Opioid Receptor-Activation: Retina Protected from Ischemic Injury

Abstract

PURPOSE.In nonocular systems, activation of opioid receptors has been shown to ameliorate tissue damage induced by ischemic stress. The current study was an investigation of whether opioid receptors activated by endogenous or exogenous agonists can ameliorate ischemic retinal injury. METHODS. In an investigation of whether endogenous opioid receptor-activation reduces ischemic injury, the effects of the opioid antagonist naloxone (3 mg/kg; IP) on retinal neuroprotection induced by ischemic preconditioning (IPC) were evaluated. Whether exogenous opioid administration can reduce ischemic retinal injury was determined by pretreating rats with morphine (0.01-10 mg/kg) before injury. Morphometric and electroretinogram (ERG) analyses were used to assess the differences in retinal structure and function. The expression of opioid receptor subtypes was evaluated by Western blot and immunohistochemical analyses. RESULTS. In control animals, 7 days after ischemic retinal injury, ERG a-and b-wave amplitudes were significantly reduced (23% and 41%, respectively). In addition, degeneration of the inner retina resulted in a 34% reduction in overall retina thickness. In animals receiving IPC before ischemic injury, ERG wave forms and retinal morphology were preserved. Pretreatment with naloxone reversed both the functional and structural retinal protection induced by IPC. In animals treated with morphine 24-hours before ischemic injury, ERG waveforms were preserved in a dose-dependent fashion (ED 50 ϭ 0.18 mg/kg), and this protective response was reversed by naloxone pretreatment. Immunohistochemical and Western blot data demonstrated that the ␦-, -, and -opioid receptor subtypes are expressed in the retina. CONCLUSIONS. These data provide evidence that activation of one (or more) opioid receptor(s) facilitates the development of IPC within the retina and can reduce ischemic retina injury.

Delta-Opioid Agonist SNC-121 Protects Retinal Ganglion Cell Function in a Chronic Ocular Hypertensive Rat Model

“…In the eye, activation of opioid receptors has been implicated in the regulation of iris function, accommodative power, regulation of aqueous humor dynamics (e.g., IOP), corneal wound healing, retinal development, and retina neuroprotection. 15,17,[21][22][23] d-opioid receptors (also known as DOR or DOP receptors in the International Union of Basic and Clinical Pharmacology [IUPHAR] nomenclature) are increasingly attractive due to their therapeutic potential. Along with the development of highly selective d-opioid receptor agonists and rapid progress in mouse mutagenesis approaches targeting the d-opioid receptor gene (Oprd1), novel functions of d-opioid receptors have emerged.…”

“…15 After removing the anterior segment of the eye and the lens, eyes, and isolated optic nerves were fixed in 4% PFA for 4 hours, then cryoprotected in 25% sucrose solution overnight at 48C. The eyecups and optic nerves were washed in ice cold PBS and frozen in optimal cutting temperature compound embedding medium over dry ice.…”

“…11 Studies have shown that opioid receptor activation by exogenous agonists can facilitate a protective effect against hypoxia, ischemia, cold, or an acidic environment. [12][13][14] More recently, we published that morphine pretreatment can provide significant retinal neuroprotection against acute ischemic 15 and glaucomatous injury, 16 and this neuroprotection is mediated, in part, via inhibition of TNF-a production. 16,17 However, the neuroprotective roles of d-opioid receptors against glaucomatous injury have remained fully unexplored.…”

The Neuropeptide Systems and their Potential Role in the Treatment of Mammalian Retinal Ischemia: A Developing Story

“…Concerning the role of opioid peptides in retinal ischemia, it has been reported that activation of opioid receptors facilitates the development of ischemic preconditioning within the retina and reduces the ischemic damage to the retina [70]. Recent evidence also demonstrates that activation of one or more opioid receptors can reduce the effects of ischemia-reperfusion injury by the suppression of tumor necrosis factor-α production [71].…”

Antioxidant effects of silymarin on ischaemia-reperfusion injuries of the rabbit retina

“…The IR model has been widely used for studying retinal neuronal cell damage after ischaemic insult and consists of transient ischaemia followed by natural reperfusion leading to an inflammatory and neurodegenerative response in the intact retina (Osborne et al, 2004). Histologic analysis demonstrated that the IR injury causes selective neuronal loss indicated by reduced thickness of retinal layers including the ganglion cell layer, inner nuclear layer, and inner plexiform layer (Husain et al, 2009). A recent study demonstrated that IR also induced vascular abnormalities such as capillary dropout after 8 to 14 days of reperfusion and concluded that these vascular changes occurred after neuronal loss (Zheng et al, 2007).…”