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

Abstract

d-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 F2a 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-1a (HIF-1a) and DOR, but intravitreal administration of HIF-1a-specific small interfering RNA abrogated the up-regulation of DOR. This suggested that DOR functions downstream of HIF-1a. 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 HPCmediated retinoprotection whereby HIF-1a 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.

The Role of Inflammation in the Pathogenesis of Glaucoma

“…Peng et al and Tsai et al demonstrated a neuroprotective role of HIF-a through production of erythropoietin (EPO) and activation of deltaopiod receptors (DOR). 57,82 The interaction between EPO and EPO-R prevents apoptosis of the RGC through the inhibition of caspase-3. Furthermore, expression of DOR is upregulated in response to HIF-a, resulting in activation of the ERK pathway.…”

Preservation of Retina Ganglion Cell Function by Morphine in a Chronic Ocular-Hypertensive Rat Model

“…8 Functional evidence of opioid-receptor subtypes has been demonstrated in the anterior segment tissues as well as in the retina. 8,29,30 Recently, we have demonstrated that opioidreceptor-activation is required for the development of ischemic preconditioning within the retina, and that the administration of morphine can reduce ischemic retina injury. 8 Although the cellular mechanisms that are involved in opioid-mediated retina neuroprotection are poorly understood, we have shown that morphine-induced retina neuroprotection against ischemiainduced retina injury was mediated via, in part, inhibition of TNF-a production by glial cells.…”

“…Additional studies have shown that the d-opioid-receptor-antagonist, naltrindole, attenuated hypoxicpreconditioning-mediated upregulation of antioxidant proteins in the retina. 29 In nonocular systems, activation of opioid receptors reduced infarct size in stroke and myocardial ischemia models. 31,32 Moreover, chronic morphine treatment protected cultured human neurons against serum deprivation and staurosporin-induced cytotoxicity via downregulation of pro-apoptotic proteins.…”

The Neuropeptide Systems and their Potential Role in the Treatment of Mammalian Retinal Ischemia: A Developing Story

“…Enkephalin was detected in inner retinal neurons of guinea pigs [65] and in rat retinal extract [66], while the expression of β-endorphin has been demonstrated in cholinergic amacrine cells of the mouse retina [67]. μ and δ opioid receptors have been detected in rat retina using PCR and Western blot [66], and μ receptors were also detected by immunohistochemistry on processes of bistratified ganglion cells [68]. μ and δ opioid receptors have also been reported recently in ganglion cells as well as in GABAergic and dopaminergic amacrine cells of mouse retinas [69].…”

“…In addition, intravitreal administration of morphine immediately after reperfusion blunts the effects of ischemia-reperfusion injury, and pharmacologic evidence suggests that this protective action may be mediated, at least in part, by opioid receptors [72-73]. Finally, an involvement of the δ opioid receptor has been reported in mediating the protective effects against ischemic damage of hypoxic preconditioning [66]. …”