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S. Husain, D. E. Potter, C. E. Crosson; Opioid Receptor Activation Protects the Retina from Ischemic Injury by Suppressing the Activity of TNF-. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2008.
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Current studies were designed to determine the role(s) of opioid receptor activation in ischemia/stress-induced TNF-α release and the protection of retinal ganglion cell death.
Retinal ischemia was induced in anesthetized female Brown Norway rats by raising intraocular pressure (IOP) above systolic blood pressure (155-160 mmHg) for 45 minutes. The contralateral eye was left untreated for the control. Selected rats were treated (i.p.) with an opioid receptor agonist, morphine (1 mg/kg), for 24 hours prior to the ischemic event. To quantitate post-ischemic functional recovery, we performed electroretinograms seven days following ischemic insult. TNF-α release was measured by ELISA, and retinal ganglion cell death was measured by live/dead viability assay. RGC-5 cell line was used for in vitro studies.
Administration of opioid receptor agonist, 1 mg/kg morphine, resulted in 62% protection against ischemic retina injury when measured by b-wave amplitude. Rat retinas were collected at 2, 4, 8, and 24 hours post ischemia followed by TNF-α measurement by ELISA. There was a robust increase in TNF-α release between 2-24 hours post-ischemia, with peak release occurring at 4 hours (non-ischemic rats 45 ±7 pg/mg versus ischemic rats 1186 ±12 pg/mg protein, n = 3-6). Ischemia-induced TNF-α release was significantly inhibited when animals were treated with morphine (1 mg/kg) 24 hours prior to ischemia. In addition, TNF-α treatment resulted in retinal ganglion cell death in a concentration-dependent manner, and this effect was significantly inhibited in the presence of morphine.
The data presented herein demonstrate that the release of TNF-α after ischemic retina injury is an early event, which may initiate a downstream signaling cascade that leads to retinal ganglion cell death. Current data also provide evidence that release of TNF-α under ischemic/stress conditions is opposed by opioid receptor activation. Moreover, TNF-α-induced retina ganglion cell death is significantly inhibited in the presence of morphine. Overall, the in vivo and in vitro data provide evidence that opioidergic ligands have the potential to protect against neuropathies, particularly those associated with glaucoma.
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