Morphine will lower intraocular pressure in humans, and conjunctival instillation of naloxone, a non-selective opioid receptor antagonist, will reverse the ocular hypotension. Moreover, opiate-like immunoreactivity has been detected throughout organs innervated by the automatic nervous system of humans and animals, including the eye, suggesting that endogenous opioid peptides participate in the neuroendocrine regulation of ocular hydrodynamics. This project will test the hypothesis that altered opioidergic activity is one factor that contributes to episodic ocular hypertension that eventually becomes sustained and subsequently damages the optic nerve head causing loss of visual field (glaucoma). Thus, alteration of the opioidergic system could result in dysfunction of ocular hydrodynamics, greater susceptibility to stress and enhanced predisposition to glaucoma. This hypothesis will be tested by examining the role of the opioid system (endogenous opioids and opioid receptors) in modulating ocular hydrodynamics. Experiments will be performed to: (1) characterize the activity of relatively selective opioid receptor agonists (kappa, delta) on intraocular pressure, aqueous inflow and outflow facility in rabbits; (2) determine sites and subtypes of opioid receptors in the anterior segment by evaluating the effects of opioid agonists and antagonists on tissues that regulate aqueous inflow and outflow; (3) examine, at the cellular level, the signal transduction mechanisms (cAMP/cGMP, GTP-binding proteins [G proteins], potassium and calcium channels, protein kinase C [PKC]) associated with opioid agonist-induced alterations in ocular function; and (4) assess whether endogenous opioid tone exists in the anterior segment by using: (a) simulated exercise to activate the opioid system, (b) inhibitors of opioid peptide catabolism, (c) selective depletion of co-transmitters and (d) antagonism of """"""""dominant"""""""" receptors that mask effects of opioid agonists. Opioid-induced changes in sympathetic neurotransmitter release will be determined in two neuronal models, and signal transduction will be assessed utilizing isolated tissues (iris/ciliary bodies, superior cervical ganglia) and cultured cells (sympathetic nerves, ciliary epithelium, trabecular meshwork cells). This project should define the mode of action of opioid drugs on aqueous humor dynamics and offer evidence for mechanisms involved in altered opioid function as a contributor to the dysregulation of intraocular pressure in glaucoma. The ultimate goals of the project are to: (1) define the participation of the opioidergic system in ocular hydrodynamics, (2) gain evidence that dysfunction of this system contributes to the etiology of glaucoma syndromes and (3) provide a better understanding of the mechanisms of action of opioidergic drugs on opioid and non-opioid receptors in the eye which could aid in the design of innovative therapeutic approaches for the management of glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011977-04
Application #
6329564
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Liberman, Ellen S
Project Start
1997-12-01
Project End
2002-03-31
Budget Start
2000-12-01
Budget End
2002-03-31
Support Year
4
Fiscal Year
2001
Total Cost
$261,481
Indirect Cost
Name
Morehouse School of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30310
Husain, Shahid; Potter, David E; Crosson, Craig E (2009) Opioid receptor-activation: retina protected from ischemic injury. Invest Ophthalmol Vis Sci 50:3853-9
Husain, Shahid; Potter, David E (2008) The opioidergic system: potential roles and therapeutic indications in the eye. J Ocul Pharmacol Ther 24:117-40
Dortch-Carnes, Juanita; Potter, David E (2005) Bremazocine: a kappa-opioid agonist with potent analgesic and other pharmacologic properties. CNS Drug Rev 11:195-212
Potter, David E; Russell, Karen R M; Manhiani, Marlina (2004) Bremazocine increases C-type natriuretic peptide levels in aqueous humor and enhances outflow facility. J Pharmacol Exp Ther 309:548-53
Dortch-Carnes, Juanita; Potter, David E (2003) Delta-opioid agonist-stimulated inositol phosphate formation in isolated, rabbit iris-ciliary bodies: role of G(i/o) proteins and Gbetagamma-subunits. Exp Eye Res 77:647-52
Dortch-Carnes, Juanita; Potter, David E (2002) Inhibition of cAMP accumulation by kappa-receptor activation in isolated iris-ciliary bodies: role of phosphodiesterase and protein kinase C. J Pharmacol Exp Ther 301:599-604
Russell, Karen R M; Potter, David E (2002) Dynorphin modulates ocular hydrodynamics and releases atrial natriuretic peptide via activation of kappa-Opioid receptors. Exp Eye Res 75:259-70
Chu, Teh-Ching; Potter, David E (2002) Ocular hypotension induced by electroacupuncture. J Ocul Pharmacol Ther 18:293-305
Dortch-Carnes, Juanita; Potter, David E (2002) Effect of bremazocine, a kappa-opioid receptor agonist, on inositol phosphate formation in isolated iris-ciliary bodies. Pharmacology 66:100-6
Russell, K R; Potter, D E (2001) Biphasic alterations of cAMP levels and inhibition of norepinephrine release in iris-ciliary body by bremazocine. J Pharmacol Exp Ther 298:941-6

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