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S. Husain, C. E. Crosson; Neuroprotective Actions of Morphine Against Glaucomatous Injury. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5460.
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Recently we have demonstrated that opioid-receptor activation is required for the development of retinal ischemic preconditioning against ischemic injury. This study was designed to evaluate the cellular events involved in the neuroprotective action of morphine, an opioid-receptor agonist, against glaucomatous injury using chronic ocular hypertensive rat models.
Brown Norway rats were used to elevate intraocular pressure (IOP) either by injecting 50 µL of 2M hypertonic saline into the circumferential limbal veins or by argon laser treatment of the limbal and episcleral veins. IOP was recorded as the average of 6-8 consecutive measurements on a weekly-basis, using a calibrated Tonolab. Pattern electroretinograms (PERG) were recorded using black and white alternating contrast reversing-bars with spatial frequency of 0.033 cycles/degree and reversal frequency of 1 Hz using UTAS-2000 system. Retinal ganglion cells (RGCs) were visualized by retrograde-labeling using hydroxystilbamidine methanesulfonate. Primary optic nerve head (ONH) astrocytes were isolated from the human eyes and purified by immunopanning. To evaluate the source of TNF-α production under stress conditions, astrocytes were stimulated with 10 µg/mL lipopolysaccharide (LPS) for 6 hours. TNF-α was measured by Western blotting and ELISA using retinal extract and conditioned media, respectively.
PERG amplitudes and RGCs were significantly (P<0.05) reduced in ocular hypertensive eyes at 4th week when compared with control eyes. Daily morphine (1 mg/kg; i.p) treatment for 4 weeks increased the PERG amplitudes and RGC counts. There was a robust increase in TNF-α expression in the retinas of ocular hypertensive rats at 3 days, which was significantly inhibited by 1 mg/kg morphine treatment (Control eyes 100 ±00; ocular hypertensive eyes 1482 ±290; and morphine-treated ocular hypertensive eyes 457 ±214; n=5-7; P<0.05; vlaues are reported as percent of control). LPS triggered a robust increase in the release of TNF-α from ONH astrocytes, which was significantly inhibited by morphine treatment (Control 9.7 ±5.4; LPS 136 ±12; and morphine + LPS 52 ±13 pg/mg protein; n=5-7; P<0.05). Morphine-mediated reduction in LPS-induced TNF-α release was blocked by naloxone, an opioid-receptor antagonist.
These results provide evidence that the opioidergic system exhibits the potential to preserve RGC function in glaucoma. TNF-α after glaucomatous injury is an early event, which is opposed by opioid-receptor activation. Based on this data, it appears that ONH astrocytes are the primary source of TNF-α under stress conditions, such as that seen in glaucoma.
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