Opiate and N-methyl-D-aspartate receptors in form-deprivation myopia

Abstract

Pharmacological studies have implicated retinal opiate pathways in the visual regulation of ocular growth. However, the effects of opiate receptor subtype-specific compounds on form-deprivation myopia (FDM) are inconsistent (Seltner et al., 1997), and may be mediated by non-opiate receptors. The purpose of this study was to test whether opiate receptor-inactive (D-) enantiomers elicit the same FDM-suppressing effect as their opiate receptor-active (L-) counterparts. Since some opiates are thought to act at NMDA receptors, we also tested whether NMDA receptor agonists and antagonists influence ocular growth or FDM. We found that both L- and D- enantiomers of morphine-like compounds (dextrorphanol and levorphanol, and D- and L-naloxone) were equally effective in blocking FDM. The NMDA receptor antagonists dextromethorphan, MK801, and AP5 also suppressed FDM. A single toxic dose of NMDA, that destroys many subtypes of amacrine cells (including those that synthesize the opioid peptide enkephalin), induced myopia and ocular enlargement in ungoggled eyes, and eliminated the ability of form-deprivation to enhance ocular growth. The NR-1 subunit of the NMDA receptor was localized to a narrowly stratified, intense stratum at approximately 50% depth in the inner plexiform layer, diffusely throughout the proximal inner plexiform layer, and to many somata in the amacrine and ganglion cell layers. These observations suggest that most effects of opiate receptor ligands on FDM in the chick are mediated by non-opiate receptors, which are likely to include NMDA receptors. NMDA as an excitotoxin transiently enhances ocular growth, but thereafter disables retinal mechanisms that promote emmetropization and FDM. These observations are consistent with a prominent role for pathways utilizing NMDA receptors in FDM and ocular growth-control.

Sonic Hedgehog Expression and Its Role in Form-Deprivation Myopia in Mice

“…26,28,29 Other agents that can influence eye growth when given to open eyes are a group of neurotoxins, such as colchicine, kainic acid, quisqualic acid, and N-methyl-D-aspartate, which act by destroying the normal structure of the retina. [44][45][46][47] Although the pathologic study revealed no changes in retinal morphology after administration of Shh-N or cyclopamine, it is difficult to determine whether the effects of both drugs are due to a receptor-mediated mechanism or retinal toxicity. Further research, using immunocytochemical markers or electroretinogram (ERG), for example, is needed.…”

Light- and focus-dependent expression of the transcription factor ZENK in the chick retina

“…However, we have shown that about half of all amacrine cells can be destroyed by the excitotoxin quisqualic acid without impairing the visual control of ocular growth 3,4 . Form-deprivation myopia can be suppressed by antagonists to NMDA-type glutamate receptors 5 , whereas NMDA-induced excitotoxicity transiently enhances growth rates and subsequently destroys retinal pathways that control eye growth 2,5 . Stimulation of NMDA receptors often activates immediate-early response genes 10,11 , such as members of the Fos family of transcription factors and the transcription factor known in chicken as ZENK 12 , an acronym for Zif268 (ref.…”

“…Anesthesia and injections were as described [3][4][5][6] . The left eye (control) was injected with 20 µl of sterile saline, and the right eye (treated) was injected with 20 µl of 0.5 mM NMDA (total dose 10 nmol) or 1 mM MK-801 (total dose, 20 nmol) dissolved in sterile saline.…”

“…Standard procedures were used for indirect immunofluorescence, as described [3][4][5][6]34 . All antisera have been well characterized in previous studies [3][4][5][6]34 . We detected ZENK in cryostat sections of chicken retina with affinity-purified antiserum of rabbits immunized with a 14 amino-acid peptide at the carboxyl terminus of murine Egr-1 (#588; Santa Cruz Biotechnology).…”

“…Normal retinal functions and ocular growth in experimental animals can be perturbed by blurring the retinal image 1 or by disrupting retinal circuitry with certain neurotoxins [2][3][4][5][6][7] ; both manipulations normally cause myopia. Furthermore, myopia or hyperopia can be induced by chronically displacing the projected image behind or in front of the retina, respectively 1 .…”