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Yasir Abdul, Craig E. Crosson, Shahid Husain; Role of -Opioid-Receptor Activation in Retina Neuroprotection Against Ischemic Retinal Injury. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2656.
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To determine the role of Δ-opioid-receptor activation in retina neuroprotection against ischemic retinal injury using endogenous and exogenous neuroprotective strategies.
Brown Norway rats were used for ischemic preconditioning (IPC) and ischemia by raising intraocular pressure (IOP) above systolic blood pressure (155-160 mmHg) for 5 and 45 minutes, respectively. Selected rats were treated with a Δ-opioid-receptor antagonist (naltrindole, 3 mg/kg, i.p.) 1 hour prior to the IPC. Additionally, animals were treated with the Δ-opioid-receptor agonist SNC-121 (0.1-1 mg/kg; i.p.) 30 minutes post ischemia and daily, up to 7 days. To quantitate post-ischemic functional recovery, electroretinograms (ERG) were performed 7 days following ischemic injury. TNF-α and matrix metalloproteinase-2 (MMP-2) were measured by immunohistochemistry and Western blotting.
In eyes subjected to 45 minutes of ischemia, mean b-wave amplitudes were significantly reduced when compared to the contralateral control eyes (control 657 ±31 vs. ischemic eyes 343 ±33; P<0.05), as determined by ERG measurement 7 days following retinal ischemia. In eyes that received an ischemic preconditioning (IPC) stimulus 24-hours prior to the ischemic injury, the b-wave amplitudes were significantly greater in amplitude (P<0.05) when compared to the ischemic eyes. In contrast, IPC-mediated retina neuroprotection was completely abolished when animals were treated with a highly selective Δ-opioid-receptor antagonist, naltrindole (3 mg/kg), one hour prior to IPC (IPC + ischemic eyes 607±35 vs. naltrindole + IPC + ischemic eyes 197±35). Post-ischemia treatment of animals with SNC-121 (0.1-1 mg/kg; i.p.) for 7 days resulted in improvement in the b-wave amplitudes. There was a robust increase in TNF-α and MMP-2 production in the optic nerve head and inner retinal layers at 4-hours post ischemia. The production of both TNF-α and MMP-2 was attenuated in the presence of the opioid-receptor agonist.
These results provide evidence that the endogenous activity of the Δ-opioid-receptor is required for IPC-mediated retina neuroprotection. In addition, exogenous activation of the Δ-opioid-receptor by SNC-121 provides retina neuroprotection against ischemic injury. Current data also demonstrate that production of MMP-2 and TNF-α are early events in ischemic injury, which are opposed by opioid-receptor-activation. Overall, these results provide evidence that the opioidergic system exhibits the potential to protect the retina against ischemic injuries.
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