title: Regulation of nitric oxide production by δ-opioid receptors during glaucomatous injury.
abstract: To determine the roles of nitric oxide in glaucomatous injury and its regulation by δ-opioid-receptor activation, animals were treated with: 1) a selective inducible nitric oxide synthase (iNOS) inhibitor (aminoguanidine; AG; 25 mg/kg, i.p.); 2) δ-opioid-receptor agonist (SNC-121; 1 mg/kg, i.p.); or 3) with both drugs simultaneously for 7 days, once daily. The loss in retinal ganglion cell (RGC) numbers and their function in glaucomatous eyes were significantly improved in the presence of AG or SNC-121; however, we did not see any significant additive or synergistic effects when animals were treated with both drugs simultaneously. The levels of nitrate-nitrite were significantly increased in the glaucomatous retina when compared with normal retina (normal retina 86±9 vs. glaucomatous retina 174±10 mM/mg protein), which was reduced significantly when animals were treated either with SNC-121 (121±7 mM/mg protein; P<0.05) or AG (128±10 mM/mg protein; P<0.05). Additionally, SNC-121-mediated reduction in nitrate-nitrite levels was not only blocked by naltrindole (a δ-opioid-receptor antagonist), but naltrindole treatment potentiated the nitrate-nitrite production in glaucomatous retina (235±4 mM/mg protein; P<0.001). As expected, naltrindole treatment also fully-blocked SNC-121-mediated retina neuroprotection. The nitrotyrosine level in the glaucomatous retina was also increased, which was significantly reduced in the SNC-121-treated animals. Additionally, the expression level of iNOS was clearly increased over the control levels in the glaucomatous retina and optic nerves, which was also reduced by SNC-121 treatment. In conclusion, our data support the notion that nitric oxide plays a detrimental role during glaucomatous injury and inhibition of nitric oxide production provided RGC neuroprotection. Furthermore, δ-opioid receptor activation regulates the production of nitric oxide via inhibiting the activity of iNOS in the retina and optic nerve.
authors.affiliation: Hewitt Laboratory of the Ola B. Williams Glaucoma Center, Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Shahid
authors.initials: S
authors.lastname: Husain
authors.affiliation: Hewitt Laboratory of the Ola B. Williams Glaucoma Center, Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Yasir
authors.initials: Y
authors.lastname: Abdul
authors.affiliation: Hewitt Laboratory of the Ola B. Williams Glaucoma Center, Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Sudha
authors.initials: S
authors.lastname: Singh
authors.affiliation: Hewitt Laboratory of the Ola B. Williams Glaucoma Center, Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Anis
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Hewitt Laboratory of the Ola B. Williams Glaucoma Center, Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Mahvash
authors.initials: M
authors.lastname: Husain
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D004596:Electroretinography; D005260:Female; D005901:Glaucoma / Q000378:metabolism* / Q000473:pathology; D006146:Guanidines / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000473:pathology*; D013266:Stilbamidines
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D001549:Benzamides; D006146:Guanidines; D010879:Piperazines; D017465:Receptors, Opioid, delta; D013266:Stilbamidines; C102990:SNC 121; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine