extracellular signal‐regulated kinase triggers cellular events that correct the redox imbalance in the post‐ischemic retina.