Date of Award

7-1-2000

Degree Type

Thesis

Degree Name

M.S.

Department

Department of Biological Sciences

First Advisor

Dr. David E. Potter

Abstract

Opioid receptors have been demonstrated to modulate various functions in the eye. This research was designed to determine and compare the effects of kappa agonists on ocular hydrodynamics. Experiments were done to determine the effects of ICI 204,448 (ICI), which is not capable of penetrating the blood-brain barrier, and U-62066 (spiradoline) on: 1) intraocular pressure (IOP) and pupil diameter (PD), 2) pre- (neuronal) and postjunctional sites of action, and 3) atrial natriuretic peptide (ANP) levels in aqueous humor. Dark-adapted New Zealand White (NZW) male, rabbits were used in all experiments. IOP (mmHg) was measured by a pneumatonometer and PDs (mm) were measured by an optistick before each IOP reading. Baseline readings were taken at 1/2 and 0 hours prior to drug adminstration. Post-drug measurements were made at 1/2, 1, 2, 3, 4, and 5 hours after topical drug application. The release of norepinephrine was measured from perfused ICBs and expressed as the percent change of the control. Cyclic AMP concentrations in the ICBs and ANP levels in aqueous were quantified by radioimmunoassay techniques. The kappa antagonist, norbinaltorphimine (nor-BNI), was applied 30 minutes prior to agonist application in all experiments. ICI and spiradoline decreased IOP in a dose-dependent manner in normal rabbits, but only spiradoline showed significant changes in PD. Both kappa agonist inhibited the release of NE from perfused ICBs. Isoproterenol-stimulated cAMP levels in ICBs were lowered by both kappa receptor agonists. ANP levels in the aqueous humor increased in response to the kappa opioid agonists. These data suggest that spiradoline and ICI lower IOP by activating kappa opioid receptors in the eye. The effect of spiradoline on PD indicates that this kappa agonist activates receptors in the eye and/or the brain. The inhibition of NE release and cAMP accumulation in the ICB, suggests pre- and postjunctional sites of action for kappa agonists. The increase of ANP levels in aqeous suggests a role for ANP in lowering IOP. If these drugs can be shown to lower IOP safely and effectively in humans, then they may be utilized in the treatment of glaucoma.

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