Glaucoma, one of the world's leading causes of visual impairment and blindness, is characterized by excavation of the optic nerve head and selective apoptotic loss of retinal ganglion cells (RGCs), resulting in a progressive decline in visual function. Nearly 67 million people worldwide are believed to have glaucoma, including an estimated 2.2 million in the USA. The etiology of the optic neuropathy is complex involving metabolic and biomechanical stress to the optic nerve head. The activation of astrocytes appears to have a central role in progressive optic neuropathy, serving as the cellular source of multifunctional cytokines and enzymes (matrix metalloproteinases [MMPs]) responsible for remodeling the extracellular matrix within the optic nerve head. In mammals, endogenous opioidergic peptides, such as enkephalins, dynorphins, and endorphins, are physiological modulators of neuroendocrine, immune, and inflammatory challenges that are released in response to stress. The effects of opioids are mediated through activation of three opioid receptor subtypes d, ?, and ?. Under stressful conditions (e.g., ischemic, oxidative, and inflammatory stress), endogenous opioidergic peptides are released reducing stress-related injuries. In addition, activation of opioid-receptors by an exogenous agonist has been shown to elicit a protective effect during the situations of stress. Preliminary data presented in this application provide concrete evidence that: 1) administration of morphine in a chronic ocular-hypertensive rat model protected functional and structural integrity of RGCs;2) activation of opioid receptors by endogenous ligands is required for the development of neuroprotection induced by ischemic preconditioning;and 3) Morphine inhibits production of tumor necrosis factor-a (TNF-a) and MMP-2 from both the ocular hypertension and acute ischemia rat models. Based on the new preliminary data, I hypothesize that opioid-receptor activation protects the optic nerve head and retinal ganglion cells from injury, in part, by suppressing the production and activity of inflammatory cytokines from ONH astrocytes. To test this hypothesis, three specific aims are proposed:
Specific Aim 1 : Determine if activation of specific opioid-receptor subtypes promotes retina neuroprotection in a chronic ocular-hypertension rat model.
Specific Aim 2 : Identify the signaling pathways modulated by d-opioid-receptors in human ONH astrocytes for attenuation of TNF-a and MMP production.
Specific Aim 3 : Ascertain that activation of d-opioid-receptor protects the retina against glaucomatous injury by suppressing TNF-a and MMP activity within the optic nerve head. Outcomes of this project will provide valuable leads in the discovery of more effective therapies that can delay or prevent vision loss associated with neurodegenerative diseases such as glaucoma. 5

Public Health Relevance

Glaucoma is one of the leading causes of blindness worldwide. Although, a major risk factor for the development of glaucoma is elevated IOP;the pathophysiological mechanisms by which elevated IOP leads to optic nerve atrophy and retina degeneration are unknown. Hence there is a need to develop neuroprotective strategies to prevent vision loss in the glaucomatous individual.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Agarwal, Neeraj
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Medical University of South Carolina
Schools of Medicine
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Husain, Shahid; Ahmad, Anis; Singh, Sudha et al. (2017) PI3K/Akt Pathway: A Role in ?-Opioid Receptor-Mediated RGC Neuroprotection. Invest Ophthalmol Vis Sci 58:6489-6499
Husain, Shahid (2015) Opioid receptors: methods for detection and their modes of actions in the eye. Methods Mol Biol 1230:243-51
Husain, Shahid; Abdul, Yasir; Webster, Christine et al. (2014) Interferon-gamma (IFN-?)-mediated retinal ganglion cell death in human tyrosinase T cell receptor transgenic mouse. PLoS One 9:e89392
Husain, Shahid; Abdul, Yasir; Singh, Sudha et al. (2014) Regulation of nitric oxide production by ?-opioid receptors during glaucomatous injury. PLoS One 9:e110397
Akhter, Naseem; Nix, Melissa; Abdul, Yasir et al. (2013) Delta-opioid receptors attenuate TNF-?-induced MMP-2 secretion from human ONH astrocytes. Invest Ophthalmol Vis Sci 54:6605-11
Abdul, Yasir; Akhter, Naseem; Husain, Shahid (2013) Delta-opioid agonist SNC-121 protects retinal ganglion cell function in a chronic ocular hypertensive rat model. Invest Ophthalmol Vis Sci 54:1816-28
Husain, Shahid; Abdul, Yasir; Potter, David E (2012) Non-analgesic effects of opioids: neuroprotection in the retina. Curr Pharm Des 18:6101-8
Husain, Shahid; Abdul, Yasir; Crosson, Craig E (2012) Preservation of retina ganglion cell function by morphine in a chronic ocular-hypertensive rat model. Invest Ophthalmol Vis Sci 53:4289-98
Husain, Shahid; Liou, Gregory I; Crosson, Craig E (2011) Opioid receptor activation: suppression of ischemia/reperfusion-induced production of TNF-? in the retina. Invest Ophthalmol Vis Sci 52:2577-83